Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 5, pp. 637-657 © Pleiades Publishing, Ltd., 2026.

ISSN 0006-2979, Biochemistry (Moscow), 2026. © Pleiades Publishing, Ltd., 2026.

637

REVIEW

Integrating Dopamine and BDNF Hypotheses:

The Role of Dopamine–BDNF Crosstalk

in Neuropathologies

Marah Alsalloum

1,2,a

, Anton Tsybko

1,2,b

*, and Vladimir Naumenko

1,c

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences,

630090 Novosibirsk, Russia

Novosibirsk State University, 630090 Novosibirsk, Russia

e-mail: Alsallummm@bionet.nsc.ru

e-mail: antontsybko@bionet.nsc.ru

e-mail: naumenko2002@bionet.nsc.ru

Received November 28, 2025

Revised February 17, 2026

Accepted February 18, 2026

Abstract— The dopamine system plays an important role in numerous physiological processes, such as

locomotion, emotions, reward behavior, memory, and learning. Differentiation and proper functioning of

dopaminergic neurons are largely promoted by the brain-derived neurotrophic factor (BDNF). BDNF is one

of the most abundant neurotrophins in the mammalian brain and is implicated in neuronal development,

differentiation, and plasticity. Dysfunction of dopaminergic system and BDNF signaling are linked to the

pathogenesis of many neurological disorders, including Parkinson’s disease, schizophrenia, autism spectrum

disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and others. Accumulating evidence indicates

a significant crosstalk between BDNF and dopamine system, the disruption of which might underlie the

development of various neuro- and psychopathologies. In this review, we summarized recent data on the

interplay between BDNF and brain dopamine system under physiological conditions, as well as in neuro-

developmental and neurodegenerative disorders. The available data suggest that the crosstalk between the

brain dopamine system and BDNF is essential for normal neurophysiology; it is also involved in neuropa-

thology and could serve as a target for therapeutic strategies aimed at correcting pathological behaviors.

DOI: 10.1134/S0006297925604125

Keywords: brain-derived neurotrophic factor, Bdnf, dopamine, neurodevelopmental disorders, neurodegen-

erative disorders

* To whom correspondence should be addressed.

INTRODUCTION

Dopamine, a metabolite of the amino acid tyro-

sine, is a catecholaminergic neurotransmitter that is

critically involved in voluntary movement, feeding,

affect, reward, sleep, attention, working memory,

and learning  [1]. Four major dopaminergic pathways

have been identified in the mammalian brain: the

nigrostriatal, mesolimbic, mesocortical, and tuberoin-

fundibular  [2]. The physiological effects of dopamine

are mediated via two groups of G protein-coupled

receptors (GPCRs): the D1-like and D2-like dopamine

receptors. The D1-like subfamily includes D1 and

D5 receptors (D1R and D5R), while D2-like subfami-

ly includes D2, D3 and D4 receptors (D2R, D3R, and

D4R). This classification was initially based on the

receptor ability to modulate adenylate cyclase (AC)

activity. D1-like receptors activate the Gα

s/olfactory

family of G-proteins that stimulate production of cy-

clic adenosine monophosphate (cAMP) by AC, where-

as D2-like receptors couple to Gα

i/o

family proteins,

thereby induce inhibition of AC  [1]. In the striatum,

medium-sized spiny neurons (MSNs) are divided into

two populations based on their projection sites and

protein expression profiles, forming the direct and

indirect pathways of the striatum. MSNs that form

the direct pathway express D1Rs (D1R-expressing

MSNs), while neurons of the indirect pathway ex-

press D2Rs (D2R-expressing MSNs)  [3]. Abnormalities

in the dopamine system have been observed in many

ALSALLOUM et al.638

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

disorders such as Parkinson’s disease, schizophrenia,

autism spectrum disorder and Huntington’s disease,

which is anticipated considering its involvement in

different critical physiological functions [4-7].

The positive effects of neurotrophic factors on

dopaminergic neurons have been extensively studied.

Neurotrophic factors, including cerebral dopamine

neurotrophic factor (CDNF), glial cell line-derived

neurotrophic factor (GDNF), brain derived neuro-

trophic factor (BDNF), fibroblast growth factor (FGF),

epidermal growth factor (EGF), transforming growth

factor (TGF), insulin-like growth factor (IGF), cili-

ary neurotrophic factor (CTNF), and platelet-derived

growth factor (PDGF), have been shown to promote

the survival of dopaminergic neurons and protect

against dopaminergic lesions [3, 8-10].

BDNF is a neurotrophin that modulates neuro-

nal survival and neuroplasticity and plays essential

roles in the growth, survival, differentiation, and

repair of neurons  [11]. Numerous studies have indi-

cated the crucial role of BDNF in the development,

maturation, and maintenance of dopaminergic neu-

rons [3,  12,  13]. The biological effects of BDNF are

mediated by tropomyosin receptor kinase  B (TrkB).

The binding of mature BDNF to the full-length TrkB

(TrkB.FL) induces receptor dimerization, followed by

autophosphorylation of tyrosine residue in its intra-

cellular domain, which creates binding sites for intra-

cellular target proteins and leads to the activation of

three major downstream signaling pathways mediat-

ed by phospholipase  C  γ (PLCγ), phosphatidylinositol

3-kinase (PI3K), and extracellular signal-regulated ki-

nases (ERK)/mitogen-activated protein kinase (MAPK).

Mature BDNF binds, with a comparable affinity, to

the TrkB truncated isoform (TrkB.T1), inducing large-

ly unknown signaling pathways [14,  15]. ProBDNF,

the premature form of BDNF, binds with P75

NTR

re-

ceptor and mediates processes substantially opposite

to those induced by mature BDNF  [16]. Dysregula-

tion of BDNF signaling has been strongly implicated

in the pathophysiology of many neurodegenerative,

neurodevelopmental, and neuropsychiatric disorders,

including major depressive disorder, bipolar disorder,

schizophrenia, and autism spectrum disorder [11,

16-20].

Although BDNF and the dopamine system are

both involved in various disorders, studies focused on

their interaction are still very scarce. Taking into con-

sideration that biological systems do not always func-

tion as separate units and that interactions between

systems, such as serotonin and dopamine systems

[21], as well as between BDNF and serotonin systems

[22] are well-established, we focused on the crosstalk

between BDNF and dopaminergic system. Here, we

present evidence of their interaction under physiolog-

ical conditions and in neurodegenerative and neuro-

developmental disorders, highlighting its potential as

a therapeutic target in various neuropsychiatric and

neurological pathologies and encouraging further re-

search on the crosstalk between dopamine and BDNF.

BDNF AND DOPAMINE INTERPLAY UNDER

PHYSIOLOGICAL CONDITIONS

Dopamine signaling. Dopamine binding to the

GPCR induces dissociation of the G-protein from the

receptor into its α and βγ subunits. The α subunit

modulates the activity of AC. Activation of D1-like re-

ceptors stimulates AC via the  G

protein α subunit,

leading to increased intracellular cAMP concentra-

tions. In contrast, activation of D2-like receptors leads

to the release of the inhibitory G

-α subunit, which

inhibits AC and reduces cAMP production  [23]. cAMP

primarily activates protein kinase  A (PKA), which

modulates several downstream targets, including

1)  cAMP response element binding protein (CREB),

2)  MAPK [23], 3)  glutamate receptors and ion channels

[7], 4)  dopamine and cAMP-regulated phosphoprotein

32-kDa (DARPP-32) [24]. Phosphorylation of DARPP-32

at Thr34 by PKA promotes its inhibitory activity to-

wards protein phosphatase  1 (PP1). By inhibiting PP1,

DARPP-32 promotes a net increase in phosphorylation,

thus enhancing the efficacy of PKA  [7]. Predictably,

D2R activation reduces DARPP-32 phosphorylation at

Thr34 due to a decreased PKA activity. DARPP-32 can

also be dephosphorylated by protein phosphatases,

including PP2A and Ca

-activated phosphatase: PP2B.

Several lines of evidence suggest that D1R can

couple to Gα

and stimulate PLC via a mechanism

that remains incompletely characterized  [25]. Three

potential mechanisms may underlie PLC activation

following dopamine stimulation: 1)  activation of the

Gα

-coupled D5R, 2)  signaling through D1R:D2R het-

erodimers, and 3)  activation by the Gβγ subunit

released upon D2-like receptor activation  [7]. PLC

activation leads to the production of inositol 1,4,5-tri-

phosphate (IP3) and diacylglycerol (DAG)  [1]. IP3 pro-

motes the release of Ca

from the endoplasmic retic-

ulum. Eventually, DAG and IP3 jointly activate protein

kinase  C (PKC)  [26].

Multiple MAPKs have been shown to act as “coin-

cidence detectors” that integrate dopaminergic signal-

ing with inputs from other neurotransmitter systems

[1]. Both D1- and D2-like receptors regulate ERK1 and

ERK2, with D1R being essential for activating them in

the MSNs, while D2-class dopamine receptors medi-

ate their inhibition in the striatum  [1]. Activation of

ERK by D1R is achieved by interaction with N-meth-

yl-D-aspartate (NMDA) receptor. Upon activation,

NMDA receptor triggers the Ras/Raf/MEK/ERK signal-

ing pathway, which is counteracted by the activity

CROSSTALK BETWEEN DOPAMINE AND BDNF 639

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

of striatal-enriched tyrosine phosphatase (STEP). The

activity of STEP depends on its dephosphorylation

by PP1. Dopamine stimulation of D1R/PKA/DARPP-32

signaling leads to the inhibition of PP1 and subse-

quent inactivation of STEP, allowing for ERK activa-

tion [1,  7]. The mechanism of ERK activation by D2R

is still poorly understood. Overall, dopamine-induced

activation of the Ras/Raf/MEK/ERK cascade is complex

and can be modulated by additional pathways  [27].

G  protein-coupled receptor kinases (GRKs) and

regulators of G  protein signaling (RGSs) also modu-

late the dopamine signaling cascade. RGS proteins

promote inhibitory effects on GPCRs by accelerating

GTP hydrolysis on Gα subunits. On the other hand,

GRKs phosphorylate the receptors in response to con-

tinuous stimulation. This phosphorylation recruits

scaffold proteins known as β-arrestins. Formation of

the receptor–β-arrestin complex prevents further re-

ceptor activation, signals for receptor internalization,

and may recruit other scaffold proteins leading to the

activation of G  protein-independent pathways, such

as ERK, C-Jun N-terminal kinase (JNK), and protein

kinase  B (Akt) signaling cascades  [7]. β-arrestin iso-

forms are widely expressed across tissues, with β-ar-

restin-2 being the predominant form in the brain  [7].

Dopamine-induced β-arrestin signaling is primarily

mediated by D2-class receptors  [27], which recruit

PP2A and cause subsequent inhibition of Akt  [23]. Akt

inhibition reduces phosphorylation of its substrate

glycogen synthase kinase 3 (GSK3), leading to GSK3

activation  [7]. Given its delayed onset, the β-arrestin/

Akt axis is likely involved in late response to dopa-

mine  [1].

BDNF signaling. Mature BDNF binds with a high

affinity to TrkB.FL, triggering several downstream

pathways critical for neuronal function and survival

[28]. Binding of BDNF leads to TrkB.FL dimerization

and autophosphorylation of tyrosine residues in the

receptor intracellular domain  [29]. Phosphorylated

TrkB.FL activates several signaling cascades, includ-

ing those mediated by PI3K/Akt, MAPK/ERK, PLCγ,

and Rho family GTPases  [29]. The PI3K/Akt path-

way promotes neuronal survival, modulates NMDA

receptor-dependent synaptic plasticity, and enhanc-

es dendritic growth and branching through protein

synthesis and cytoskeleton development  [29]. Activa-

tion of the MAPK pathway leads to the activation of

the ERK/CREB pathway, expression of early response

genes, synthesis of cytoskeletal proteins, and stimu-

lation of dendritic growth and branching  [29]. The

PLCγ pathway activates Ca

/calmodulin-dependent

protein kinase (CaMKII) and PKC, which, in turn, in-

creases the content of Ca

ions and DAG, enhancing

synaptic plasticity. Activation of Rho GTPases stim-

ulates the synthesis of actin and microtubules  [29].

Many of thetranscriptional responses following TrkB.

FL activation involve genes known to activate BDNF

transcription, forming a positive feedback loop  [30].

TrkB.T1 has an extracellular domain identical to

that of TrkB.FL and binds BDNF with a similar af-

finity. However, TrkB.T1 acts as a dominant-negative

regulator by sequestering BDNF and limiting its avail-

ability for TrkB.FL activation  [31]. In neurons, TrkB.

T1 is predominantly recycled to the cell membrane

after BDNF binding, further modulating TrkB.FL/

MAPK pathway activation, while in astrocytes, TrkB.

T1 appears to mediate the storage of endocytosed

BDNF [31].

ProBDNF interacts preferentially with P75

NTR

, a

member of the tumor necrosis factor (TNF) receptor

family  [29]. P75

NTR

activation triggers several signal-

ing cascades, including the JNK pathway associated

with neuronal apoptosis, RhoA (Ras homology gene

family member  A) pathway, which regulates neuronal

growth, and nuclear factor kappa  B (NF-kB) signaling,

which promotes neuronal survival  [29].

BDNF and dopamine interplay. In the adult stri-

atum, BDNF levels are high despite virtually undetect-

able levels of Bdnf mRNA. This reflects the fact that

striatal BDNF is largely synthesized in other brain re-

gions, such as cerebral cortex, substantia nigra pars

compacta, amygdala, and thalamus, and then antero-

gradely transported to striatal neurons  [3]. In con-

trast, the cortex and brain stem contain both Bdnf

mRNA and BDNF protein, indicating local BDNF syn-

thesis in these regions  [32]. TrkB.FL is predominant-

ly expressed throughout all brain regions, although

its distribution shows region-specific expression pat-

terns  [33]. Both TrkB.FL mRNA and protein have been

detected in the adult striatum, although TrkB was ob-

served mostly in D2R-expressing MSNs in this brain

region  [3].

During striatal neurogenesis, neurotrophins

play a critical role in determining the striatum size

by promoting survival of newborn striatal neurons.

BDNF/TrkB.FL signaling is essential for the survival of

developing MSNs of the indirect striatal pathway  [3].

Furthermore, developing MSNs require trophic sup-

port before they migrate to the striatum and extend

axons. On the other hand, MSNs of the direct striatal

pathway depend on the neurotrophic factor  3/TrkC

signaling for their survival during development. Bay-

dyuk and Xu  [3] concluded that nigrostriatal dopami-

nergic neurons can regulate the size of their largest

target, the striatum, by controlling the survival of im-

mature striatal neurons at their point of origin.

During postnatal development, cortical BDNF

is required for long-term survival of dopaminergic

neurons and for normal dendritic morphogenesis  [3].

Global deletion of BDNF results in a marked reduc-

tion in DARPP-32, a key marker of differentiated

striatal MSNs  [3]. Also, BDNF is an important factor

ALSALLOUM et al.640

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

for the formation and maintenance of corticostriatal

synapses and can modulate their strength.

Projection neurons of the striatum, which consti-

tute the primary input nucleus of the basal ganglia,

receive excitatory synaptic inputs from the cortex and

the thalamus. These inputs modulate the firing rate

of MSNs, making synaptic plasticity at corticostriatal

and thalamostriatal synapses essential for processes

such as habit formation, goal-directed behavior, and

action selection. The plasticity at these synapses, in-

cluding long-term potentiation (LTP) and long-term

depression (LTD), is regulated by several neuromod-

ulators including dopamine, adenosine, and acetyl-

choline  [34]. Importantly, the presynaptic release of

BDNF at corticostriatal synapses promotes postsynap-

tic events that lead to the induction and expression

of LTP  [35]. BDNF plays a critical role in the molec-

ular processes underlying both LTP and LTD. During

LTP, BDNF clusters AMPA and NMDA receptors at the

spines, creating efficient signaling zones, and the de-

gree of synaptic potentiation correlates with BDNF

availability  [36]. Conversely, during LTD, BDNF mod-

ulates endocytosis of AMPA receptors, thereby pro-

moting synaptic depression  [36]. Furthermore, BDNF/

TrkB.FL signaling promotes endocannabinoid-mediat-

ed plasticity (both LTD and LTP) in the striatum  [37].

Specifically, TrkB.FL activation prolongs intracellular

calcium transients, thus promoting the synthesis and

release of endocannabinoids  [37].

D1Rs and D2Rs can form heterodimers (D1R:D2R),

which have been observed in heterologous systems

and primary striatal neurons, as well as in vivo,

primarily in rat striatum  [27]. In 2009, Hasbi and

co-authors identified a link between striatal BDNF

production and D1R:D2R heteromers  [38]. Exclusive

stimulation of D1R:D2R heteromers activated a sig-

naling cascade that resulted in BDNF production.

The main stages of this cascade are as follows: 1)  ac-

tivation of dopamine D1R:D2R heteromers and sub-

sequent rapid activation and translocation of Gq-pro-

tein followed by activation of PLC and mobilization

of intracellular calcium from IP3-sensitive stores;

2)  activation of cytosolic and nuclear CaMKIIα; 3)  in-

creased BDNF expression; 4)  subsequent development,

maturation, and differentiation of striatal neurons

(in primary cultures) through activation of BDNF sig-

naling. This cascade was also activated in adult rat

brain, although it was largely limited to the nucleus

accumbens (NAc) [38].

Furthermore, D1R:D2R heteromers have been

shown to transactivate TrkB.FL in cultured striatal neu-

rons  [27]. Administration of a D1-like receptor agonist

promoted TrkB.FL activation in embryonic striatal neu-

rons  [39]. Induction of TrkB.FL activity was accompa-

nied by the phosphorylation of downstream signaling

proteins, including PLCγ, Akt, and MAPK. One possi-

ble explanation is that the increase in BDNF levels

induced by DA receptor stimulation leads to TrkB.

FL activation. However, this hypothesis was tested

and found insufficient. Iwakura and colleagues used

truncated TrkB to sequester BDNF in striatal cultures,

which blocked TrkB.FL activation of by BDNF but

failed to inhibit TrkB.FL phosphorylation induced by

D1R agonist treatment  [39].

In 2013, the effect of D5R activation on BDNF

signaling in rodent prefrontal cortex (PFC) was stud-

ied  [40]. Selective D5R activation significantly upreg-

ulated total CaMKIIα expression and elevated BDNF

expression in the PFC  [40]. This activation also in-

creased the TrkB.FL/TrkB.T1 ratio. Additionally, D5R

activation upregulated total Akt expression in the PFC

and promoted Akt phosphorylation at Ser473. Cor-

respondingly, phosphorylation of the Akt substrates

GSK-3α and GSK-3β was also increased.

Conversely, in embryonic neuronal culture, BDNF

stimulated dopamine release via TrkB.FL activa-

tion  [41]. Bastioli and colleagues have demonstrated

that physical exercise increased electrically evoked

dopamine release in the dorsal striatum and in the

NAc core and shell. This elevation in the dorsal stri-

atum and in the NAc core was BDNF-dependent, as

it was absent in BDNF

+/−

mice  [42]. Furthermore, a

2-hour activation of TrkB.FL with a TrkB.FL agonist

in ex  vivo brain sections enhanced electrically evoked

dopamine release in the dorsal striatal and in the

NAc core and shell. This enhancement was mediated

by PLC in all regions except for the NAc shell, where

it was dependent on PI3K signaling.

THE INTERPLAY BETWEEN

BDNF AND DOPAMINE SYSTEMS

INNEURODEVELOPMENTAL DISORDERS

Autism spectrum disorder (ASD). ASD is a neu-

rodevelopmental disorder characterized by deficits in

social communication alongside restricted and repeti-

tive behaviors  [43]. Over the past few years, the dopa-

mine theory of ASD has received increasing attention

[44-46]. Briefly, this theory suggests that dysregulation

of the dopamine mesocorticolimbic pathway may al-

ter reward representation for social stimuli and im-

pact social motivation, while dysfunction of the dopa-

mine nigrostriatal pathway contributes to stereotyped

and purposeless behavioral patterns  [46].

Numerous studies have implicated BDNF in ASD

pathogenesis. Some studies reported elevated serum

BDNF levels among individuals with ASD, while oth-

ers reported reduced serum BDNF levels compared

to neurotypical controls  [19]. A meta-analysis suggest-

ed an increase in peripheral BDNF levels in subjects

with ASD  [18]. On the other hand, ASD-like phenotype

CROSSTALK BETWEEN DOPAMINE AND BDNF 641

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

was exhibited by both mice with diminished activ-

ity-dependent BDNF signaling and with attenuated

proBDNF to mature-BDNF conversion  [17,  47].

Dysregulated dopaminergic neurotransmission

has been demonstrated in BTBR T

  tf/J (BTBR) mice,

a model of idiopathic ASD [48-50]. Notably, these

mice exhibited concurrent disruptions in BDNF and

dopamine systems. Reduced BDNF expression in the

hippocampus (HC) along with decreased dopamine

level in the amygdala were accompanied by elevated

levels of dopamine metabolites  [50]. Furthermore, a

dysregulation in Bdnf, Drd1, and Drd2 expression has

been observed in both prenatal and postnatal peri-

ods in BTBR mice  [51], as well as reduced expression

of CDNF in the frontal cortex  [51]. Whether CDNF

directly regulates BDNF expression remains specula-

tive, considering that CDNF modulates the activity of

Xbp1[52, 53], a transcription factor for BDNF [54-56].

In our recent study, we identified an additional

crosstalk between BDNF and dopamine in the con-

text of ASD [20]. We studied the effects of both acute

intracerebroventricular BDNF administration and

hippocampal adeno-associated virus (AAV)-mediated

BDNF overexpression in BTBR mice on ASD-like be-

havior and on the expression of genes of the dopa-

mine system. Both interventions modulated stereo-

typical behavior, as assessed in the marble burying

test. BDNF injection reduced mRNA level of cate-

chol-O-methyltransferase (COMT), a key enzyme of

the dopamine metabolism, in the HC and the frontal

cortex of BTBR mice. Additionally, BDNF overexpres-

sion increased D1R mRNA levels in the HC.

D2R

+/−

heterozygous mice subjected to early life

stress caused by maternal separation, developed

ASD-like behavior, while wild-type mice subjected to

the same stress and D2R

+/−

mice raised under nor-

mal conditions had a phenotype similar to that ob-

served in the wild-type animals  [57]. This ASD-like

phenotype was associated with altered expression

of BDNF/TrkB.FL signaling pathway proteins. Spe-

cifically, D2R

+/−

mice exhibiting the ASD-like behav-

ior demonstrated reduced expression of TrkB.FL

and BDNF, as well as decreased levels of the TrkB.

FL signaling downstream targets pAKT, pERK1/2, and

pCREB, in the striatum [57]. Notably, treatment with a

TrkB.FL agonist rescued the ASD-like behavioral defi-

cits of D2R

+/−

mice subjected to early life stress, as

was evidenced by improved sociability in the three

chamber and home cage social interaction tests. Fur-

thermore, inhibition of TrkB.FL receptors using stri-

atal TrkB-siRNA, blocked the positive effects of TrkB.

FL receptor agonist on the sociability of D2R

+/−

mice.

This study showed that downregulation of TrkB.FL

and D2R pathways are both critical in the manifes-

tation of ASD-like behavioral phenotype. It is possi-

ble that the combination of early life stress and D2R

deficiency directly or indirectly suppresses the TrkB.

FL signaling, triggering molecular events that even-

tually manifest as ASD-like behavior. Similar patterns

were reported by Wearick-Silva and colleagues who

showed that early life stress in mice, induced by

limited bedding protocol, was accompanied by low

mRNA levels of hippocampal TrkB.FL and D2R [58].

It can be concluded that the ASD phenotype in-

volves not only classical dopaminergic pathways but

also the HC. Specifically, BDNF/TrkB signaling within

the HC may enhance dopaminergic neurotransmis-

sion. Consequently, disruption of the BDNF system

could underlie the dysregulation of dopaminergic

signaling observed in ASD. This hypothesis is sup-

ported by several lines of evidence, such as naturally

decreased levels of hippocampal BDNF in BTBR mice,

the fact that experimental manipulation of BDNF also

alters components of the dopamine system  [20], and

the ability of striatal BDNF/TrkB signaling to rescue

ASD-like phenotypes  [57]. Environmental factors,

such as stress, could act as initial triggers, induc-

ing changes in the BDNF system that subsequently

dysregulate the dopamine system either directly or

indirectly. Several treatments for ASD target com-

ponents of both the dopamine and BDNF systems.

For instance, lithium carbonate, used off-label to

manage mood fluctuations in ASD, modulates signal-

ing pathways such as PI3K/Akt/CREB/BDNF and PI3K/

Akt/GSK3β [59]. Similarly, atypical antipsychotics,

such as risperidone and aripiprazole, exert their be-

havioral effects in part through D2R antagonism  [59].

Also, trials for old drugs that are known to stimulate

BDNF, such as loxapine and amitriptyline  [60], for

ASD had been recently recommended  [61].

Attention-deficit/hyperactivity disorder (ADHD).

ADHD is a neurodevelopmental condition character-

ized by core symptoms of inattention, hyperactivi-

ty, and impulsivity  [62]. Many studies have focused

on reduced dopamine (DA) and/or norepinephrine

(NE) function in ADHD  [63]. However, several stud-

ies have pointed to a hyperactive DA and/or NE sys-

tems in affected individuals  [63]. Both the hypoactive

and hyperactive catecholamine hypotheses of ADHD

have been integrated by the observation that DA and

NE may exhibit an inverted U-shaped dose-response

curve  [63]. Beyond catecholamines, evidence also

points to a possible correlation between BDNF and

ADHD  [64]. A recent study demonstrated that plasma

BDNF levels are significantly higher in children with

ADHD compared to controls  [65]. A study on sponta-

neously hypertensive rats (SHRs), a model for ADHD,

reported a significant reduction of tyrosine hydroxy-

lase  (TH), the rate-limiting enzyme in dopamine syn-

thesis, in the striatum and substantia nigra, along

with decreased BDNF content in the HC. Based on

these results, the authors suggested that hyperactivity

ALSALLOUM et al.642

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

and memory deficit in SHR rats are associated with

downregulation of dopamine in the striatum and the

substantia nigra, and decreased BDNF expression

in the hippocampus, respectively [66].

Dopamine transporter (DAT) knockout (DAT-KO)

rats display ADHD-like behaviors, including pro-

nounced spontaneous locomotor hyperactivity and

impaired working memory  [67]. They also exhibit

dysregulation in BDNF signaling that manifests as fol-

lows: 1)  reduced total BDNF mRNA levels in the PFC;

2)  decreased TrkB.FL activation; 3)  increased cytosolic

BDNF in the dorsolateral striatum (DLstr); 4)  reduced

BDNF levels in the DLstr postsynaptic density, indicat-

ing that DAT is involved in the subcellular redistribu-

tion of BDNF in this brain region; 5)  reduced TrkB.

FL expression and phosphorylation in the DLstr post-

synaptic density. DAT-KO mice show similar features

regarding the reduced mRNA level of BDNF and TrkB.

FL receptor in the frontal cortex  [68]. Taken togeth-

er, these findings highlight the importance of DAT in

the regulation of BDNF signaling.

Using Aroclor1254 (a polychlorinated biphenyl

mixture), Nam and colleagues induced ADHD-like be-

havior in mice. Subsequently, they evaluated the effect

of YY162 (a compound containing terpenoid-strength-

ened Ginkgo biloba and ginsenoside Rg3) on p-TrkB,

BDNF and DAT in the prefrontal cortex of these

mice. Initially, Aroclor1254 induced ADHD and led

to reduction in phospho-TrkB, BDNF, DAT and nor-

epinephrine transporter (NET) expression. YY162 ad-

ministration reversed these effects. Interestingly, the

protective effects of YY162 on p-TrkB/TrkB, BDNF,

and DAT were counteracted by TrkB.FL antagonist,

K252a, suggesting that these effects are mediated

by TrkB.FL receptor [69].

In a similar study, Yaqun and co-authors tested

the effects of a traditional Chinese medicine An Shen

Ding Zhi Ling on SHRs, and the role of TrkB.FL signal-

ing was again highlighted  [70]. The researchers sug-

gested that this formulation can relieve the symptoms

of ADHD by regulating the balance between BDNF/

TrkB.FL (promoting vesicle circulation) and proBDNF/

P75NTR/JNK1/NF-kB (inhibiting vesicle circulation) sig-

naling pathways in synaptosomes of the PFC and HC,

ultimately increasing DA levels in the synaptic cleft.

It can be postulated that in hypodopaminergic

ADHD, downregulation of the BDNF/TrkB signaling

in the PFC negatively impacts dopamine release and

vesicle fusion with the presynaptic membrane  [71],

resulting in decreased synaptic dopamine levels. Con-

versely, when extracellular dopamine levels are ele-

vated, due to DAT dysfunction or other causes, the

increase in dopamine appears to influence the BDNF

system in both the PFC and dorsal striatum. This ef-

fect could represent an adaptive response aimed to

prevent further synaptic dopamine accumulation.

Alternatively, it may indicate that DAT can modulate

BDNF circulation and expression. If the latter is the

case, the bidirectional regulation between the dopa-

minergic and BDNF systems in the PFC and dorsal

striatum may be disrupted in ADHD.

This hypothesis is supported by preclinical evi-

dence. For example, administration of theobromine

improved ADHD-like behavior in hypertensive rats by

modulating both the dopamine system and BDNF lev-

els in the PFC  [72]. Similarly, antihypertensive treat-

ment of pregnant SHRs alleviated ADHD-like symp-

toms in their male offspring, likely through elevated

DA and BDNF levels in the PFC and striatum  [73].

Schizophrenia. Schizophrenia is a psychiatric

disorder with a heterogeneous genetic and neurobio-

logical background that influences early brain devel-

opment. Clinically, it is characterized by a combina-

tion of psychotic symptoms, along with motivational

and cognitive dysfunctions  [74]. With increasing sup-

port for the neurodevelopmental theory of schizo-

phrenia [75-79], we summarized here available data

on the roles of dopamine system and BDNF in schizo-

phrenia pathogenesis.

In patients with schizophrenia, coexisting differ-

ences in dopamine regulation have been reported.

These differences are believed to arise from a deficit

in cortical dopamine and excessive subcortical do-

pamine  [80]. Numerous studies have shown elevated

BDNF levels in the HC and anterior cingulate cortex,

accompanied by reduced TrkB.FL content in the HC

and PFC of schizophrenia patients  [81]. Meta-analy-

ses have demonstrated that serum BDNF levels are

strongly associated with the course of severe schizo-

phrenia [82]. Also, genetic studies conducted in popu-

lation of the European part of Russia have identified

three polymorphisms associated with schizophrenia:

rs6265 in BDNF, rs1800955 in DRD4, and rs6313 in

HTR2A  [83].

In 2007, Guillin and colleagues hypothesized a

link between cortical dopamine neurotransmission

and schizophrenia mediated by BDNF  [84]. The au-

thors suggested that enhanced D1R function in the

dorsolateral PFC  [85] increases BDNF expression.

Elevated BDNF elicits overexpression of D3R in the

striatum  [86], ultimately contributing to the devel-

opment of the positive symptoms of schizophrenia

(pathological exaggerations or distortions of normal

functions, including hallucinations, delusions, disorga-

nized speech, and grossly disorganized or catatonic

behavior  [87]). This hypothesis was based on sever-

al lines of evidence, including the beneficial role of

BDNF in the survival and differentiation of dopami-

nergic neurons, BDNF involvement in the regulation

of GABAergic neurons in the PFC local circuits, func-

tional interplay between BDNF and dopamine, and

BDNF control over D3R expression  [88].

CROSSTALK BETWEEN DOPAMINE AND BDNF 643

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Years later, Wang and colleagues suggested that

the link between dopamine and BDNF in schizophre-

nia is mediated by CREB. Dopamine along with other

signaling molecules, can activate CREB and its down-

stream target BDNF through multiple intracellular

pathways  [89]. The deficit of the CREB/BDNF signaling

impairs neurodevelopment and is implicated in the

pathophysiology of schizophrenia [89].

The neurotrophic support by BDNF appears to be

deficient in schizophrenia, affecting structures such

as the HC and anterior cingulate cortex. In these

regions, despite elevated BDNF levels, a decrease in

TrkB.FL receptors seem to result in inefficient activa-

tion of the downstream signaling cascades  [81]. This

trophic deficit is also observed in the midbrain of pa-

tients with schizophrenia, where increased expression

of the TrkB.T1 isoform and p75

NTR

has been report-

ed  [90]. Insufficient trophic support for dopaminergic

neurons may underlie the dysregulated subcortical

expression of key dopamine system genes, especially

given the established role of BDNF in the regulation

of D2R and D3R  [91]. Alternatively, the deficit in BDNF

signaling could itself be a consequence of disrupted

cortical dopamine transmission via CREB-mediated

pathways, as suggested previously [88, 89]. The mul-

tifactorial etiology of schizophrenia and the involve-

ment of multiple neural circuits preclude the iden-

tification of a simple, linear pathogenic mechanism.

This complexity is reflected in the pharmacological

profiles of emerging therapeutic agents. For example,

TPN672MA, an innovative antipsychotic currently un-

dergoing clinical evaluation for the treatment of core

schizophrenia symptoms, acts as a partial D2R/D3R

agonist, an agonist of serotonin 5-HT

receptor, and

an antagonist of serotonin 5-HT

receptor  [92]. Nota-

bly, it also enhances BDNF expression, supporting a

multifactorial nature of schizophrenia pathophysiolo-

gy. This multifactorial perspective is further support-

ed by adjunctive treatment strategies. For example, a

combination of the atypical antipsychotic olanzapine

with the traditional Chinese herbal formula Yueju pill

has been reported to improve psychiatric symptoms,

cognitive functions, and social performance in pa-

tients with schizophrenia, concomitant with increases

in BDNF, dopamine, and serotonin levels [93].

THE INTERPLAY BETWEEN BDNF

AND DOPAMINE SYSTEMS

INNEURODEGENERATIVE DISEASES

Parkinson’s disease (PD). Parkinson’s disease

is a progressive neurodegenerative disorder charac-

terized primarily by tremor and bradykinesia, rep-

resenting a common neurologic disorder [94]. It is

marked by the progressive loss of dopaminergic neu-

rons. Levels of BDNF were shown to be decreased in

PD patients  [95], while increase of BDNF level exerts

a neuroprotective effect  [96].

Two recent studies [97,  98] revealed that D1R

and D2R signaling modulate the sensitivity of stri-

atal MSNs to BDNF in both the direct and indirect

pathways, thereby contributing to the PD pathology.

Using a biotinylation assay on fluorescence-activated

cell sorting (FACS)-enriched D1R-expressing MSNs,

Andreska and colleagues demonstrated that D1R acti-

vation promotes TrkB.FL translocation from the intra-

cellular compartments to the cell surface, thereby en-

hancing BDNF sensitivity in direct pathway. Moreover,

D1R activation decreased TrkB.FL translocation to the

lysosomes and limited its degradation. In contrast, re-

duced D1R activity achieved through dopamine deple-

tion resulted in the formation of perinuclear TrkB.

FL clusters in a subset of MSNs. In  vivo data from

hemi-parkinsonian rats (rats with a unilateral degen-

eration of dopamine neurons) and Drd1−/− mice also

revealed perinuclear TrkB.FL accumulation in striatal

MSNs of the direct pathway following dopamine de-

pletion. It was suggested that in the absence of D1R

activation, TrkB.FL forms clusters that are unable to

enter canonical degradation pathways. Similar clus-

ters were observed in the postmortem striatum of pa-

tients with PD. The same team later showed that D2R

activation in FACS-enriched D2R-expressing MSNs led

to the translocation of TrkB.FL from the cell surface

and subsequent lysosomal degradation  [98].

The treatment of hemi-parkinsonian mice with

L-DOPA led to the upregulation of TrkB.FL mRNA and

protein levels in the striatum, enhanced activation of

TrkB.FL evidenced by the increased phosphorylation

of its tyrosine residue, and elevated BDNF mRNA lev-

els in the frontal cortex  [99]. TrkB.FL upregulation

was found to be D1R-dependent, which is consistent

with findings presented in [97,  98]. Because selective

deletion of TrkB.FL in D1R-expressing striatal neu-

rons has exacerbated the L-DOPA-induced dyskinesia

(LID, a common side effect of L-DOPA treatment),

it was suggested that TrkB.FL activation following

L-DOPA treatment plays a protective role against LID

development.

BDNF derived from corticostriatal neurons in-

duced behavioral sensitization by triggering upregu-

lation of D3R in the striatum of hemi-parkinsonian

rats [88]. Also, BDNF overexpression in the substan-

tia nigra, combined with D3R pharmacological acti-

vation, led to the normalization of motor coordina-

tion, elimination of muscle rigidity associated with

dopamine depletion, and recovery of nigral neu-

rons and dopamine innervation of the striatum in

hemi- parkinsonian rats [100].

These data provide direct evidence of a bidirec-

tional interplay between the dopamine and BDNF

ALSALLOUM et al.644

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

systems in the striatum in PD. This interplay involves

not only the BDNF’s crucial support for the surviv-

al of susceptible dopaminergic neurons, but also di-

rect modulation of the BDNF system by dopamine

through the control of TrkB.FL trafficking to and from

the cell surface. Based on findings from hemi-parkin-

sonian models, dopamine may play a similar regula-

tory role in other brain structures. Moreover, such

modulation of BDNF sensitivity might also occur un-

der normal physiological conditions.

Research in mice indicates the therapeutic poten-

tial of simultaneously targeting both dopamine and

BDNF systems for PD treatment. In a mouse model

of 6-hydroxydopamine-induced PD, administration of

garlic-derived allicin improved motor function and

reduced the loss of dopaminergic neurons. These

effects were likely mediated by upregulation of the

PKA/p-CREB/BDNF signaling pathway and restoration

of DAT expression  [101]. Similarly, activation of D3R

with the preferential agonist pramipexole, combined

with BDNF gene transfection in the substantia nigra,

restored the number of TH-positive neurons in the

substantia nigra and ventral tegmental area (VTA), as

well as the spines of striatal projection neurons, in

a bilateral rat PD model. This combination therapy

normalizedmotor coordination, balance, and working

memory [102].

Alzheimer’s disease (AD). AD is characterized

by a specific onset and progression of cognitive and

functional decline associated with aging, along with

distinct neuropathological features  [103]. Function-

al brain magnetic resonance imaging (fMRI) studies

have revealed disrupted connectivity between the

VTA and the rest of the brain in AD patients  [104].

Also, nigrostriatal dopaminergic dysfunction is asso-

ciated with visuospatial/executive dysfunction in pa-

tients with AD  [105]. Several studies have reported

an association of the Val158/108Met polymorphism

in the COMT gene responsible for dopamine me-

tabolism, with deficits in specific cognitive domains

and psychosis in AD  [106]. On the other hand, BDNF

expression is severely reduced in the HC, temporal

cortex, and frontal cortex of AD patients [107,  108].

In a study using 5×FAD (familial AD) transgenic

mice, restoration of normal BDNF signaling follow-

ing microglia repopulation resulted in the amelio-

ration of AD-related cognitive deficits, along with

increased synaptic protein levels and enhanced

hippocampal LTP [109]. It was found that physical

exercise has protective effects on the hippocam-

pal neurons from AD-related degeneration through

BDNF/TrkB.FL-related mechanisms [110].

Recently, novel associations between dopamine,

neurotrophic factor genes, and AD pathology were

identified  [111]. Polymorphisms in the DAT (rs6347 in

DAT1/SLC6A3) and BDNF (Val66Met in BDNF) genes

were evaluated for their effects on β-amyloid and tau

pathology, HC volume, and cognition. It was shown

that carriers of both the DAT1 CC genotype and BDNF

Met allele exhibited more β-amyloid and tau accumu-

lation, and a greater decline in the HC volume over

time [111]. Additionally, a significant DAT and BDNF

interaction on longitudinal change in hippocampal

volume was also revealed. Furthermore, the neuro-

protective effects of curcumin (a well-known antiox-

idant with neuroprotective effects in AD) have been

shown to be mediated by enhancement of both BDNF

and dopamine levels in the brain [112].

The protective role of BDNF in neurodegenera-

tive disorders is consistent with its well-established

functions in neuronal support and survival. It is

plausible that diminished BDNF levels reduce synap-

tic plasticity in the HC, striatum, and limbic system

[110], potentially leading to the functional dissocia-

tion of the VTA from other brain regions and con-

tributing to the pathological abnormalities observed

in AD. In this context, the hypothesis that the dopa-

mine system contributes to AD pathology alongside

BDNF [111] merits further investigation.

Accordingly, a study on a mouse model of AD

(induced by intracerebroventricular amyloid-β42

oligomer injection) showed that repetitive transcra-

nial magnetic stimulation (rTMS) led to cognition

recovery, and that high frequency rTMS enhanced

dopamine concentration and upregulated D4R, along

with an elevation in BDNF levels. Corroborating these

findings, in vitro experiments on hippocampal cells

demonstrated that high-frequency rTMS treatment in-

creased both dopamine and BDNF levels  [113].

THE INTERPLAY BETWEEN

BDNF AND DOPAMINE SYSTEMS

IN OTHER DISORDERS

Substance use disorder. DARPP-32, a key com-

ponent in the dopamine receptor signaling cascade,

is modulated by different drugs of abuse, including

alcohol, opioids, nicotine, and psychostimulants  [114].

BDNF is involved in the mechanisms of actions of

psychoactive substances and in the development of

substance use disorders  [115]. While rs6265 Met  (T)

allele may be a protective factor against the develop-

ment of substance use disorder, other single-nucleo-

tide polymorphisms in the BDNF gene are associated

with an increased risk of its development.

Administration of psychostimulants modulates

BDNF/TrkB.FL signaling via D1R. Methyl-CpG-bind-

ing protein  2 (MeCp2) is a methyl DNA-binding tran-

scriptional regulator that binds to promoter  IV in the

BDNF gene and suppresses its transcription. Howev-

er, psychostimulants have been found to promote

CROSSTALK BETWEEN DOPAMINE AND BDNF 645

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

D1R-mediated dissociation of MeCP2 from the BDNF

promoter, thereby activating BDNF expression [116,

117].

A single BDNF injection into the VTA induced

nicotine withdrawal-like behavior in mice and shifted

the neurobiological mediation of the conditioned re-

sponse to nicotine from D1R to D2R [118]. Also, TrkB.

FL mRNA levels were elevated in the VTA of nico-

tine-dependent and nicotine-withdrawn mice, suggest-

ing involvement of BDNF signaling in the VTA in the

transition to nicotine dependence  [118]. Furthermore,

gestational nicotine exposure elevated BDNF levels

throughout the mesocorticolimbic dopamine system

during adolescent development  [119].

BDNF/TrkB.FL signaling in the NAc plays an im-

portant role in the behavioral abnormalities observed

following methamphetamine withdrawal [120]. Rats

with ethanol dependence, following 21 days of eth-

anol consumption, were found to have decreased

levels of BDNF protein and mRNA in the NAc after

ethanol withdrawal [121].

Chronic morphine treatment alters BDNF protein

levels in the VTA, with variations depending on drug

consumption history  [122]. Additionally, locomotor

sensitization in a morphine-paired environment was

accompanied by a significant increase in the BDNF

levels in the NAc. Moreover, BDNF administration

in the VTA promoted a shift to an opiate-dependent

state in drug-naive rats. Single injection of BDNF into

the VTA was sufficient to shift reward processing

from dopamine-independent to dopamine-dependent

mechanisms in opiate non-dependent rats  [122]. Juve-

nile rats exposed to methylphenidate, a norepineph-

rine-dopamine reuptake inhibitor, exhibited perma-

nently reduced prefrontal BDNF transcription. Also,

this exposure reduced BDNF gene translation upon

cocaine exposure in adulthood by a D3R-mediated

mechanism [123].

It can be concluded that BDNF plays a significant

role in the VTA in the context of substance use dis-

order, where it appears to mediate a state of depen-

dence through dopamine receptor modulation. The

BDNF gene also appears to be regulated by dopamine

receptors in this circuitry. Furthermore, the NAc is

another key structure, as BDNF there seems to be im-

plicated in sustaining the behavioral state following

substance withdrawal [120,  121].

The mechanistic interplay between dopamine

and BDNF in substance use disorders is strongly

supported by pharmacological intervention studies.

Research on tetrahydrocannabinol (THC)-dependent

mice demonstrated that melatonin and Prosopis

farcta extract (luteolin) reduced signs of THC with-

drawal. These effects were likely due to decreased do-

pamine concentration and an increased BDNF protein

expression in the mice brains  [124]. Furthermore,

a study on nicotine-addicted Wistar rats revealed

that Graptophyllum grandulosum (a plant traditional-

ly used for its various medicinal properties) reduced

addictive behavior by modulating dopaminergic and

BDNF pathways, among others. Specifically, the levels

of both dopamine and BDNF were decreased in the

striatum and HC of experimental animals following

the treatment [125].

Mood disorders. BDNF/TrkB.FL signaling exerts

region-specific effects on the development of depres-

sive-like phenotypes [126-128]. For example, BDNF

administration in the HC produced the anti-stress

effects  [129]. Cycloprolylglycine (a neuropeptide com-

posed of glycine and proline) was found to exert

the antidepressant effects in the frontal cortex via

a BDNF-dependent mechanism  [130]. Central BDNF

administration ameliorated genetically determined

depressive-like phenotype in mice  [131]. In contrast,

BDNF can act as a pro-stress factor in the NAc [128,

129], and its infusion directly into the VTA was suf-

ficient to induce depressive-like behaviors, as evalu-

ated by the forced swim test [127,  128]. This pro-de-

pressive effect of BDNF in the mesolimbic pathway

has been explained by the importance of BDNF sig-

naling in the VTA–NAc for establishing associations

with negative emotion stimuli, which under normal

conditions supports adaptive threat and reward mem-

ory  [128]. However, under pathological conditions, ab-

errant BDNF signaling may establish excessive inap-

propriate negative associations, thereby contributing

to depression symptomatology  [128].

TrkB.T1 overexpression in D2R-MSNs of the NAc

mitigated consequences of chronic social stress and

prevented stress susceptibility induced by intra-NAc

BDNF. Conversely, overexpression of TrkB.T1 in D1R-

MSNs promoted stress susceptibility  [129]. These ef-

fects likely arise from the TrkB.T1-mediated inhibition

of BDNF/TrkB.FL signaling, thereby reducing associat-

ed synaptic plasticity and neuronal activation. There-

fore, the D2R-MSNs pathway appears to mediate sus-

ceptibility to BDNF-induced stress possibly through

enhancing plasticity of D2R-MSNs and modulating

their response to excitatory inputs, consistent with a

high TrkB.FL density in these neurons  [129].

A recent study examined the effects of NAc deep

brain stimulation (DBS) on depressive-like behav-

ior in a chronic social defeat stress (CSDS) mouse

model  [132]. Researchers found that DBS of the NAc

increased BDNF release, resulting in enhanced met-

abolic activity in the dopaminergic pathway and

increased TH levels, as well as upregulated expres-

sion of Drd1 and Drd2 in the NAc, VTA, and other

brain regions. Hence, DBS alleviated depression-like

behavior and restored impaired emotional respons-

es in CSDS mice  [132]. Given the variable behavior-

al outcomes of BDNF modulation across different

ALSALLOUM et al.646

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table  1. BDNF-dopamine system dysregulation and interaction in neurodevelopmental and neurovegetative

disorders

Disorders BDNF dysregulation DA system

dysregulation

Co-occurring

dysregulation

Proposed crosstalk

pattern

Neurodevelopmental disorders

Autism spectrum disorder

– dysregulated BDNF

serum levels have

been reported

in individuals

with ASD [18, 19];

− reduced BDNF

signaling in mice

induces ASD-like

phenotypes [17, 47]

– the dopamine

hypothesis suggests

that dysfunction

in the mesolimbic

pathway disrupts

social motivation,

whereas

abnormalities

in the nigrostriatal

pathway contribute

to the emergence

of repetitive

behaviors in ASD

[44-46]

− the BTBR mouse

model displays

disruptions in both

DA and BDNF

signaling pathways

[50, 51];

− increasing BDNF

levels in BTBR mice

directly influences

the DA system

and modulates

stereotyped

behaviors [20];

− in mice, stress

combined with

reduced D2R and

BDNF signaling

in the HC

and striatum

induces ASD-like

behaviors [57]

− evidence suggests

that BDNF exerts

a unidirectional

regulatory effect

on the DA system,

with the HC

implicated

as the primary site

of this regulation

ADHD

− children with ADHD

exhibit elevated

plasma levels of

BDNF [65]

− the hypo- and

hyper-dopaminergic

hypothesis has

been proposed

to explain the

pathophysiology

of ADHD [63];

− DAT-KO mice

and rats exhibit

behaviors

analogous to those

observed in ADHD

[67, 68]

− DAT-KO models

exhibit dysregulation

of the BDNF system

in the PFC

and dorsal striatum

[67, 68];

− attenuation of ADHD-

associated molecular

changes in animal

models is mediated

by the BDNF/TrkB

axis [69, 70]

− in the hy-

podopaminergic

model, BDNF

dysregulation may

reduce synaptic DA

availability;

– in the hyper-

dopaminergic

model, impaired

DAT function

appears to modulate

the BDNF system

in the corticostriatal

circuits

Schizophrenia

− increased BDNF

levels alongside

decreased TrkB.

FL are observed in

the HC and anterior

cingulate cortex

of patients with

schizophrenia [81]

− schizophrenia

is characterized

by reduced DA

activity in the

cortex and elevated

DA activity

in subcortical

regions [80]

− reduced trophic

support is observed

in the midbrain

of patients with

schizophrenia [81].

− polymorphisms in

BDNF and DRD4

have been associated

with an increased risk

of schizophrenia [83]

− a bidirectional

regulatory

crosstalk is

postulated:

− reduced BDNF

trophic support

may contribute

to dopaminergic

dysregulation;

− conversely,

dopaminergic

dysregulation

may impair

neurodevelopment

by altering BDNF

expression through

CREB-related

pathways [89]

CROSSTALK BETWEEN DOPAMINE AND BDNF 647

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table 1 (cont.)

Disorders BDNF dysregulation DA system

dysregulation

Co-occurring

dysregulation

Proposed crosstalk

pattern

Neurodegenerative disorders

Parkinson’s disease

− BDNF exerts

neuroprotective

effects in PD

patients [96]

− degeneration

of dopaminergic

neurons in the

substantia nigra

is the primary

pathological

hallmark of PD

− in the striatum, D1R

and D2R modulate the

sensitivity of MSNs

to BDNF [97, 98];

− L-DOPA treatment

in a PD mouse

model, modulates key

elements of BDNF

system in the striatum

and PFC [99];

− in a PD rat model,

BDNF overexpression

in the substantia

nigra along with D3R

activation rescues

motor deficits [100]

− a bidirectional

interplay exists:

DA modulates

striatal sensitivity

to BDNF, while

BDNF provides

trophic support

for the survival

and functioning

of dopaminergic

neurons

Alzheimer’s disease

− BDNF levels are

reduced in the HC,

PFC, and temporal

cortex of patients

with AD [107, 108];

− exercise exerts

beneficial effects

in AD, presumably,

through mechanisms

involving

BDNF [110]

− functional con-

nectivity between

the VTA and other

brain regions is dis-

rupted in patients

with AD [105];

− polymorphism in

the COMT gene

is associated

with psychosis

in AD [106]

− carriers of

polymorphisms in

the BDNF and DAT1

exhibit more severe

β-amyloid and tau

pathology [111];

− the neuroprotective

effects of curcumin

are mediated via

both BDNF and DA

systems [112]

− reduced BDNF

trophic support

may compromise

synaptic integrity

and plasticity of

VTA dopaminergic

circuits, contributing

to their functional

isolation in AD

Other disorders

Substance use disorders

− BDNF is involved

in the mechanisms

of action of

psychoactive

substances [115]

− DARPP-32 is

modulated by

different drugs

of abuse [114];

− psychostimulant

administration

modulates BDNF

transcription via

D1R [116, 117]

− a single BDNF in-

jection into the VTA

induces nicotine with-

drawal-like behavior

in mice and promotes

an opiate-dependent

state in drug-naive

rats [118, 122];

− BDNF signaling in the

NAc is implicated in

mediating the behav-

ioral state following

substance withdrawal

[120, 121]

− BDNF appears to

mediate dependence

states via DA

receptor modulation

in the VTA and NAc;

− administration

of drugs of abuse

can modulate

BDNF transcription

through DA receptor

signaling

Mood disorders

− BDNF/TrkB.FL

signaling has

region-specific

effects on the

development

of depressive-like

phenotype [126-128];

− BDNF in the HC

has anti-stress

effect [129]

− dopaminergic

signaling via

D2R-expressing

MSNs in the NAc

is implicated

in the pro-

depressive effects

of mesolimbic

BDNF [129]

− DBS of the NAc ele-

vates BDNF release

and DA metabolism,

alleviating depres-

sion-like behavior

in mice [132];

− genetic interactions

between DA and

BDNF are implicated

in the pathophys-

iology of bipolar

disorder [135]

− BDNF exerts

structure-specific

effects on mood

regulation;

− the effects of BDNF

in dopaminergic

structures appear

to be further

modulated

by DA receptors,

influencing the

behavioral outcome

ALSALLOUM et al.648

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Fig. 1. Possible interactions between BDNF and dopamine systems. Molecules shared by the BDNF and DA intracellular

signaling cascades and likely involved in the crosstalk between these two systems are highlighted in yellow. TrkB.FL, D2R,

and D1R:D2R dimers activate PLC, thereby increasing Ca

levels, affecting dopamine release, BDNF expression, TrkB.FL

expression, and PP2B. DARPP-32 modulates ERK, one of the key elements of the PLC pathway, and is inhibited by PP2B.

CREB, an executive molecule of the PLC signaling cascade, modulates BDNF expression and can be modulated by it. cAMP

regulates the TrkB.FL translocation to and from the cell surface. Dotted arrows indicate modulation; interrupted arrows

signify that not all the signaling pathway is shown.

dopaminergic structures, the role of BDNF in mood

regulation appears to be both region-specific and sub-

ject to additional modulation by dopamine receptors.

Interestingly, the antidepressant effects of ketamine

(an off-label drug for treatment-resistant depression)

were found to depend on the rapid BDNF synthesis

and D1R activity in the medial PFC, among other mo-

lecular mechanisms. Furthermore, (S)-ketamine has

been reported to induce a pronounced increase in

dopamine levels [133].

Chang and colleagues provided evidence that

BDNF Val66Met and D3R Ser9Gly genotypes interact

in bipolar-II disorder (chronic mood disorder char-

acterized by recurrent episodes of major depression

and hypomania, without full manic episodes or psy-

chosis  [134]). Additionally, the existence of gene-gene

interaction between BDNF and D2R in this disorder

was suggested  [135]. The key findings on the inter-

play between dopamine and BDNF systems in neuro-

developmental, neurodegenerative, and other psychi-

atric disorders are summarized in Table  1.

POSSIBLE MECHANISMS

OF DOPAMINE–BDNF CROSSTALK

Current literature suggests that alterations in ei-

ther the dopamine or BDNF system can induce spe-

cific changes in the other, both under physiological

and pathological conditions. However, the molecular

mechanisms underlying this cross-modulation remain

poorly understood. Here, we propose two potential

mechanisms that may mediate this interplay.

The first mechanism involves interconnected sig-

naling cascades (Fig.  1). As illustrated in the figure,

TrkB.FL, D1R, and D2R share several intracellular tar-

gets. Both TrkB.FL and D2R activate PLC, leading to

the recruitment of secondary messengers DAG and IP3.

The resulting increase in the intracellular Ca

may

regulate dopamine release from intracellular vesicles

[136]. Also, TrkB.FL expression is Ca

-sensitive  [137],

suggesting that it could be under control of D2R and

TrkB.FL itself via a feedback mechanism. TrkB.FL

translocation to the cell surface is cAMP-dependent

CROSSTALK BETWEEN DOPAMINE AND BDNF 649

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

and can be regulated by finely tuned cAMP synthesis

and by dopamine receptors, as previously described

[97,  98]. Another Ca

-dependent cellular protein is

PP2B. One of its targets is DARPP-32 [138], which is a

key molecule in the D1R signaling pathway. DARPP-32,

on the other hand, has been found to regulate one of

the proteins activated in the BDNF/TrkB.FL pathway:

ERK in D1R-expressing MSNs  [139]. When phosphory-

lated at Thr75, DARPP-32 inhibits the activity of PKA

[24], which suggests its role in the fine-tuning of

both D1R and TrkB.FL functioning. Finally, CREB is a

shared downstream target of TrkB.FL, D1R, D2R, and

D1R:D2R signaling pathways, making it a convergence

point between dopamine and BDNF systems, as pre-

viously proposed [89, 128]. The functional crosstalk

between the D1R and TrkB.FL signaling has also been

suggested by Iwakura et  al.  [39].

The second possible mechanism of interaction

between the dopamine and BDNF systems is het-

erodimerization of TrkB.FL with dopamine receptors.

This hypothesis is plausible because 1)  both TrkB.FL

and dopamine receptors share common PLC-depen-

dent signaling pathway; 2)  TrkB.FL is known to form

heterodimers with other GPCRs, such as the 5-HT

receptor  [140], which also signals via PLC; 3)  D2R

can form heterodimers with serotonin 5-HT

recep-

tors  [141]. The co-expression of TrkB.FL and dopa-

mine receptors in the striatum further supports this

assumption  [98].

The existence of heterodimers between TrkB.FL

and dopamine receptors may enable cross-regulation

of their respective signaling pathways, providing a

potential mechanism for the crosstalk between the

dopamine and BDNF systems. Beyond this, molecules

such as DARPP-32 and CREB could serve as nodes

of integration between these two systems.

CONCLUSION

Our review highlights a critical bidirectional in-

terplay between the BDNF and dopamine systems:

(i)  BDNF is essential for proper functioning and sur-

vival of dopaminergic neurons; (ii)  dopamine recep-

tor activation modulates the expression and activity

of BDNF/TrkB.FL pathway; (iii)  in turn, BDNF release

and TrkB.FL sensitivity are modulated by the dopa-

mine system; (iv)  BDNF influences dopamine release.

In neurodevelopmental disorders (ADHD, ASD,

and schizophrenia) this crosstalk is disrupted during

early development due to genetic (e.g., SHANK3 mu-

tations, Val66Met polymorphism) and/or environmen-

tal factors. Both dopaminergic and BDNF signaling

pathways are affected, necessitating structure-specif-

ic therapeutic approaches, due to divergent cortical

and subcortical dopamine dynamics.

Similar regulatory mechanisms operate in neuro-

degenerative disorders, albeit with distinct temporal

onset patterns. Growing evidence indicates that BDNF

is implicated in the pathophysiology of these disor-

ders, highlighting its potential as a therapeutic target.

For example, impaired neuroprotective functions of

BDNF may contribute to the progressive loss of do-

paminergic neurons in PD. In mood disorders, BDNF

plays structure-dependent roles in behavioral regula-

tion, as well as exerts distinct effects in the direct

and indirect dopaminergic pathways. The interaction

between BDNF and D2R on both gene and protein

levels appears particularly important in the mech-

anisms underlying mood disorders. BDNF is a key

mediator of drug-induced neuroplasticity, influencing

addiction-related behaviors through region-specific

effects and interactions with dopamine receptors. Its

dysregulation contributes to dependence, withdraw-

al, and long-term behavioral changes following drug

exposure.

Multiple studies highlight the intricate interplay

between the BDNF and dopamine systems under both

physiological conditions and in various psycho- and

neuropathologies. Although further research is re-

quired to elucidate the precise mechanisms of this

crosstalk, it has become evident that these systems

are interdependent and should not be studied in

isolation. The interdependence of the dopamine and

BDNF systems offers promising prospects for the

development of novel therapeutic strategies. Rather

than targeting each pathway independently, future re-

search should prioritize combinatorial pharmacolog-

ical approaches. Such strategies could involve agents

that simultaneously modulate BDNF/TrkB signaling

and specific dopamine receptor subtypes to restore

the functional balance. Furthermore, when targeting

one system, it is essential to account for and evaluate

the components of the other to accurately predict the

therapeutic outcomes and the nature of this crosstalk.

Achieving the necessary brain region-specific target-

ing will require innovations in drug delivery systems.

Ultimately, viewing the dopamine-BDNF axis as an

integrated pharmacological target holds potential for

developing more effective therapies for a wide spec-

trum of nervous system disorders.

Abbreviations

AC adenylyl cyclase

AD Alzheimer’s disease

ADHD attention-deficit/hyperactivity disorder

Akt protein kinase  B

ASD autism spectrum disorder

BDNF brain-derived neurotrophic factor

cAMP cyclic adenosine monophosphate

COMT catechol-O-methyltransferase

D1R–D5R dopamine receptors 1-5

ALSALLOUM et al.650

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

DA dopamine

DAG diacylglycerol

DAT dopamine transporter

DAT-KO dopamine transporter knockout

DBS deep brain stimulation

ERK extracellular signal-regulated kinase

GPCR G protein-coupled receptor

GSK3 glycogen synthase kinase  3

HC hippocampus

IP3 inositol 1,4,5-triphosphate

JNK C-Jun N-terminal kinase

LTD long-term depression

LTP long-term potentiation

MAPK mitogen-activated protein kinase

MSN medium-sized spiny neuron

NAc nucleus accumbens

PD Parkinson’s disease

PFC prefrontal cortex

PI3K phosphatidylinositol 3-kinase

PKA protein kinase  A

PLC phospholipase  C

PP1 protein phosphatase  1

TH tyrosine hydroxylase

TrkB tropomyosin-related receptor kinase  B

TrkB.FL full-length TrkB

TrkB.T1 TrkB truncated isoform

VTA ventral tegmental area

Contributions

A.Ts. developed the study concept; M.A. collected and

analyzed the data and wrote the text of the article;

V.N. and A.Ts. reviewed the manuscript.

Funding

The study was supported by the by the Russian Sci-

ence Foundation (project no. 25-15-00043).

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man or animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

REFERENCES

1. Beaulieu, J. M., and Gainetdinov, R. R. (2011) The physiology, signaling, and pharmacology of dopamine recep-

tors, Pharmacol. Rev., 63, 182-217, https://doi.org/10.1124/pr.110.002642.

2. Popova, N. K., Kulikov, A. V., and Naumenko, V. S. (2020) Spaceflight and brain plasticity: Spaceflight effects on

regional expression of neurotransmitter systems and neurotrophic factors encoding genes, Neurosci. Biobehav.

Rev., 119, 396-405, https://doi.org/10.1016/j.neubiorev.2020.10.010.

3. Baydyuk, M., and Xu, B. (2014) BDNF signaling and survival of striatal neurons, Front. Cell Neurosci., 8, 254,

https://doi.org/10.3389/fncel.2014.00254.

4. Koch, E. T., and Raymond, L. A. (2019) Dysfunctional striatal dopamine signaling in Huntington’s disease, J.

Neurosci. Res., 97, 1636-1654, https://doi.org/10.1002/jnr.24495.

5. Grace, A. A. (2016) Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depres-

sion, Nat. Rev. Neurosci., 17, 524-532, https://doi.org/10.1038/nrn.2016.57.

6. Mandic-Maravic, V., Grujicic, R., Milutinovic, L., Munjiza-Jovanovic, A., and Pejovic-Milovancevic, M. (2022)

Dopamine in autism spectrum disorders – focus on D2/D3 partial agonists and their possible use in treatment,

Front. Psychiatry, 12, 787097, https://doi.org/10.3389/fpsyt.2021.787097.

7. Klein, M. O., Battagello, D. S., Cardoso, A. R., Hauser, D. N., Bittencourt, J. C., and Correa, R. G. (2019) Dopa-

mine: functions, signaling, and association with neurological diseases, Cell. Mol. Neurobiol., 39, 31-59, https://

doi.org/10.1007/s10571-018-0632-3.

8. Von Bohlen und Halbach, O., and Unsicker, K. (2009) Neurotrophic support of midbrain dopaminergic neurons,

Adv. Exp. Med. Biol., 651, 73-80, https://doi.org/10.1007/978-1-4419-0322-8_7.

9. Lindahl, M., Saarma, M., and Lindholm, P. (2017) Unconventional neurotrophic factors CDNF and MANF:

structure, physiological functions and therapeutic potential, Neurobiol. Dis., 97, 90-102, https://doi.org/10.1016/

j.nbd.2016.07.009.

10. Conway, J. A., Ince, S., Black, S., and Kramer, E. R. (2020) GDNF/RET signaling in dopamine neurons in vivo,

Cell Tissue Res., 382, 135-146, https://doi.org/10.1007/s00441-020-03268-9.

11. Lin, C. C., and Huang, T. L. (2020) Brain-derived neurotrophic factor and mental disorders, Biomed. J., 43, 134-

142, https://doi.org/10.1016/j.bj.2020.01.001.

12. Singh, M., Kakkar, A., Sharma, R., Kharbanda, O. P., Monga, N., Kumar, M., Chowdhary, S., Airan, B., and

Mohanty, S. (2017) Synergistic effect of BDNF and FGF2 in efficient generation of functional dopaminergic neu-

rons from human mesenchymal stem cells, Sci. Rep., 7, 10378, https://doi.org/10.1038/s41598-017-11028-z.

13. Trzaska, K. A., King, C. C., Li, K. Y., Kuzhikandathil, E. V., Nowycky, M. C., Ye, J.-H., and Ramesh-

war, P. (2009) Brain-derived neurotrophic factor facilitates maturation of mesenchymal stem cell-derived

CROSSTALK BETWEEN DOPAMINE AND BDNF 651

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

dopamine progenitors to functional neurons, J. Neurochem., 110, 1058-1069, https://doi.org/10.1111/j.1471-4159.

2009.06201.x.

14. Fenner, B. M. (2012) Truncated TrkB: beyond a dominant negative receptor, Cytokine Growth Factor Rev., 23,

15-24, https://doi.org/10.1016/j.cytogfr.2012.01.002.

15. Alsalloum, M., Ilchibaeva, T., Tsybko, A., Ermin, D., and Naumenko, V. (2023) A truncated receptor TrkB isoform

(TrkB.T1) in mechanisms of genetically determined depressive-like behavior of mice, Biomedicines, 11, 2573,

https://doi.org/10.3390/biomedicines11092573.

16. Kakizawa, S. (2021) Brain-derived neurotrophic factor, in Handbook of Hormones, Elsevier, pp. 479–482, https://

doi.org/10.1016/B978-0-12-820649-2.00122-4.

17. Ma, K., Taylor, C., Williamson, M., Newton, S. S., and Qin, L. (2023) Diminished activity-dependent BDNF signaling

differentially causes autism-like behavioral deficits in male and female mice, Front. Psychiatry, 14, 1182472,

https://doi.org/10.3389/fpsyt.2023.1182472.

18. Armeanu, R., Mokkonen, M., and Crespi, B. (2017) Meta-analysis of BDNF levels in autism, Cell. Mol. Neurobiol.,

37, 949-954, https://doi.org/10.1007/s10571-016-0415-7.

19. Halepoto, D. M., Bashir, S., and Al-Ayadhi, L. (2014) Possible role of brain-derived neurotrophic factor (BDNF)

in autism spectrum disorder: current status, J.Coll. Physicians Surg. Pak., 24, 274-278.

20. Ilchibaeva, T., Tsybko, A., Lipnitskaya, M., Ermin, D., Milutinovich, K., Naumenko, V., and Popova, N. (2023)

Brain-derived neurotrophic factor (BDNF) in mechanisms of autistic-like behavior in BTBR mice: Crosstalk with

the dopaminergic brain system, Biomedicines, 11, 1482, https://doi.org/10.3390/biomedicines11051482.

21. De Deurwaerdère, P., Chagraoui, A., and Di Giovanni, G. (2021) Serotonin/dopamine interaction: Electrophysio-

logical and neurochemical evidence, Prog. Brain Res., 261, 161-264, https://doi.org/10.1016/bs.pbr.2021.02.001.

22. Popova, N. K., and Naumenko, V. S. (2019) Neuronal and behavioral plasticity: The role of serotonin and BDNF

systems tandem, Expert Opin. Ther. Targets, 23, 227-239, https://doi.org/10.1080/14728222.2019.1572747.

23. Channer, B., Matt, S. M., Nickoloff-Bybel, E. A., Pappa, V., Agarwal, Y., Wickman, J., and Gaskill, P. J. (2023) Do-

pamine, immunity, and disease, Pharmacol. Rev., 75, 62-158, https://doi.org/10.1124/pharmrev.122.000618.

24. Girault, J. A., and Nairn, A. C. (2021) DARPP-32 40 years later, Adv. Pharmacol., 90, 67-87, https://doi.org/

10.1016/bs.apha.2020.09.004.

25. Jones-Tabah, J., Mohammad, H., Paulus, E. G., Clarke, P. B. S., and Hébert, T. E. (2022) The signaling and phar-

macology of the dopamine D1 receptor, Front. Cell. Neurosci., 15, 806618, https://doi.org/10.3389/fncel.2021.

806618.

26. Ma, H. (2025) PKC in the perspective of dopamine receptor signaling, Acta Biochim. Pol., 72, 14488, https://

doi.org/10.3389/abp.2025.14488.

27. Beaulieu, J. M., Espinoza, S., and Gainetdinov, R. R. (2015) Dopamine receptors – IUPHAR review 13, Br. J.

Pharmacol., 172, 1-23, https://doi.org/10.1111/bph.12906.

28. Wang, C. S., Kavalali, E. T., and Monteggia, L. M. (2022) BDNF signaling in context: From synaptic regulation to

psychiatric disorders, Cell, 185, 62-76, https://doi.org/10.1016/j.cell.2021.12.003.

29. Kowiański, P., Lietzau, G., Czuba, E., Waśkow, M., Steliga, A., and Moryś, J. (2018) BDNF: A key factor with

multipotent impact on brain signaling and synaptic plasticity, Cell. Mol. Neurobiol., 38, 579-593, https://doi.org/

10.1007/s10571-017-0510-4.

30. Barde, Y. A. (2025) The physiopathology of brain-derived neurotrophic factor, Physiol. Rev., 105, 2073-2140,

https://doi.org/10.1152/physrev.00038.2024.

31. Tessarollo, L., and Yanpallewar, S. (2022) TrkB truncated isoform receptors as transducers and determinants of

BDNF functions, Front. Neurosci., 16, 847572, https://doi.org/10.3389/fnins.2022.847572.

32. Conner, J. M., Lauterborn, J. C., Yan, Q., Gall, C.M., and Varon, S. (1997) Distribution of brain-derived neurotroph-

ic factor (BDNF) protein and mRNA in the normal adult rat CNS: Evidence for anterograde axonal transport,

J. Neurosci., 17, 2295-2313, https://doi.org/10.1523/JNEUROSCI.17-07-02295.1997.

33. Yan, Q., Radeke, M. J., Matheson, C. R., Talvenheimo, J., Welcher, A. A., and Feinstein, S. C. (1997) Immunocy-

tochemical localization of TrkB in the central nervous system of the adult rat, J.Comp. Neurol., 378, 135-157,

https://doi.org/10.1002/(SICI)1096-9861(19970203)378:1<135::AID-CNE8>3.3.CO;2-9.

34. Lerner, T. N., and Kreitzer, A. C. (2011) Neuromodulatory control of striatal plasticity and behavior, Curr. Opin.

Neurobiol., 21, 322-327, https://doi.org/10.1016/j.conb.2011.01.005.

35. Jia, Y., Gall, C. M., and Lynch, G. (2010) Presynaptic BDNF promotes postsynaptic long-term potentiation in the

dorsal striatum, J. Neurosci., 30, 14440-14445, https://doi.org/10.1523/JNEUROSCI.3310-10.2010.

36. Toader, C., Serban, M., Munteanu, O., Covache-Busuioc, R. A., Enyedi, M., Ciurea, A. V., and Tataru, C. P. (2025)

From synaptic plasticity to neurodegeneration: BDNF as a transformative target in medicine, Int. J. Mol. Sci.,

26, 4271, https://doi.org/10.3390/ijms26094271.

ALSALLOUM et al.652

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

37. Gangarossa, G., Perez, S., Dembitskaya, Y., Prokin, I., Berry, H., and Venance, L. (2020) BDNF controls bidirec-

tional endocannabinoid plasticity at corticostriatal synapses, Cereb. Cortex, 30, 197-214, https://doi.org/10.1093/

cercor/bhz081.

38. Hasbi, A., Fan, T., Alijaniaram, M., Nguyen, T., Perreault, M. L., O’Dowd, B. F., and George, S. R. (2009) Calcium

signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth,

Proc. Natl. Acad. Sci. USA, 106, 21377-21382, https://doi.org/10.1073/pnas.0903676106.

39. Iwakura, Y., Nawa, H., Sora, I., and Chao, M. V. (2008) Dopamine D1 receptor-induced signaling through TrkB

receptors in striatal neurons, J.Biol. Chem., 283, 15799-15806, https://doi.org/10.1074/jbc.M801553200.

40. Perreault, M. L., Hasbi, A., O’Dowd, B. F., and George, S. R. (2014) Heteromeric dopamine receptor signal-

ing complexes: emerging neurobiology and disease relevance, Neuropsychopharmacology, 39, 156-168, https://

doi.org/10.1038/npp.2013.148.

41. Blöchl, A., and Sirrenberg, C. (1996) Neurotrophins stimulate the release of dopamine from rat mesencephal-

ic neurons via Trk and p75(LNTR) receptors, J.Biol. Chem., 271, 21100-21107, https://doi.org/10.1074/jbc.271.

35.21100.

42. Bastioli, G., Arnold, J. C., Mancini, M., Mar, A. C., Gamallo-Lana, B., Saadipour, K., Chao, M. V., and Rice, M. E.

(2022) Voluntary exercise boosts striatal dopamine release: Evidence for the necessary and sufficient role of

BDNF, J. Neurosci., 42, 4725-4736, https://doi.org/10.1523/JNEUROSCI.2273-21.2022.

43. Hodges, H., Fealko, C., and Soares, N. (2020) Autism spectrum disorder: definition, epidemiology, causes, and

clinical evaluation, Transl. Pediatr., 9, S55-S65, https://doi.org/10.21037/tp.2019.09.09.

44. Pavăl, D. (2023) The dopamine hypothesis of autism spectrum disorder: A comprehensive analysis of the evi-

dence, Int. Rev. Neurobiol., 173, 1-42, https://doi.org/10.1016/bs.irn.2023.08.009.

45. Pavăl, D. (2017) A dopamine hypothesis of autism spectrum disorder, Dev. Neurosci., 39, 355-360, https://

doi.org/10.1159/000478725.

46. Pavăl, D., and Micluția, I. V. (2021) The dopamine hypothesis of autism spectrum disorder revisited: current

status and future prospects, Dev. Neurosci., 43, 73-83, https://doi.org/10.1159/000515751.

47. Yang, F., You, H., Mizui, T., Ishikawa, Y., Takao, K., Miyakawa, T., Li, X., Bai, T., Xia, K., Zhang, L., Pang, D.,

Xu, Y., Zhu, C., Kojima, M., and Lu, B. (2024) Inhibiting proBDNF to mature BDNF conversion leads to ASD-like

phenotypes in vivo, Mol. Psychiatry, 29, 3462-3474, https://doi.org/10.1038/s41380-024-02595-5.

48. Chao, O. Y., Pathak, S. S., Zhang, H., Dunaway, N., Li, J., Mattern, C., Nikolaus, S., Huston, J. P., and Yang, Y.-M.

(2020) Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse

models of autism, Mol. Brain, 13, 111, https://doi.org/10.1186/s13041-020-00649-7.

49. Squillace, M., Dodero, L., Federici, M., Migliarini, S., Errico, F., Napolitano, F., Krashia, P., Maio, A. D.,

Galbusera, A., Bifone, A., Scattoni, M. L., Pasqualetti, M., Mercuri, N. B., Usiello, A., and Gozzi, A. (2014) Dysfunc-

tional dopaminergic neurotransmission in asocial BTBR mice, Transl. Psychiatry, 4, e427, https://doi.org/10.1038/

tp.2014.69.

50. Bove, M., Palmieri, M. A., Santoro, M., Agosti, L.P., Gaetani, S., Romano, A., Dimonte, S., Costantino, G., Sikora,V.,

Tucci, P., Schiavone, S., Morgese, M. G., and Trabace, L. (2024) Amygdalar neurotransmission alterations in the

BTBR mice model of idiopathic autism, Transl. Psychiatry, 14, 193, https://doi.org/10.1038/s41398-024-02905-z.

51. Pravikova, P. D., Arssan, M. A., Zalivina, E. A., Kondaurova, E. M., Kulikova, E. A., Belokopytova, I. I., and

Naumenko, V. S. (2024) Dopamine receptors and key elements of the neurotrophins (BDNF, CDNF) expression

patterns during critical periods of ontogenesis in the brain structures of mice with autism-like behavior (BTBR)

or its absence (C57BL/6J), Vavilov J. Genet. Breed., 28, 407-415, https://doi.org/10.18699/vjgb-24-46.

52. Kaminskaya, Y. P., Ilchibaeva, T. V., Khotskin, N. V., Naumenko, V. S., and Tsybko, A. S. (2023) Effect of hippo-

campal overexpression of dopamine neurotrophic factor (CDNF) on behavior of mice with genetic predisposition

to depressive-like behavior, Biochemistry (Moscow), 88, 1070-1091, https://doi.org/10.1134/S0006297923080035.

53. Eesmaa, A., Yu, L.-Y., Göös, H., Danilova, T., Nõges, K., Pakarinen, E., Varjosalo, M., Lindahl, M., Lindholm, P., and

Saarma, M. (2022) CDNF interacts with ER chaperones and requires UPR sensors to promote neuronal survival,

Int. J. Mol. Sci., 23, 9489, https://doi.org/10.3390/ijms23169489.

54. An, J., Zhang, X., Jia, K., Zhang, C., Zhu, L., Cheng, M., Li, F., Zhao, S., and Hao, J. (2021) Trichostatin A increases

BDNF protein expression by improving XBP-1s/ATF6/GRP78 axis in Schwann cells of diabetic peripheral neurop-

athy, Biomed. Pharmacother., 133, 111062, https://doi.org/10.1016/j.biopha.2020.111062.

55. Saito, A., Cai, L., Matsuhisa, K., Ohtake,Y., Kaneko, M., Kanemoto, S., Asada, R., and Imaizumi, K. (2018) Neuronal

activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived

neurotrophic factor in cell soma, J. Neurochem., 144, 35-49, https://doi.org/10.1111/jnc.14221.

56. Martínez, G., Vidal, R. L., Mardones, P., Serrano, F. G., Ardiles, A. O., Wirth, C., Valdés, P., Thielen, P., Schneider,

B. L., Kerr, B., Valdés, J. L., Palacios, A. G., Inestrosa, N. C., Glimcher, L. H., and Hetz, C. (2016) Regulation

CROSSTALK BETWEEN DOPAMINE AND BDNF 653

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

of memory formation by the transcription factor XBP1, Cell Rep., 14, 1382-1394, https://doi.org/10.1016/

j.celrep.2016.01.028.

57. Lee, Y., and Han, P. L. (2019) Early-life stress in D2 heterozygous mice promotes autistic-like behaviors through

the downregulation of the BDNF-TrkB pathway in the dorsal striatum, Exp. Neurobiol., 28, 337-351, https://

doi.org/10.5607/en.2019.28.3.337.

58. Wearick-Silva, L. E., Orso, R., Martins, L. A., Creutzberg, K. C., Centeno-Silva, A., Xavier, L. L., Grassi-Oliveira, R.,

and Mestriner, R. G. (2019) Dual influences of early life stress induced by limited bedding on walking adapt-

ability and Bdnf/TrkB and Drd1/Drd2 gene expression in different mouse brain regions, Behav. Brain Res., 359,

66-72, https://doi.org/10.1016/j.bbr.2018.10.025.

59. Aljead, M., Qashta, A., Jalal, Z., and Jones, A. M. (2025) Review of autism spectrum disorder (ASD): Epidemiology,

aetiology, pathology, and pharmacological treatment, Pharmaceuticals (Basel), 18, 1644, https://doi.org/10.3390/

ph18111644.

60. Hellings, J. A., Arnold, L. E., and Han, J. C. (2017) Dopamine antagonists for treatment resistance in autism

spectrum disorders: Review and focus on BDNF stimulators loxapine and amitriptyline, Expert Opin. Pharma-

cother., 18, 581-588, https://doi.org/10.1080/14656566.2017.1308483.

61. Hellings, J. (2023) Pharmacotherapy in autism spectrum disorders, including promising older drugs warranting

trials, World J. Psychiatry, 13, 262-277, https://doi.org/10.5498/wjp.v13.i6.262.

62. Dobrosavljevic, M., Larsson, H., and Cortese, S. (2023) The diagnosis and treatment of attention-deficit hyper-

activity disorder (ADHD) in older adults, Expert Rev. Neurother., 23, 883-893, https://doi.org/10.1080/14737175.

2023.2250913.

63. Sharma, A., and Couture, J. (2014) A review of the pathophysiology, etiology, and treatment of attention-deficit

hyperactivity disorder (ADHD), Ann. Pharmacother., 48, 209-225, https://doi.org/10.1177/1060028013510699.

64. Liu, D. Y., Shen, X. M., Yuan, F. F., Guo, O. Y., Zhong, Y., Chen, J. G., Zhu, L. Q., and Wu, J. (2015) The phys-

iology of BDNF and its relationship with ADHD, Mol. Neurobiol., 52, 1467-1476, https://doi.org/10.1007/s12035-

014-8956-6.

65. Demirci, E., Gül, M. K., Sener, E. F., Onal, M. G., and Dal, F. (2024) Assessment of BDNF and sialic acid lev-

els in children with ADHD: Relation of chronotypes, Int. J. Dev. Neurosci., 84, 857-866, https://doi.org/10.1002/

jdn.10376.

66. Kim, H., Heo, H. I., Kim, D. H., Ko, I. G., Lee, S. S., Kim, S. E., Kim, B. K., Kim, T. W., Ji, E. S., Kim, J. D.,

Shin, M. S., Choi, Y. W., and Kim, C. J. (2011) Treadmill exercise and methylphenidate ameliorate symptoms

of attention deficit/hyperactivity disorder through enhancing dopamine synthesis and brain-derived neuro-

trophic factor expression in spontaneous hypertensive rats, Neurosci. Lett., 504, 35-39, https://doi.org/10.1016/

j.neulet.2011.08.052.

67. Leo, D., Sukhanov, I., Zoratto, F., Illiano, P., Caffino, L., Sanna, F., Messa, G., Emanuele, M., Esposito, A.,

Dorofeikova, M., Budygin, E. A., Mus, L., Efimova, E., Niello, M., Espinoza, S., Sotnikova, T. D., Hoener, M. C.,

Laviola, G., Fumagalli, F., Adriani, W., and Gainetdinov, R. R. (2018) Pronounced hyperactivity, cognitive dys-

functions, and BDNF dysregulation in dopamine transporter knock-out rats, J. Neurosci., 38, 1959-1972, https://

doi.org/10.1523/JNEUROSCI.1931-17.2018.

68. Fumagalli, F., Racagni, G., Colombo, E., and Riva, M. A. (2003) BDNF gene expression is reduced in the fron-

tal cortex of dopamine transporter knockout mice, Mol. Psychiatry, 8, 898-899, https://doi.org/10.1038/sj.mp.

4001370.

69. Nam, Y., Shin, E. J., Shin, S. W., Lim, Y. K., Jung, J. H., Lee, J. H., Ha, J. R., Chae, J. S., Ko, S. K., Jeong, J. H.,

Jang, C. G., and Kim, H. C. (2014) YY162 prevents ADHD-like behavioral side effects and cytotoxicity induced

by Aroclor1254 via interactive signaling between antioxidant potential, BDNF/TrkB, DAT and NET, Food Chem.

Toxicol., 65, 280-292, https://doi.org/10.1016/j.fct.2013.12.046.

70. Yaqun, L., Haixia, Y., Yuchen, S., Mingxin, Z., Manqi, L., Yunlong, T., Aizhen, W., and Xinmin, H. (2022) An Shen

Ding Zhi Ling ameliorates the symptoms of attention deficit hyperactivity disorder via modulating brain-de-

rived neurotrophic factor-related signaling pathways, Evid. Based Complement. Alternat. Med., 2022, https://

doi.org/10.1155/2022/5471586.

71. Bosse, K. E., Maina, F. K., Birbeck, J. A., France, M. M., Roberts, J. J., Colombo, M. L., and Mathews, T. A. (2012)

Aberrant striatal dopamine transmitter dynamics in brain-derived neurotrophic factor-deficient mice, J. Neuro-

chem., 120, 385-395, https://doi.org/10.1111/j.1471-4159.2011.07531.x.

72. Matsuzaki, K., Sugimoto, N., Hossain, S., Islam, R., Sumiyoshi, E., Hashimoto, M., Kishi, H., and Shido, O.

(2024) Theobromine improves hyperactivity, inattention, and working memory via modulation of dopaminergic

neural function in the frontal cortex of spontaneously hypertensive rats, Food Funct., 15, 5579-5595, https://

doi.org/10.1039/d4fo00683f.

ALSALLOUM et al.654

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

73. Li, H. B., Xu, M. L., Xia, W. J., Dong, Y. Y., Peng, B., Su, Q., Wang, X. M., Yu, J. Y., Gao, Y. N., Wu, J. Z., Xu, M. Y.,

Yang, J. B., Dai, Z. M., Chen, L., Li, Y., and Bai, J. (2024) Antihypertensive treatment during pregnancy induces

long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring,

Toxicol. Appl. Pharmacol., 486, 116946, https://doi.org/10.1016/j.taap.2024.116946.

74. Kahn, R. S., Sommer, I. E., Murray, R. M., Meyer-Lindenberg, A., Weinberger, D. R., Cannon, T. D., O’Donovan, M.,

Correll, C. U., Kane, J. M., Van Os, J., and Insel, T. R. (2015) Schizophrenia, Nat. Rev. Dis. Prim., 1, 15067, https://

doi.org/10.1038/nrdp.2015.67.

75. Marenco, S., and Weinberger, D.R. (2000) The neurodevelopmental hypothesis of schizophrenia: Following a trail

of evidence from cradle to grave, Dev. Psychopathol., 12, 501-527, https://doi.org/10.1017/S0954579400003138.

76. Murray, R. M., Bhavsar, V., Tripoli, G., and Howes, O. (2017) 30 years on: How the neurodevelopmental hypothesis

of schizophrenia morphed into the developmental risk factor model of psychosis, Schizophr. Bull., 43, 1190-1196,

https://doi.org/10.1093/schbul/sbx121.

77. Insel, T. R. (2010) Rethinking schizophrenia, Nature, 468, 187-193, https://doi.org/10.1038/nature09552.

78. Egerton, A., Grace, A. A., Stone, J., Bossong, M. G., Sand, M., and McGuire, P. (2020) Glutamate in schizophre-

nia: Neurodevelopmental perspectives and drug development, Schizophr. Res., 223, 59-70, https://doi.org/10.1016/

j.schres.2020.09.013.

79. Fatemi, S.H., and Folsom, T. D. (2009) The neurodevelopmental hypothesis of schizophrenia, revisited, Schizophr.

Bull., 35, 528-548, https://doi.org/10.1093/schbul/sbn187.

80. Ijomone, O. K., Oria, R. S., Ijomone, O. M., Aschner, M., and Bornhorst, J. (2024) Dopaminergic perturbation in

the aetiology of neurodevelopmental disorders, Mol. Neurobiol., 62, 2420-2434, https://doi.org/10.1007/s12035-

024-04418-8.

81. Favalli, G., Li, J., Belmonte-de-Abreu, P., Wong, A. H. C., and Daskalakis, Z. J. (2012) The role of BDNF in

the pathophysiology and treatment of schizophrenia, J. Psychiatr. Res., 46, 1-11, https://doi.org/10.1016/

j.jpsychires.2011.09.022.

82. Peng, S., Li, W., Lv, L., Zhang, Z., and Zhan, X. (2018) BDNF as a biomarker in diagnosis and evaluation of

treatment for schizophrenia and depression, Discov. Med., 26, 127-136.

83. Morozova, A., Ushakova, V., Pavlova, O., Bairamova, S., Andryshenko, N., Ochneva, A., Abramova, O., Zorkina, Y.,

Spektor, V. A., Gadisov, T., Ukhov, A., Zubkov, E., Solovieva, K., Alexeeva, P., Khobta, E., Nebogina, K., Kozlov, A.,

Klimenko, T., Gurina, O., Shport, S., Kostuyk, G., Chekhonin, V., and Pavlov, K. (2024) BDNF, DRD4, and HTR2A

gene allele frequency distribution and association with mental illnesses in the European part of Russia, Genes,

15, 240, https://doi.org/10.3390/genes15020240.

84. Guillin, O., Demily, C., and Thibaut, F. (2007) Brain-derived neurotrophic factor in schizophrenia and its relation

with dopamine, Int. Rev. Neurobiol., 78, 377-395, https://doi.org/10.1016/S0074-7742(06)78012-6.

85. Abi-Dargham, A., Mawlawi, O., Lombardo, I., Gil, R., Martinez, D., Huang, Y., Hwang, D.-R., Keilp, J., Kochan, L.,

Van Heertum,R., Gorman, J.M., and Laruelle,M. (2002) Prefrontal dopamine D1 receptors and working memory

in schizophrenia, J. Neurosci., 22, 3708-3719, https://doi.org/10.1523/JNEUROSCI.22-09-03708.2002.

86. Gurevich, E. V., Bordelon, Y., Shapiro, R. M., Arnold, S. E., Gur, R. E., and Joyce, J. N. (1997) Mesolimbic dopa-

mine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study, Arch. Gen.

Psychiatry, 54, 225-232, https://doi.org/10.1001/archpsyc.1997.01830150047009.

87. Striebel, J. M. (2024) What is schizophrenia – symptomatology, CNS Spectr., 30, e12, https://doi.org/10.1017/

S1092852924000622.

88. Guillin, O., Diaz, J., Carroll, P., Griffon, N., Schwartz, J. C., and Sokoloff, P. (2001) BDNF controls dopamine

D3 receptor expression and triggers behavioural sensitization, Nature, 411, 86-89, https://doi.org/10.1038/

35075076.

89. Wang, H., Xu, J., Lazarovici, P., Quirion, R., and Zheng, W. (2018) cAMP response element-binding protein (CREB):

a possible signaling molecule link in the pathophysiology of schizophrenia, Front. Mol. Neurosci., 11, 255, https://

doi.org/10.3389/fnmol.2018.00255.

90. Chandra, J. J., Zhu, Y., Petty, A., Kostoglou, Y., Haynes, W. X., Webster, M. J., and Weickert, C. S. (2025) Tran-

scriptional evidence of reduced BDNF trophic capacity in the post-mortem human midbrain of schizophrenia

cases with high inflammation, Transl. Psychiatry, 15, 162, https://doi.org/10.1038/s41398-025-03359-7.

91. Sierakowska, A., Niewiadomska, E., Łabuda, S., Bieniasiewicz, A., Roszak, M., and Łabuz-Roszak, B. (2025) Bio-

markers in schizophrenia: current approaches and new developments – a literature review, Behav. Neurol.,

2025, 2991323, https://doi.org/10.1155/bn/2991323.

92. Cheng, J., Wu, C., Wang, Y., Wang, Z., He, Y., and Shen, J. (2024) The antidepressant-like effect and proposed

mechanism of action of TPN672MA, a novel serotonin-dopamine receptor modulator for the treatment of schizo-

phrenia, Pharmacol. Biochem. Behav., 242, 173809, https://doi.org/10.1016/j.pbb.2024.173809.

CROSSTALK BETWEEN DOPAMINE AND BDNF 655

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

93. Zhu, D. M., Lu, Y., Xiao, X. D., Sun, Y., Tao, G., Long, B., and Zhao, J. (2025) Enhancing schizophrenia treatment

efficacy: The combined impact of Yueju pill and olanzapine through quercetin target modulation, World J.

Psychiatry, 15, 101658, https://doi.org/10.5498/wjp.v15.i10.101658.

94. Hayes, M. T. (2019) Parkinson’s disease and parkinsonism, Am. J. Med., 132, 802-807, https://doi.org/10.1016/

j.amjmed.2019.03.001.

95. Huang, Y., Yun, W., Zhang, M., Luo, W., and Zhou, X. (2018) Serum concentration and clinical significance of

brain-derived neurotrophic factor in patients with Parkinson’s disease or essential tremor, J.Int. Med. Res., 46,

1477-1485, https://doi.org/10.1177/0300060517748843.

96. Palasz, E., Wysocka, A., Gasiorowska, A., Chalimoniuk, M., Niewiadomski, W., and Niewiadomska, G. (2020)

BDNF as a promising therapeutic agent in Parkinson’s disease, Int. J. Mol. Sci., 21, 1170, https://doi.org/

10.3390/ijms21031170.

97. Andreska, T., Lüningschrör, P., Wolf, D., McFleder, R. L., Ayon-Olivas, M., Rattka, M., Drechsler, C., Perschin, V.,

Blum, R., Aufmkolk, S., Granado, N., Moratalla, R., Sauer, M., Monoranu, C., Volkmann, J., Ip, C. W., Stigloher, C.,

and Sendtner, M. (2023) DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal

medium spiny neurons, Cell Rep., 42, 112575, https://doi.org/10.1016/j.celrep.2023.112575.

98. Ayon-Olivas, M., Wolf, D., Andreska, T., Granado, N., Lüningschrör, P., Ip, C. W., Moratalla, R., and Sendtner, M.

(2023) Dopaminergic input regulates the sensitivity of indirect pathway striatal spiny neurons to brain-derived

neurotrophic factor, Biology (Basel), 12, 1360, https://doi.org/10.3390/biology12101360.

99. Pelosi, A., Nakamura, Y., Girault, J. A., and Hervé, D. (2023) BDNF/TrkB pathway activation in D1 receptor-ex-

pressing striatal projection neurons plays a protective role against L-DOPA-induced dyskinesia, Neurobiol. Dis.,

185, 106238, https://doi.org/10.1016/j.nbd.2023.106238.

100. Razgado-Hernandez, L. F., Espadas-Alvarez, A. J., Reyna-Velazquez, P., Sierra-Sanchez, A., Anaya-Martinez, V.,

Jimenez-Estrada, I., Bannon, M. J., Martinez-Fong, D., and Aceves-Ruiz, J. (2015) The transfection of BDNF to

dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation,

dendritic spines and motor behavior in an aged rat model of Parkinson’s disease, PLoS One, 10, e0117391,

https://doi.org/10.1371/journal.pone.0117391.

101. Zeng, W., Wang, Y., Liu, Y., Liu,X., and Qi, Z. (2025) Garlic-derived allicin attenuates Parkinson’s disease via PKA/

p-CREB/BDNF/DAT pathway activation and apoptotic inhibition, Molecules (Basel), 30, 3265, https://doi.org/10.3390/

molecules30153265.

102. Benítez-Castañeda, A., Anaya-Martínez,V., Espadas-Alvarez, A. J., Gutierrez-Váldez, A.L., Razgado-Hernández,L. F.,

Reyna-Velazquez, P. E., Quintero-Macias, L., Martínez-Fong, D., Florán-Garduño, B., and Aceves, J. (2024) Trans-

fection of the BDNF gene in the surviving dopamine neurons in conjunction with continuous administration of

pramipexole restores normal motor behavior in a bilateral rat model of Parkinson’s disease, Parkinson’s Dis.,

2024, 3885451, https://doi.org/10.1155/2024/3885451.

103. Schachter, A. S., and Davis, K. L. (2000) Alzheimer’s disease, Dialogues Clin. Neurosci., 2, 91-100, https://

doi.org/10.31887/DCNS.2000.2.2/asschachter.

104. Bozzali, M., D’Amelio, M., and Serra, L. (2019) Ventral tegmental area disruption in Alzheimer’s disease, Aging,

11, 1325-1326, https://doi.org/10.18632/aging.101852.

105. Kang, S., Jeon, S., Lee, Y.-G., and Ye, B. S. (2023) Striatal dopamine transporter uptake, parkinsonism and cog-

nition in Alzheimer’s disease, Eur. J. Neurol., 30, 3105-3113, https://doi.org/10.1111/ene.15995.

106. Perkovic, M. N., Strac, D. S., Tudor, L., Konjevod, M., Erjavec, G. N., and Pivac, N. (2018) Catechol-O-methyltrans-

ferase, cognition and Alzheimer’s disease, Curr. Alzheimer Res., 15, 408-419, https://doi.org/10.2174/15672050156

66171212094229.

107. Amidfar, M., de Oliveira, J., Kucharska, E., Budni, J., and Kim, Y.-K. (2020) The role of CREB and BDNF in neu-

robiology and treatment of Alzheimer’s disease, Life Sci., 257, 118020, https://doi.org/10.1016/j.lfs.2020.118020.

108. Gao, L., Zhang, Y., Sterling, K., and Song, W. (2022) Brain-derived neurotrophic factor in Alzheimer’s disease

and its pharmaceutical potential, Transl. Neurodegener., 11, 4, https://doi.org/10.1186/s40035-022-00279-0.

109. Wang, W., Li, Y., Ma, F., Sheng, X., Chen, K., Zhuo, R., Wang, C., Zheng, H., Zhang, Y. W., Bu, G., Chen, X. F.,

and Zhong, L. (2023) Microglial repopulation reverses cognitive and synaptic deficits in an Alzheimer’s dis-

ease model by restoring BDNF signaling, Brain Behav. Immun., 113, 275-288, https://doi.org/10.1016/j.bbi.

2023.07.011.

110. Pahlavani, H. A. (2023) Exercise therapy to prevent and treat Alzheimer’s disease, Front. Aging Neurosci., 15,

1243869, https://doi.org/10.3389/fnagi.2023.1243869.

111. Ciampa, C. J., Morin, T. M., Murphy, A., Joie, R. L., Landau, S. M., and Berry, A. S. (2024) DAT1 and BDNF

polymorphisms interact to predict Aβ and tau pathology, Neurobiol. Aging, 133, 115-124, https://doi.org/10.1016/

j.neurobiolaging.2023.10.009.

ALSALLOUM et al.656

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

112. Ottonelli, I., Sharma, A., Ruozi,B., Tosi,G., Duskey, J. T., Vandelli, M.A., Lafuente, J. V., Nozari, A., Muresanu, D.F. ,

Buzoianu, A. D., Tian, Z. R., Zhang, Z., Li, C., Feng, L., Wiklund, L., and Sharma, H. S. (2023) Nanowired deliv-

ery of curcumin attenuates methamphetamine neurotoxicity and elevates levels of dopamine and brain-derived

neurotrophic factor, Adv. Neurobiol., 32, 385-416, https://doi.org/10.1007/978-3-031-32997-5_10.

113. Choung, J. S., Kim, J. M., Ko, M. H., Cho, D. S., and Kim, M. (2021) Therapeutic efficacy of repetitive tran-

scranial magnetic stimulation in an animal model of Alzheimer’s disease, Sci. Rep., 11, 437, https://doi.org/

10.1038/s41598-020-80147-x.

114. Greener, M. R., and Storr, S. J. (2022) Exploring the role of DARPP-32 in addiction: A review of the current

limitations of addiction treatment pathways and the role of DARPP-32 to improve them, NeuroSci., 3, 494-509,

https://doi.org/10.3390/neurosci3030035.

115. Peregud, D., Baronets, V., Pavlova, O., and Pavlov, K. (2025) BDNF gene polymorphisms and substance use dis-

orders: a systematic review, Rev. Neurosci., 37, 141-188, https://doi.org/10.1515/revneuro-2025-0112.

116. Shen, B., Zhang, D., Zeng, X., Guan, L., Yang, G., Liu, L., Huang, J., Li, Y., Hong, S., and Li, L. (2022) Cannabidiol

inhibits methamphetamine-induced dopamine release via modulation of the DRD1-MeCP2-BDNF-TrkB signaling

pathway, Psychopharmacology (Berl.), 239, 1521-1537, https://doi.org/10.1007/s00213-021-06051-y.

117. Deng, J. V., Rodriguiz, R. M., Hutchinson, A. N., Kim, I. H., Wetsel, W. C., and West, A. E. (2010) MeCP2 in the

nucleus accumbens contributes to neural and behavioral responses to psychostimulants, Nat. Neurosci., 13,

1128-1136, https://doi.org/10.1038/nn.2614.

118. Grieder, T. E., Yee, M., Vargas-Perez, H., Maal-Bared, G., George, S., Ting-A-Kee, R., George, O., and van der

Kooy, D. (2022) Administration of BDNF in the ventral tegmental area produces a switch from a nicotine-non-

dependent D1R-mediated motivational state to a nicotine-dependent-like D2R-mediated motivational state, Eur.

J. Neurosci., 55, 714-724, https://doi.org/10.1111/ejn.15579.

119. Harrod, S. B., Lacy, R. T., Zhu, J., Hughes, B. A., Perna, M. K., and Brown, R. W. (2011) Gestational IV nicotine

produces elevated brain-derived neurotrophic factor in the mesocorticolimbic dopamine system of adolescent

rat offspring, Synapse (N. Y.), 65, 1382-1392, https://doi.org/10.1002/syn.20975.

120. Ren, Q., Ma, M., Yang, C., Zhang, J. C., Yao, W., and Hashimoto, K. (2015) BDNF-TrkB signaling in the nucleus

accumbens shell of mice has key role in methamphetamine withdrawal symptoms, Transl. Psychiatry, 5, e666,

https://doi.org/10.1038/tp.2015.157.

121. Peregud, D. I., Baronets, V. Y., Terebilina, N. N., and Gulyaeva, N. V. (2023) Role of BDNF in neuroplasticity as-

sociated with alcohol dependence, Biochemistry (Moscow), 88, 404-416, https://doi.org/10.1134/S0006297923030094.

122. Nikulina, E. M., Johnston, C. E., Wang, J., and Hammer, R. P., Jr. (2014) Neurotrophins in the ventral tegmental

area: role in social stress, mood disorders and drug abuse, Neuroscience, 282, 122-138, https://doi.org/10.1016/

j.neuroscience.2014.05.028.

123. Andersen, S. L., and Sonntag, K. C. (2014) Juvenile methylphenidate reduces prefrontal cortex plasticity via D3

receptor and BDNF in adulthood, Front. Synaptic Neurosci., 6, 1, https://doi.org/10.3389/fnsyn.2014.00001.

124. Ghasemian-Yadegari, J., Adineh, A., Mohammadi, H., Davari, S., Veisani, Y., Ghaneialvar, H., Aidy, A., Abbasi, N.,

and Karimi, E. (2024) Attenuation of cannabis withdrawal symptoms by Prosopis farcta extract, its luteolin and

melatonin in mice: Involvement of brain-derived neurotrophic factor and dopamine, Cell Biochem. Funct., 42,

e3980, https://doi.org/10.1002/cbf.3980.

125. Ngoufack, S. B. K., Ngoupaye, G. T., Kouémou, N. E., Noubouwo, J. C., and Foutsop, A. F. (2025) Graptophyllum

grandulosum prevents nicotine addiction in pubescent adolescent rats: Evidence on dopaminergic, cholinergic,

BDNF and neuroinflammatory pathways, Neurochem. Res., 50, 186, https://doi.org/10.1007/s11064-025-04436-5.

126. De Vry, J., Vanmierlo, T., Martínez-Martínez, P., Losen, M., Temel, Y., Boere, J., Kenis, G., Steckler, T.,

Steinbusch,  . W. M., Baets, M. D., and Prickaerts, J. (2016) TrkB in the hippocampus and nucleus accumbens

differentially modulates depression-like behavior in mice, Behav. Brain Res., 296, 15-25, https://doi.org/10.1016/

j.bbr.2015.08.027.

127. Eisch, A. J., Bolaños, C. A., De Wit, J., Simonak, R. D., Pudiak, C. M., Barrot, M., Verhaagen, J., and Nestler, E. J.

(2003) Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depres-

sion, Biol. Psychiatry, 54, 994-1005, https://doi.org/10.1016/j.biopsych.2003.08.003.

128. Nestler, E. J., and Carlezon, W. A. (2006) The mesolimbic dopamine reward circuit in depression, Biol. Psychiatry,

59, 1151-1159, https://doi.org/10.1016/j.biopsych.2005.09.018.

129. Pagliusi, M., Franco, D., Cole, S., Morais-Silva, G., Chandra, R., Fox, M. E., Iñiguez, S. D., Sartori, C. R., and

Lobo, M. K. (2022) The BDNF-TrkB pathway acts through nucleus accumbens D2 expressing neurons to mediate

stress susceptible outcomes, Front. Psychiatry, 13, 854494, https://doi.org/10.3389/fpsyt.2022.854494.

130. Abdullina, A. A., Vasileva, E. V., Kulikova, E. A., Naumenko, V. S., Plyusnina, A. V., Gudasheva, T. A.,

Kovalev, G. I., and Seredenin, S. B. (2022) The neuropeptide cycloprolylglycine produces antidepressant-like

CROSSTALK BETWEEN DOPAMINE AND BDNF 657

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

effect and enhances BDNF gene expression in the mice cortex, J. Psychopharmacol., 36, 214-222, https://

doi.org/10.1177/02698811211069101.

131. Naumenko, V. S., Kondaurova, E. M., Bazovkina, D. V., Tsybko, A. S., Tikhonova, M. A., Kulikov, A. V., and

Popova, N. K. (2012) Effect of brain-derived neurotrophic factor on behavior and key members of the brain

serotonin system in genetically predisposed to behavioral disorders mouse strains, Neuroscience, 214, 59-67,

https://doi.org/10.1016/j.neuroscience.2012.04.031.

132. Li, S. J., Lo, Y. C., Tseng, H. Y., Lin, S. H., Kuo, C. H., Chen, T. C., Chang, C. W., Liang, Y. W., Lin, Y. C., Wang, C. Y.,

Cho, T. Y., Wang, M. H., Chen, C. T., and Chen, Y. Y. (2023) Nucleus accumbens deep brain stimulation improves

depressive-like behaviors through BDNF-mediated alterations in brain functional connectivity of dopaminergic

pathway, Neurobiol. Stress, 26, 100566, https://doi.org/10.1016/j.ynstr.2023.100566.

133. Jelen, L. A., Young, A. H., and Stone, J. M. (2021) Ketamine: A tale of two enantiomers, J. Psychopharmacol., 35,

109-123, https://doi.org/10.1177/0269881120959644.

134. Swartz, H. A., and Suppes, T. (2023) Bipolar II disorder: Understudied and underdiagnosed, Focus, 21, 354-362,

https://doi.org/10.1176/appi.focus.20230015.

135. Huang, C. C., Chang, Y. H., Lee, S. Y., Chen, S. L., Chen, S. H., Chu, C. H., Huang, S. Y., Tzeng, N. S., Lee, I. H.,

Yeh, T. L., Yang, Y. K., and Lu, R. B. (2012) The interaction between BDNF and DRD2 in bipolar II disorder but

not in bipolar I disorder, Am. J. Med. Genet. B. Neuropsychiatr. Genet., 159B, 501-507, https://doi.org/10.1002/

ajmg.b.32055.

136. Liu, C., and Kaeser, P. S. (2019) Mechanisms and regulation of dopamine release, Curr. Opin. Neurobiol., 57,

46-53, https://doi.org/10.1016/j.conb.2019.01.001.

137. Kingsbury, T. J., Murray, P. D., Bambrick, L. L., and Krueger, B. K. (2003) Ca2+-dependent regulation of TrkB

expression in neurons, J.Biol. Chem., 278, 40744-40748, https://doi.org/10.1074/jbc.M303082200.

138. Ahn, J. H., Jee, Y. S., McAvoy, T., Nishi, A., Janssens, V., Goris, J., Greengard, P., and Nairn, A. C. (2007) The B″/

PR72 subunit mediates Ca

-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A, Proc. Natl.

Acad. Sci. USA, 104, 9876-9881, https://doi.org/10.1073/pnas.0703589104.

139. Santini, E., Feyder, M., Gangarossa, G., Bateup, H. S., Greengard, P., and Fisone, G. (2012) Dopamine- and

cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated ki-

nase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism,

J. Biol. Chem., 287, 27806-27812, https://doi.org/10.1074/jbc.M112.388413.

140. Ilchibaeva, T., Tsybko, A., Zeug, A., Müller, F. E., Guseva, D., Bischoff, S., Ponimaskin, E., and Naumenko, V. (2022)

Serotonin receptor 5-HT2A regulates TrkB receptor function in heteroreceptor complexes, Cells, 11, 2384, https://

doi.org/10.3390/cells11152384.

141. Łukasiewicz, S., Polit, A., Kędracka-Krok, S., Wȩdzony, K., Mackowiak, M., and Dziedzicka-Wasylewska, M. (2010)

Hetero-dimerization of serotonin 5-HT2A and dopamine D2 receptors, Biochim. Biophys. Acta Mol. Cell Res.,

1803, 1347-1358, https://doi.org/10.1016/j.bbamcr.2010.08.010.

Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published

maps and institutional affiliations. AI tools may have been used in the translation or editing of this article.