Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 6, pp. 847-866 © Pleiades Publishing, Ltd., 2026.

847

REVIEW

Neuroinflammation, Glia–Neuron Crosstalk,

and Energy Metabolism in Alcohol Use Disorder

Valentin Yu. Skryabin

1,a

*, Svetlana I. Sokolova

, and Anton V. Masyakin

Moscow Research and Practical Centre on Addictions, Moscow Healthcare Department,

109390 Moscow, Russia

e-mail: sardonios@yandex.ru

Received November 24, 2025

Revised May 27, 2026

Accepted June 4, 2026

Abstract— Chronic alcohol and other psychoactive substance use is accompanied not only by disturbances

in classical neurotransmitter systems but also by persistent activation of innate and adaptive immunity,

leading to neuroinflammation. This review summarizes experimental and clinical data on how microglia

and astrocytes act as central mediators at the intersection of immune, metabolic, and neuronal processes

in alcohol-related disorders. We  discuss Toll-like receptor  4 (TLR4)-dependent pathways, activation of the

NLRP3 inflammasome, impaired glutamate clearance, metabolic “reprogramming” of glia, and mitochon-

drial dysfunction. These changes lead to energy deficiency, oxidative stress, and persistent remodeling of

reward, stress, and cognitive control networks. Particular attention is given to the impact of neuroinflam-

mation on dopaminergic, glutamatergic, GABAergic, and serotonergic neurotransmission, including the shift

of tryptophan metabolism toward the kynurenine pathway. We also consider the role of the gut–liver–brain

axis, dysbiosis, endotoxemia, systemic inflammation, and impaired production of short-chain fatty acids in

maintaining neuroimmune–metabolic stress. Contribution of hepatic and adipose tissue to the formation of

a chronic inflammatory milieu and its effect on blood–brain barrier (BBB) permeability is discussed. Based

on the combined data, the authors propose an integrative model of dependence as a state arising at the

intersection of disrupted neural signaling, disordered energy metabolism, and altered inter-organ commu-

nication. Promising therapeutic targets are outlined, including normalization of glial function, modulation

of the gut microbiota, reduction of systemic inflammation, and targeting energy metabolism. The need to

develop biomarker panels to identify subgroups of patients with the pronounced neuroinflammatory burden

is emphasized.

DOI: 10.1134/S0006297925604149

Keywords: alcohol use disorder, neuroinflammation, microglia, astrocytes, mitochondrial dysfunction, ky-

nurenine pathway

* To whom correspondence should be addressed.

INTRODUCTION

Chronic use of psychoactive substances (PS),

primarily alcohol, is increasingly viewed not only

as a consequence of imbalances in classical neu-

rotransmitter systems but also as a state associated

with persistent activation of innate and adaptive

immunity, leading to formation of sustained neu-

roinflammation in the brain structures responsible

for motivation, reward, and cognitive control [1, 2].

At the molecular level, this is reflected in activa-

tion of the TLR-dependent pathways, nuclear factor

kappa  B (NF-κB)-mediated transcription, changes in

the profile of pro- and anti-inflammatory cytokines,

and remodeling of the microglial and astrocytic phe-

notypes [1-3].

In alcohol use disorder (AUD), neuroimmune

changes are associated with the increased negative

affectivity, impaired stress-reactive axes, and height-

ened tendency toward relapse. This allows to consider

neuroinflammation as a key pathogenetic component

complementing classical dopaminergic and GABA

(gamma-aminobutyric acid) – glutamatergic models

of dependence [1, 2, 4].

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Fig.  1. Integrative scheme of the pathological cycle “neuroinflammation – energy deficit – neurotransmitter imbalance” in

alcohol use disorder. Activation of TLR4- and NLRP3-dependent pathways leads to production of pro-inflammatory cytokines

(IL-1β, TNF-α, IL-6), accompanied by mitochondrial dysfunction and reduction in the efficiency of the astrocyte–neuron

lactate shuttle (ANLS). The resulting energy deficit disrupts the balance of neurotransmitter systems (decreased dopamine,

GABA, and serotonin with increased glutamatergic activity), forming addictive behavior. Oxidative stress and inflammatory

signals maintain a self-sustaining pathological cycle through the positive feedback mechanisms.

Although many of the described mechanisms are

common to various classes of PS, alcohol has unique

neuroimmune–metabolic effects. First, ethanol and its

metabolite acetaldehyde activate the Toll-like recep-

tor  4 (TLR4)-associated signaling cascades, triggering

immune response without involvement of the classical

pathogen-associated molecular patterns. Second, hepa-

totoxic effect of alcohol creates a powerful additional

source of systemic inflammation (through activation

of Kupffer cells and endotoxemia), which is not char-

acteristic of stimulants or opioids. Third, the brain

acetate metabolism during prolonged alcohol use cre-

ates specific metabolic vulnerability during withdraw-

al. These features comprise the focus of this review

devoted to the alcohol-specific mechanisms; data on

other PS are provided only where they expand our

understanding of general mechanisms of dependence.

Central hypothesis of this review is as follows:

chronic alcohol use initiates a self-sustaining patho-

logical cycle in which primary activation of innate

immunity (via TLR4 and NLRP3 [NLR family pyrin

domain-containing  3]) disrupts energy metabolism of

glial cells, which, in turn, destabilizes neurotransmit-

ter homeostasis and synaptic plasticity. Peripheral or-

gans (intestine, liver, adipose tissue) amplify this cy-

cle through systemic inflammatory load and barrier

dysfunction. Itis this tripartite interaction – neuroin-

flammation, energy deficit, and inter-organ dysregu-

lation – that underlies the characteristic clinical pic-

ture of alcohol dependence: cognitive impairments,

affective dysregulation, and high tendency toward

relapse (Fig.  1).

Clinical and neuroimaging data confirm signifi-

cance of the neuroinflammatory processes in the clin-

ical context of addictions in humans. Meta-analysis of

the studies using PET with the translocator protein

(18  kDa) [TSPO] ligands, cerebrospinal fluid analysis,

and analysis of postmortem samples demonstrated

that the patients with AUD and associated cognitive

impairments exhibit elevated central markers of glial

activation. Severity of these changes correlates with

the severity of the clinical phenotype  [5]. Modern re-

views on neuroinflammation imaging in addictions

show that the changes in the TSPO binding, glial me-

tabolites, and indirect markers of microglial reactiv-

ity are observed not only in AUD but also in other

substance use disorders. These changes are associated

with impairments in affective regulation and impulse

control  [6].

At the same time, the neuroinflammatory cas-

cades are linked to the persistent white matter dam-

age, synaptic plasticity impairments, and deficits in

attention and executive functions, as confirmed by

both review studies on neuroimmune regulation in

alcohol dependence and systematic reviews focusing

on the relationship between the inflammatory mark-

ers and cognitive functioning in the patients with

AUD [1, 4].

A promising direction is the search for peripheral

markers of glial and neuronal damage associated not

just with the presence of the disease but with specific

cognitive domains. In the pilot clinical study of the

patients with AUD, serum levels of the calcium-bind-

ing protein (S100B) and myelin basic protein (MBP)

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

were elevated compared to the controls, while the

GFAP levels did not differ significantly  [7]. The S100B

levels correlated with the number of errors in the

Go/No-Go task and duration of the disorder, while

the MBP levels correlated with the impairments in

inhibitory control and a smaller volume of spatial

working memory. These data suggest that some se-

rum neuromarkers may be useful for identifying

subgroups of the patients with more pronounced ex-

ecutive deficits and, possibly, more severe neuroin-

flammatory-degenerative phenotype.

In this context, glial cells are considered not

as passive “supporting elements” but as key media-

tors between inflammation, metabolic pathways, and

neuronal network activity. The review on glial dys-

function in the substance use disorders shows that

chronic exposure to alcohol and other PS leads to

the persistent shift in microglial and astrocytic phe-

notypes toward a pro-inflammatory state, with subse-

quent remodeling of the synaptic transmission in the

reward and stress circuits  [3].

Experimental studies have shown that the

changes in metabolism of microglia and astrocytes –

switching between oxidative phosphorylation and

glycolysis, shifts in lactate and glutamate exchange –

serve as an important mechanism for maintaining

pathological excitability of the neuronal networks

during chronic inflammation  [8,  9]. Modern concept

of neuroimmunometabolism emphasizes close re-

lationship between the immune signals and energy

metabolism in the brain: cytokines, by activating

signaling pathways in glia, alter profile of the sub-

strate consumption and production of the lactate and

ketone bodies, while metabolic shifts, in turn, mod-

ulate strength and duration of the inflammatory re-

sponse  [8].

Classical and modern reviews on the brain en-

ergy metabolism emphasize that the sustained func-

tioning of neuronal networks is only possible with

preservation of cooperation between the neurons and

astrocytes, ensuring rapid transport and processing

of glucose, lactate, ketone bodies, and lipids  [9,  10].

Disorders of astrocytic metabolism, including dysreg-

ulation of the ANLS, are considered a common link in

the pathogenesis of a number of neurodegenerative

and mental disorders [10].

Although there is still little direct data on specific

impairments of this shuttle in the alcohol depen-

dence, experimental work on the metabolic “repro-

gramming” of microglia during neuroinflammation

demonstrates that its activation could change the ra-

tio of glucose- and lactate-dependent energy supply

to neurons and thus influence the nature of network

activity  [8]. Together, this forms a rational hypothesis

that in addictions, neuroinflammatory and metabolic

processes do not merely coexist but form a mutually

reinforcing system that affects stability of the patho-

logical behavior patterns.

Special attention in the context of AUD is drawn

to the tryptophan metabolism pathways through

the kynurenine cascade. A recent review on the

kynurenine pathway in alcohol dependence shows

that chronic alcohol use and associated inflammation

shift the balance from the serotonin pathway toward

production of kynurenine and its neurotoxic metabo-

lites, which is reflected in the regulation of the hypo-

thalamic–pituitary–adrenal (HPA) axis, glutamatergic

transmission, and vulnerability to relapse  [11].

A clinical study in young adults with alcohol

dependence and behavioral addictions demonstrat-

ed elevated levels of kynurenine and increased ky-

nurenine/tryptophan (KYN/TRP) ratio, along with the

decrease in kynurenic acid concentration, as well as

association between these indicators and levels of

stress, psychological resilience, and cognitive impair-

ments  [12]. These data strengthen the view of the ky-

nurenine pathway as a point of intersection between

the immune activation, stress, and neurotransmitter

system disorders in addictions.

Finally, in recent years, increasing attention has

been paid to the intestine and liver as the key sourc-

es of inflammatory and metabolic signals affecting

the brain in chronic alcohol use. Reviews on the gut–

liver–brain axis emphasize that the alcohol-induced

increased intestinal permeability, changes in micro-

biota, and endotoxemia trigger cascades of systemic

inflammation and metabolic stress, which, through

the cytokine and neuroendocrine mechanisms, con-

tribute to the development of neuroinflammation,

mood disorders, and cognitive dysfunctions [13, 14].

These works form an important background for

more narrowly focused clinical studies demonstrating

the link between endotoxemia and systemic inflam-

matory markers with the severity of withdrawal syn-

drome, structural and functional brain changes, and

the risk of adverse outcomes. Collectively, the data

on neuroimmune, metabolic, and peripheral somat-

ic mechanisms allow to consider neuroinflammation

in alcohol and other forms of dependence as a phe-

nomenon arising at the intersection of the disrupted

neural signaling, energy metabolism, and inter-organ

communication.

Clinical and biochemical studies performed in

Russia also confirm that systemic inflammation and

oxidative stress in alcohol dependence are not limited

to the short-term reaction to intoxication. In the ear-

ly post-abstinent period, the patients exhibit elevated

levels of protein carbonyls, TBARS-reactive products,

and a wide spectrum of pro-inflammatory cytokines,

including IFNγ, IL-1β, IL-6, IL-8, IL-17A, and TNFα,

while the 8-OH-dG levels do not differ from the

controls  [15]. Importantly, during two weeks of the

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standard therapy, normalization of the lipid oxida-

tion markers is not accompanied by the comparable

reduction in cytokine activity and in the amount of

carbonylated proteins. This suggests that after de-

toxification, some patients retain a relatively stable

inflammatory–oxidative phenotype, potentially asso-

ciated with the ongoing neuroimmune dysregulation,

clinical vulnerability, and relapse risk.

Additional clinical support comes from the data

on the dynamics of peripheral inflammation medi-

ators during formation of remission in the alcohol

dependence. It has been shown that in the early ab-

stinent period, the patients have elevated levels of

lipopolysaccharide (LPS)-binding protein, tumor ne-

crosis factor alpha (TNF-α), and IL-8; after standard

therapy, the levels of LPS-binding protein and TNF-α

decrease, while the IL-8 levels remain elevated even

in the remission  [16]. Importantly, higher level of LPS

in the abstinent period is associated with the less

pronounced reduction in craving during treatment,

and persistence of the elevated LPS in remission cor-

relates with the severity of pathological alcohol crav-

ing. These data allow considering the markers of in-

testinal permeability and systemic inflammation not

only as a reflection of somatic damage but also as

potential indicators of remission instability and risk

of early relapse.

Despite the significant number of reviews devot-

ed to neuroinflammation or metabolic disorders in

alcohol dependence, this work differs from the pre-

vious ones in several key aspects. First, unlike the

reviews focused on a single mechanism, we integrate

all three levels of pathogenesis – immune, metabolic,

and inter-organ – into a single conceptual model.

Second, the review emphasizes the alcohol-specific

patterns of neuroimmune–metabolic disorders. Third,

we attempt to systematize the data by taking into ac-

count the stage-dependent nature of dependence syn-

drome and identify biochemical targets differentiated

by these stages.

In the following sections of this review, we sys-

tematize the data on the cellular mechanisms of neu-

roinflammation in addictions, with focus on microglia

and astrocytes, neurotransmitter systems, and their

connection with the key metabolic cascades, includ-

ing energy metabolism, kynurenine pathway, and

gut–liver–brain axis, in order to outline potential bio-

chemical targets for prevention and therapy.

METHODOLOGY OF LITERATURE SEARCH

The literature search was conducted in the

PubMed/MEDLINE, Scopus, and Web of Science data-

bases. The following search queries were used (in var-

ious combinations): “alcohol use disorder”, “neuroin-

flammation”, “microglia”, “astrocytes”, “mitochondrial

dysfunction”, “kynurenine pathway”, “gut–liver–brain

axis”, “energy metabolism”, “NLRP3 inflammasome”,

“TLR4”. Additional searches were conducted using

keywords in Russian in the eLibrary database.

The time range covered works from 2000 to

2025, with special emphasis on publications from the

last 5 years (2020-2025).

Inclusion criteria: Experimental and clinical stud-

ies, systematic reviews, and meta-analyses directly

related to neuroimmune, metabolic, and glial mecha-

nisms in the alcohol-related disorders.

Exclusion criteria: Works unrelated to alcohol-as-

sociated mechanisms and studies based solely on the

behavioral outcomes without biochemical analysis.

This work is a narrative review. The PRISMA

guidelines were not applied, as no systematic review

or meta-analysis was conducted.

FUNCTIONING OF MICROGLIA

AND ASTROCYTES IN CHRONIC PS USE

Cellular mechanisms of neuroinflammation are

very important components of the pathogenesis of

addictions. Microglia and astrocytes play a key role

as active mediators of disrupted interactions between

the immune, metabolic, and neuronal signaling path-

ways.

Microglial cells are the primary target of ethanol

and other PS through activation of the Toll-like re-

ceptor  4 (TLR4), as demonstrated in both cell cultures

and models of chronic alcohol use  [17]. TLR4 activa-

tion triggers the MyD88- and TRIF-dependent signal-

ing cascades, leading to NF-κB translocation and pro-

duction of the pro-inflammatory cytokines – TNF-α,

IL-1β, and IL-6 – as well as increase in formation of

reactive oxygen species (ROS) [17, 18]. This is accom-

panied by polarization of microglia into a pro-inflam-

matory (M1-like) state and increase in their sensitiv-

ity to the repeated stimuli – a phenomenon known

as immune priming. With priming, the activation

threshold of cells decreases, leading to an enhanced

response to subsequent exposure  [19].

An additional, relatively rarely discussed level

of the alcohol-induced neuroinflammation is chemo-

kine regulation. Unlike the classical pro-inflammatory

cytokines, chemokines not only maintain the inflam-

matory response but also determine its spatial orga-

nization by regulating recruitment of immune cells,

microglial activation, and neuron–glia communica-

tion. Particular attention in this context is attracted

to the CCL2/CCR2 and CCL11 axes, as well as chang-

es in CXCL8, CXCL12, and CX3CL1. The summarized

data indicate that in alcohol dependence, the chemo-

kine imbalance is detected both in brain tissues

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and peripheral blood: increase in CCL2 in the num-

ber of limbic–mesencephalic structures, increased ex-

pression of a number of CC- and CXC-chemokines and

their receptors in the orbitofrontal cortex, decrease

in CXCL12 and CX3CL1 in plasma, and increase

in CCL11 with its subsequent decrease during detox-

ification have been reported, as well as association

of the changes with the severity of dependence [20].

The phenotypically activated microglia are not

limited to cytokine synthesis: they reshape synaptic

architecture and modify neuronal transmission. One

of the key mechanisms is disruption of the gluta-

mate homeostasis due to release of glutamate and

suppression of its clearance, which leads to the ex-

cessive neuronal excitability. In the work of Takaki

et al., the activated microglia were shown to release

L-glutamate and subsequently reduce expression of

the astrocytic transporter GLT-1/EAAT2 in the neu-

roinflammation model, leading to the increase in the

extracellular glutamate concentration  [21]. As empha-

sized in the review by Kettenmann et al., microglia

not only modulate glutamatergic transmission but

also directly participate in the synaptic pruning and

remodeling, thereby influencing configuration and ef-

ficiency of the neuronal networks  [22].

Experimental studies demonstrate that microglial

activation enhances the NMDA-mediated transmission

and disrupts the mechanisms of long-term potentia-

tion (LTP) and long-term depression (LTD) in the nu-

cleus accumbens and hippocampus, structures that

are critically important for formation of addictive be-

havior. In the work of Raghuraman et  al., microglial

activation in the freshly prepared hippocampal slices

exvivo (lipopolysaccharide, clodronate) led to the im-

pairment of LTP induction and maintenance, as well

as disruption of the mechanisms of synaptic tagging

and subsequent capture of the plasticity trace in the

CA1 region  [23]. It was shown by De  Felice et  al. that

pharmacological and genetic modulation of microg-

lia differently affects the amplitude of LTP along the

longitudinal axis of the hippocampus, emphasizing its

role in the fine-tuning of synaptic plasticity even in

the absence of pronounced signs of damage  [24].

The review by Nowak et al. generalizes the data

on mesocorticolimbic pathways and shows that mi-

croglia in the nucleus accumbens and the related

structures are involved in remodeling of glutamater-

gic plasticity under chronic stress and PS exposure,

forming a vulnerability to the development of sub-

stance use disorders  [25].

However, it is necessary to critically evaluate the

evidence base linking glial activation to behavioral

symptoms of dependence. The question of whether

the glial dysfunction is a cause of addictive behav-

ior or merely an associated manifestation remains

debatable. The most compelling arguments in favor

of a causal role come from the studies with selective

suppression of microglial function: pharmacological

depletion of the microglia population using PLX5622

(a CSF1R inhibitor) reduces ethanol consumption and

decreases severity of the withdrawal symptoms in a

number of models. Genetic approaches (TLR4 knock-

out and selective deletion of MyD88 in microglia)

also reduce the alcohol-associated behavior, indicat-

ing initiating rather than reactive role of microglia.

However, these data were obtained primarily in ro-

dents, and translation to humans requires caution.

The postmortem and PET data obtained in humans

demonstrate stable correlation between the severity

of glial activation and severity of the clinical pheno-

type, however, establishing the direction of causality

is fundamentally difficult with this material.

Experimental data also indicate a region-specific

nature of the alcohol-induced neuroinflammation. For

example, in the hippocampus of rats after 4 weeks of

ethanol exposure, the increased mRNA and protein

levels of IL-1β, decreased expression of TNF-α, IL-11,

Tlr3, and Tlr7, as well as reduction in the content of

a number of microRNAs functionally associated with

the Toll-like receptor system, including miR-let-7b,

miR-96, and miR-155, were detected. Notably, after

the ethanol withdrawal, the elevated levels of IL-1β

mRNA and protein, as well as increased expression of

Hmgb1, persisted, indicating incomplete reversibility

of the inflammatory shifts in the hippocampus in the

early withdrawal period  [26].

The obtained experimental data are consistent

with the results of translational studies. In the study

of postmortem samples by He and Crews, increase

in the number of Iba-1-positive microglia and expres-

sion of the pro-inflammatory markers in a number

of brain regions of the patients with alcohol depen-

dence compared to the controls were found  [27].

De  Carvalho et al. revealed increased transcription

of TSPO and associated regulatory molecules (HDAC2,

HDAC6) in the amygdala of the men with alcohol de-

pendence, which was interpreted as a reflection of

the sustained microglial and astrocytic activation  [28].

The PET study by Kalk et al. using the TSPO radioli-

gand showed changes in the TSPO signal in the hip-

pocampus of the patients with alcohol dependence

associated with memory impairments  [29]. In the

review by Nutt et al., these observations were inte-

grated into a broader concept in which the neuroin-

flammatory changes, including increased microglial

markers (Iba-1, TSPO), were associated with acceler-

ated “aging” of the brain and cognitive deficit in the

chronic alcohol use  [30].

No less important is the role of astrocytes, which

ensure energy exchange, neuron–glia communica-

tion, and glutamate clearance. Chronic alcohol use

is accompanied by neuroinflammation and oxidative

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stress, which leads to the decrease in expression

and activity of the astrocytic glutamate transporter

EAAT2 (in rodents – GLT-1). In the work of Othman

et al., it was shown that exposure of the astrocyte

cultures to ethanol dose-dependently reduced gluta-

mate uptake, indicating functional suppression of glu-

tamate transporters  [31]. In the experiment reported

by Alhaddad et  al., chronic ethanol consumption by

the alcohol-preferring rats was accompanied by the

decrease in expression of GLT-1 and a number of

proteins associated with neuroplasticity in the nu-

cleus accumbens [32]. The review by Rao and Sari

emphasizes that GLT-1/EAAT2 is a key regulator of

glutamate homeostasis and a promising therapeu-

tic target in the alcohol dependence  [33]. The works

of Olmos and Lladó, as well as of Berríos-Cárcamo

et  al., show that the pro-inflammatory cytokines and

oxidative stress additionally suppress expression of

EAAT2/GLT-1, contribute to extracellular glutamate

accumulation, and thus create prerequisites for ex-

citotoxicity and dysregulation of the NMDA-mediated

transmission  [34,  35].

However, astrocyte dysfunction in the chronic

alcohol use is not limited to the impaired glutamate

clearance. Increasing evidence suggests that during

inflammatory activation, the astrocytes undergo

metabolic reprogramming: they change the balance

between oxidative phosphorylation and glycoly-

sis, restructure lactate exchange, and alter the pat-

tern of metabolite transfer to neurons. The review

by Calì et al. shows that in pathological conditions

of the CNS, reactive astrocytes shift toward a more

glycolytic phenotype, which is accompanied by the

changes in expression of the glycolysis and TCA cy-

cle enzymes, as well as disruption of normal energy

exchange with neurons  [36]. The review by Zhang

et al. complements this picture, emphasizing that the

pathways of glucose and lactate utilization change in

neuroinflammation and reactive astrocytosis, which

directly affects the ability of astrocytes to supply syn-

aptic activity with energy  [37]. In a more recent re-

view by Joseph etal., it is shown that dysfunction of

astrocytic metabolism – including disorders of glycol-

ysis and lactate shuttle – leads to the decrease in the

lactate availability for neurons, energy deficit, and

imbalance of excitatory and inhibitory influences in

the neuronal networks  [38].

These data are critically important for under-

standing the nature of dependence, as the Astrocyte-

Neuron Lactate Shuttle (ANLS) is considered as one

of the key mechanisms of neuronal energy supply.

The review by Alberini and Cruz shows in detail that

glycogen and lactate from astrocytes provide energy

support to the neurons during intense synaptic ac-

tivity, and disorders in the ANLS are associated with

the decrease in efficiency of the synaptic plasticity

and cognitive impairment  [39]. In the classic work

by Suzuki et  al., it was shown that blocking lactate

transport from astrocytes to neurons disrupts forma-

tion of the long-term memory while preserves the

short-term memory, which directly indicates critical

role of ANLS in the long-term synaptic plasticity  [40].

The work by Descalzi et al. demonstrates that astro-

cytic lactate is necessary for supplying energy to the

learning-induced protein synthesis in the excitatory

and inhibitory neurons, and its deficiency leads to

the impaired memory consolidation  [41]. Finally, the

review by Bonvento and Bolaños shows that metabol-

ic cooperation between the astrocytes and neurons,

including lactate shuttle, directly shapes activity of

the neuronal networks and underlies regulation of

the behavior and reward  [42].

At the same time, mitochondrial functions of

glia suffer. Reviews on neuroimmunometabolism

show that microglial activation is accompanied by

the dysfunction of the electron transport chain, in-

creased production of reactive oxygen species (par-

ticularly superoxide), and changes in the NAD

/NADH

ratio. This shifts the energy metabolism of microglia

toward predominance of glycolysis over oxidative

phosphorylation and limits its energy reserves during

chronic inflammation [8, 43-45].

In astrocytes, chronic inflammation also leads

to mitochondrial dysfunction manifested as the de-

creased activity of TCA cycle enzymes, disrupted bal-

ance between oxidative phosphorylation and glycoly-

sis, and impaired ability of mitochondria to maintain

calcium ion homeostasis and adequate ATP produc-

tion. These shifts directly affect efficiency of gluta-

mate clearance and resistance of astrocytes to meta-

bolic stress [46, 47]. These processes are considered a

key link connecting peripheral and central inflamma-

tion with energy metabolism disorders in the brain.

At the integrative level, a sustained pathological

chain is formed: activation of microglia and their

metabolic reprogramming → secondary reprogram-

ming of the mitochondrial and glycolytic profile of

astrocytes → disruption of lactate, glutamate, and en-

ergy homeostasis of neurons → increased excitability

of limbic and mesocortical networks → consolidation

of addictive behavior patterns. This model correlates

well with the fact that normalization of glial func-

tion through pharmacological interventions reduces

the alcohol-associated behavior in preclinical models.

For example, the TLR4 inhibitor T5342126 reduces

ethanol consumption and suppresses microglial acti-

vation in the alcohol-dependent mice [48], and block-

ing of the TLR4/TRIF signaling during adolescence

reduces subsequent binge drinking in adulthood  [49].

In the experiments conducted by June et al., sup-

pression of TLR4 or MCP-1 using siRNA in the cen-

tral amygdala or ventral tegmental area led to the

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reduction in binge drinking in the alcohol-preferring

rats  [50]. The review by Wu et al., as well as a more

recent analysis by Crews et al., summarize the data

demonstrating that the microglial inhibitors (e.g.,

minocycline), TLR4 antagonists (TAK-242, etc.), and

anti-inflammatory drugs could reduce the alcohol-in-

duced neuroinflammatory activation and, at least in

some models, reduced craving for alcohol and its

consumption  [51,  52]. The data that the use of azith-

romycin reduced the levels of IL-1β and Hmgb1, and

at higher doses also reduced the protein content of

IL-1β, which support the idea of the possibility of

pharmacological modulation of individual stages of

the neuroinflammatory cascade, also attract a signif-

icant interest  [26].

Thus, the accumulated data indicate that glial

cells are not passive observers but key participants

in the formation of a sustained pathological state in

dependence, arising at the junction of immune, ener-

gy, and neuronal signaling processes.

NEUROTRANSMITTER SYSTEMS

AND THEIR INTERACTION WITH METABOLIC

AND IMMUNE PATHWAYS IN ADDICTIONS

Neurotransmitter system disorders described be-

low manifest differently at various stages of the de-

pendence syndrome formation. During acute intox-

ication, ethanol directly activates GABAA receptors

and inhibits NMDA receptors, causing a transient de-

crease in excitability. With chronic use, compensatory

hyperactivation of NMDA receptors develops against

a background of decreased dopaminergic tone and

neuroinflammatory suppression of serotonergic trans-

mission. During the withdrawal syndrome, as a result

of rebound hyperactivation of the glutamatergic sys-

tem and deficit in the GABAergic inhibition, severe

neurological disorders arise. At the stage of craving

and relapse, persistent decrease in the dopaminergic

sensitivity, changes in the reward networks, and in-

flammatory hyper-excitability of the limbic structures

play a key role.

Disorders of neurotransmitter transmission, tra-

ditionally considered the central mechanism of de-

pendence, cannot now be understood outside the

context of neuroinflammatory and metabolic pro-

cesses that deeply restructure operation of the neu-

ronal networks. In AUD, neuroimmune cascades act

as a key factor modifying functions of the mesolimbic

dopaminergic system and increasing vulnerability to

relapse [1, 53].

One of the most studied elements of this inter-

action is the influence of inflammatory cytokines on

dopaminergic system, which determines motivational

behavior, sensation of the reward, and tendency to

form dependent patterns of use. The review by Felger

and Miller shows that the pro-inflammatory signals–

primarily IL-1β, IL-6, and TNF-α – exert a multifac-

eted inhibitory effect on dopaminergic transmission:

they reduce expression and activity of tyrosine hy-

droxylase, increase production of reactive oxygen

species, and lead to oxidation of tetrahydrobiopterin

(BH4), an essential cofactor for dopamine synthesis

[54-57]. Through the reduced BH4 availability and

direct effects on the tyrosine hydroxylase signaling

pathways, these cytokine effects lead to the decrease

in dopamine synthesis and depletion of the presynap-

tic mediator reserves.

Additionally, it has been shown that chronic in-

flammation disrupts regulation of the presynaptic D2

autoreceptors and reduces activity of dopaminergic

neurons in the striatum. In the model of chronic

interferon-α administration in primates, decrease in

the D2 receptor binding and reduction in the stim-

ulus-induced dopamine release in the striatum were

noted, which was associated with the development

of anhedonia and reduced motivation [58, 59]. These

data are consistent with the concept that the pro-in-

flammatory cytokines shift metabolic balance of the

dopaminergic system toward the less energy-intensive

but also less reward-sensitive mode.

Clinical neuroimaging studies consistently con-

firm these data. For example, in the patients receiv-

ing interferon-α, decrease in activation of the ven-

tral striatum in response to reward was observed

using fMRI, which correlated with the development

of anhedonia and was confirmed by the PET-derived

evidence of reduced presynaptic dopaminergic func-

tion  [60]. Similarly, experimental administration of

endotoxin to the healthy volunteers weakened the

striatal response to reward  [61]. Moreover, the elevat-

ed levels of C-reactive protein (as a marker of periph-

eral inflammation) are associated with the weakened

activation of the fronto-striatal reward circuits  [62].

Although much of this work has been done in

the context of interferon-induced inflammation and

depressive disorders, reviews of neuroimmune mech-

anisms in alcohol dependence emphasize that similar

cytokine-mediated changes in mesolimbic dopami-

nergic transmission – reduced dopamine synthesis,

altered D2 receptor function, and weakened ventral

striatal reactivity – are also observed during the

chronic alcohol use and could be one of causes of

the increased vulnerability to relapse [1, 5, 53].

Glutamatergic system represents the second key

node subjected to the profound influence from neu-

roinflammation. As described in detail in the section

on glial cells, chronic alcohol use disrupts glutamate

homeostasis through a dual mechanism: increased glu-

tamate release by the activated microglia and reduced

clearance via the astrocytic transporter GLT-1/EAAT2.

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In the context of neurotransmitter systems, a key

consequence of this imbalance is hyperactivation of

the NMDA receptors and creation of prerequisites for

excitotoxicity [63].

Importantly, pharmacological normalization of

the glutamate exchange (e.g., with ceftriaxone) not

only restores homeostasis but also leads to the pro-

nounced behavioral effects such as reduced alcohol

consumption and relapse behavior in the preclinical

models  [64-66]. These data are complemented by the

results showing that inhibition of microglial activa-

tion or modulation of the TLR4 signaling reduces the

glutamate-dependent hyperexcitability and decreas-

es the alcohol-associated behavior  [48,  51]. Together,

this confirms that the glutamatergic disorders in

chronic alcohol use are directly mediated by neuroin-

flammation and are accompanied by the pronounced

metabolic stress in glia and neurons.

Neuroinflammation also has a significant impact

on the GABAergic system. Although alcohol is a pos-

itive modulator of GABAA receptors, the pro-inflam-

matory cytokines disrupt this mechanism. Experimen-

tal data indicate that the pro-inflammatory cytokines,

in particular IL-1β and TNF-α, could reduce sensitiv-

ity of the GABAA receptors in the limbic structures

and alter their interaction with the allosteric sites.

It has been shown that IL-1β suppresses the GABA-

mediated currents in neurons of the hippocam-

pus and amygdala, weakening inhibitory transmis-

sion  [67]. TNF-α, in turn, regulates trafficking of the

GABAA receptors: the work of Pribiag et al. showed

that TNF-α facilitates the PP1-dependent internal-

ization of the GABAA receptors and decrease in the

strength of inhibitory transmission  [68]. The review

by Martins and Harrison emphasizes that such cyto-

kine-mediated changes in the GABAergic transmission

are accompanied by the increased anxiety, sleep dis-

turbances, and reduced stress resistance, especially

in conditions of chronic inflammation  [69]. For the

alcohol dependence and withdrawal syndrome, this

has a practical significance: the review by Ngui et al.

shows that the imbalance between GABA- and glu-

tamatergic transmission during alcohol withdrawal

is closely linked to the neuroinflammatory process-

es and is accompanied by the pronounced sleep

disturbances, anxiety, and increased sensitivity to

stress  [70]. Thus, the GABAergic system in chronic

alcohol use and neuroinflammation acts not only as

a direct “target” of ethanol but also as an import-

ant component of the inflammatory cascade, sup-

porting disintegration of the inhibitory networks

and clinical symptoms of withdrawal.

Serotonergic system is involved in the pathogen-

esis of dependence through the metabolic pathways

closely linked to inflammation. One of the key mech-

anisms is activation of indoleamine-2,3-dioxygenase

(IDO) and, to a lesser extent, tryptophan-2,3-dioxygen-

ase (TDO), which shifts tryptophan metabolism from

the serotonin synthesis to the kynurenine pathway.

The review by Osuch et  al. describes in detail how

the pro-inflammatory cytokines and activation of

the TLR-dependent pathways in alcohol dependence

enhance conversion of tryptophan to kynurenine,

reducing its availability for serotonin synthesis and

increasing the level of neuroactive metabolites, in-

cluding 3-hydroxykynurenine and quinolinic acid[11].

Clinical data by Mechtcheriakov et  al. showed that the

patients with alcohol dependence in the acute with-

drawal period show increase in the KYN/TRP ratio,

increase in the concentration of quinolinic acid, and

association of these changes with the markers of im-

mune activation, such as neopterin  [71]. The work by

Leclercq et al. showed that the patients with alcohol

dependence and in early abstinence exhibit steady

changes in the kynurenine pathway associated with

the increased intestinal permeability, systemic inflam-

mation, and psychiatric symptoms  [72]. In the animal

models of chronic alcohol consumption and with-

drawal, it has been shown that activation of IDO and

accumulation of kynurenine metabolites mediate the

anxiety-depressive and cognitive disorders; pharma-

cological or genetic suppression of IDO leads to the

reduction in emotional disorders and, in some cases,

decrease in alcohol consumption [12, 73, 74]. These

data allow to consider serotonergic changes in addic-

tions as a product of cross-influence of inflammation,

tryptophan metabolism, and glutamate dysfunction.

All described neurotransmitter systems – dopa-

minergic, glutamatergic, GABAergic, and serotoner-

gic – are functionally linked through a common el-

ement: influence of inflammation on the energy and

mitochondrial metabolism. Numerous data indicate

that the inflammatory cytokines disrupt mitochondri-

al function in both neurons and glial cells, leading

to the decrease in activity of the respiratory chain

complex  I, increased production of reactive oxygen

species, and decrease in the efficiency of oxidative

phosphorylation [8, 43]. Reviews on microglial and

astrocytic mitochondrial dysfunction emphasize that

during chronic inflammation, there is a shift in the

balance toward glycolysis, decrease in the reserve

respiratory capacity, and disruption of the ability of

cells to switch between the different energy sources

[44, 75]. For the areas involved in regulation of re-

ward and emotions (nucleus accumbens, hippocam-

pus, and prefrontal cortex) this is particularly criti-

cal, as high energy demand makes these structures

especially vulnerable to metabolic stress. In chronic

alcohol use and associated neuroinflammation, bioen-

ergetic flexibility of the neurons decreases, and the

ability to use glucose, lactate, and ketone bodies de-

pending on the load is disrupted, which contributes

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

to the sustained disruption of the neuro-network dy-

namics and impedes recovery after the episodes of

use and withdrawal [9, 42].

Together, these data show that disorders of neu-

rotransmitter transmission in addictions cannot be

considered in isolation. They are formed at the in-

tersection of the inflammatory cascades, energy im-

balance, and glial dysfunction, which determine the

nature of synaptic activity, plasticity, and adaptive

behavior. Such integrative model links motivational,

affective, and cognitive disorders in AUD with the

metabolic and immune processes and provides new

possibilities for therapeutic interventions that simul-

taneously target neurotransmitter, immune, and meta-

bolic components of the pathogenesis of dependence.

ENERGY METABOLISM DISORDERS,

MITOCHONDRIAL DYSFUNCTION, AND

OXIDATIVE STRESS IN ADDICTIONS

Energy deficit and oxidative stress form a com-

mon final pathway through which chronic neuroin-

flammation in alcohol dependence could profoundly

disrupt function and structure of the neuronal net-

works. In the context of alcohol dependence, oxida-

tive stress occurs not only through universal but also

through ethanol-specific mechanisms. In addition to

the inflammation-associated generation of reactive

oxygen species, chronic alcohol use creates additional

sources of oxidative load through the ethanol and acet-

aldehyde metabolism, induction of CYP2E1, disruption

of mitochondrial electron transport, shifting xanthine

dehydrogenase to the ROS-producing oxidase form,

changes in the metabolism of transition metals, and

depletion of antioxidant systems, primarily glutathione

[76]. This multilevel organization of oxidative stress

allows considering it not as a secondary epiphenome-

non but as one of the key mechanisms through which

alcohol links peripheral inflammation, mitochondrial

dysfunction, and damage to the neuron–glial networks.

The degree and reversibility of these changes

vary significantly depending on the duration and pat-

tern of alcohol use, age of onset, genetic factors, and

presence of comorbid conditions. Mitochondrial dys-

function is a central link in this process, affecting both

neurons and glial cells in the key brain structures as-

sociated with cognitive control and reward. Modern

experimental and clinical-biological data show that in

alcohol dependence and associated neuroinflammato-

ry states, activity of the respiratory chain complex-

es decreases, efficiency of oxidative phosphorylation

diminishes, and production of mitochondrial reactive

oxygen species (ROS) increases, especially in these re-

gions – hippocampus, prefrontal cortex, and nucleus

accumbens [77-79].

It has been shown that the pro-inflammatory

cytokines TNF-α and IL-1β additionally disrupt mito-

chondrial respiration through the NF-κB-dependent

mechanisms, altering expression of the respiratory

chain proteins, reducing membrane potential, and

increasing permeability of the inner mitochondrial

membrane to calcium, making neurons more vulner-

able to excitotoxicity [43, 80].

Increase in the ROS levels in chronic alcohol use

has been confirmed in both experimental models and

postmortem studies. In the brains of the patients with

long history of alcohol abuse, accumulation of lipid

peroxidation products, oxidized proteins, and a pro-

nounced decrease in the activity of key antioxidant

enzymes – superoxide dismutase (SOD), glutathione

peroxidase (GPx), and catalase – are observed [81, 82].

At the systemic level, these changes are reflected in

a shift in the antioxidant–pro-oxidant balance in the

patients with AUD, as shown in the clinical-laboratory

studies and systematic reviews on oxidative stress in

alcohol dependence  [79]. Modern in  vivo spectroscopy

methods complement this picture: the results of 7-T

MRI spectroscopy showed changes in the level of re-

duced glutathione (GSH) in the anterior parts of the

cortex in the patients with AUD, furthermore, the

GSH levels were associated with the recent episodes

of use and severity of the clinical phenotype [83, 84].

Energy disorders become especially critical

during alcohol withdrawal, when energy demand of

the neurons increases against the background of un-

stable substrate supply. In the experimental models

of chronic alcohol consumption and early withdraw-

al, it has been shown that chronic ethanol exposure

disrupts glucose and lactate homeostasis in the CNS

and disorganizes the work of the astrocyte–neuron

lactate shuttle, which limits the ability of neurons

to effectively use lactate as an alternative energy

substrate  [85]. Additionally, the MRI and PET data in

the individuals with AUD show that chronic alcohol

use shifts brain metabolism toward acetate utiliza-

tion and is accompanied by the decrease in glucose

uptake, making the brain particularly vulnerable to

energy deficit during the withdrawal phase  [86,  87].

Finally, the review devoted to neurobiology of the

withdrawal syndrome emphasizes that alcohol absti-

nence is accompanied by the pronounced oxidative

and metabolic stress involving imbalance between

glycolysis and oxidative phosphorylation and over-

load of antioxidant systems  [88].

The results of animal studies confirm that

chronic alcohol use alters mitochondrial apparatus

in the neurons of the prefrontal cortex: it disrupts

morphology and distribution of mitochondria in the

dendrites, reduces their respiratory capacity, and dis-

rupts functional connection with the synaptic struc-

tures  [89]. The review by Arzua et  al. emphasizes

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

that such mitochondrial changes in the medial pre-

frontal cortex and nucleus accumbens are consid-

ered one of the key mechanisms of impaired synap-

tic plasticity and formation of the executive function

deficits in AUD  [90]. In more general models, it has

been shown that normal distribution and dynamics

of mitochondria in the dendrites are critically import-

ant for the induction and maintenance of long-term

potentiation: blocking activity of the dendritic mito-

chondria or disrupting their division/transport leads

to the decrease in the amplitude of synaptic respons-

es and inability to form LTP [91, 92].

The effect of alcohol on mitochondria is not lim-

ited to neurons. Astrocytes transition to the reactive

A1-like phenotype under conditions of long-term al-

cohol use and neuroinflammation, which is manifest-

ed by the reduced ability to support neuronal me-

tabolism with lactate and by the increased secretion

of pro-inflammatory mediators, including glutamate

and nitric oxide  [93]. Nitric oxide, in turn, inhibits

complex  IV of the respiratory chain (cytochrome c

oxidase), enhancing mitochondrial damage and re-

ducing efficiency of oxidative phosphorylation  [94].

The inflammation-activated microglia switch to gly-

colytic metabolism and produce significant amounts

of lactate, but its utilization by the neurons may be

impaired due to dysfunction of the monocarboxylate

transporters (especially MCT2) and changes in the

activity of LDH isoenzymes [44, 95, 96]. As a result,

a phenomenon of metabolic “desynchronization” is

formed, in which glia and neurons are involved in a

mutually reinforcing energy failure.

Interaction between inflammation, energy me-

tabolism, and regulation of HPA axis is of particu-

lar importance. Chronic inflammation and oxidative

stress reduce sensitivity of the glucocorticoid recep-

tors and impair the ability of cortisol to suppress the

NF-κB-mediated cascades, leading to persistent neuro-

endocrine dysregulation  [97]. In conditions of chronic

alcohol use and during withdrawal, it is hippocam-

pus – simultaneously one of the most metabolically

active areas and a key regulator of the HPA axis –

that is particularly vulnerable to the combination of

energy and inflammatory stress, which manifests as

increased anxiety, sleep disturbances, and reduced

stress resistance  [98,  99].

In addition to biochemical defects, an important

role is played by the disruption of mitochondrial dy-

namics (fusion and division processes). It has been

shown that chronic exposure to ethanol and pro-in-

flammatory cytokines reduces the levels of expres-

sion of mitofusins (MFN1/2) and OPA1 and enhanc-

es activity of the proteins involved in mitochondrial

division (DRP1), leading to mitochondrial fragmen-

tation, disruption of their axonal transport, and de-

crease in the efficiency of synaptic transmission [43,

44, 100, 101]. Neuroimaging studies using 31P-MRS in

the patients with AUD demonstrate decrease in the

phosphocreatine levels and impaired ATP resynthesis,

which reflect global deficit in the mitochondrial ener-

gy reserve and correlate with the slower recovery of

cognitive functions in remission [102, 103].

Finally, changes in the lipid composition of neu-

ronal membranes are important components of the

energy and structural distress in AUD. Oxidative

stress and acetaldehyde-mediated reactions lead to

modification of phospholipids, peroxidation of poly-

unsaturated fatty acids, decrease in docosahexaenoic

acid (DHA) content, and disruption of the function of

membrane proteins, including receptors and trans-

porters, which increases synaptic fragility and reduc-

es their ability to undergo structural reorganization

[81, 104].

PET and MRI studies, as well as work using sta-

ble isotopes, show that DHA metabolism in the brain

is disrupted in chronic alcohol use, and the rate of

its incorporation into cortical phospholipids changes;

moreover, impaired utilization of DHA by the brain

is associated with neurocognitive deficit and affective

symptomatology [105].

Experimental data on the neuroprotective effect

of omega-3 polyunsaturated fatty acids in chronic

ethanol exposure models additionally confirm the

role of the lipid component in brain vulnerability

and recovery: it was shown in preclinical studies

that addition of DHA and other n-3 PUFAs reduces

the alcohol-induced oxidative stress, decreases neu-

roinflammation, and prevents learning and memory

impairments against a background of chronic alcohol

consumption [106-108].

Among the described energy disorders, the ques-

tion of which disorder is the earliest and most patho-

genetically significant remains debatable. The avail-

able data allow us to suggest the following hierarchy:

1. Disruption of mitochondrial respiration in neu-

rons (decreased activity of complexes  I and  IV)

is the most studied and, apparently, the earliest

consequence of the direct effects of ethanol and

acetaldehyde, as it is registered even after acute

episodes of intoxication.

2. Dysfunction of the astrocyte–neuron lactate shut-

tle (ANLS) develops with chronic use and is espe-

cially significant during withdrawal, when neuro-

nal energy demand sharply increases.

3. Glycolytic reprogramming of microglia, although

characteristic of neuroinflammation, is rather a

consequence of immune activation and enhances

energy failure but does not initiate it.

There are very few direct comparative studies

on the contribution of these three mechanisms to the

formation of dependence, which is one of the priority

areas for future work.

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Fig.  2. Schematic representation of the gut–liver–blood–brain barrier–brain axis in alcohol use disorder. Alcohol-induced

dysbiosis and reduced production of short-chain fatty acids (SCFAs) are accompanied by the increased intestinal permeability

and translocation of bacterial products (lipopolysaccharide, LPS) into the portal circulation. Activation of Kupffer cells in the

liver leads to production of pro-inflammatory cytokines and increased systemic inflammation, as well as hyperammonemia.

Systemic mediators and ammonia increase permeability of the blood–brain barrier and activate microglia and astrocytes,

forming neuroinflammation and neuronal dysfunction. An additional contribution is made by adipose tissue as a source

of pro-inflammatory cytokines.

Thus, chronic inflammation, oxidative stress, and

mitochondrial dysfunction form a mutually reinforc-

ing circuit that undermines energy stability of the

neurons, disrupts their plasticity, and reduces abili-

ty of the brain to recover during both chronic alco-

hol use and withdrawal. These processes are closely

linked to cognitive impairments, persistent anxiety,

sleep disturbances, stress vulnerability, and relapse,

making targeting of energy metabolism one of the

key therapeutic strategies for addictions, which is still

insufficiently developed.

INTERACTION OF SYSTEMIC AND BRAIN

METABOLISM

Modern concepts of the pathogenesis of addic-

tions increasingly emphasize the role of peripheral

systems – especially gastrointestinal tract, liver, and

adipose tissue – as active sources of metabolic and

immune signals that directly modulate brain function

and contribute to formation of the sustained patholog-

ical states. Chronic alcohol use disrupts composition

of microbiota, increases intestinal barrier permea-

bility, and promotes translocation of bacterial prod-

ucts – primarily lipopolysaccharides (LPS) – into the

portal and systemic circulation, leading to activation

of Kupffer cells and hepatic macrophages, increased

production of TNF-α, IL-1β, and IL-6, activation of

the NLRP3 inflammasome, and pronounced oxidative

stress [109-111]. Liver, subjected to both direct toxic

load of ethanol and enhanced flow of endotoxins, par-

tially loses its detoxification functions and becomes

a key driver of chronic systemic inflammatory load,

which is subsequently translated to the brain through

humoral and neural pathways [112, 113].

Such hepatic–intestinal load leads to the in-

creased release of ammonia, disorders of fat and car-

bohydrate metabolism, accumulation of lipid peroxi-

dation products, and activation of the hepatic NLRP3

inflammasome, which correlates with the severity

of alcohol-associated liver disease and cognitive im-

pairments [114,  115]. In turn, systemic inflammation

and metabolic stress disrupt the blood–brain barrier

(BBB): pro-inflammatory cytokines and LPS enhance

expression of the adhesion molecules ICAM-1 and

VCAM-1 on the endothelial cells, alter composition of

the basement membrane, and increase translocation

of both circulating immune cells and microbial me-

tabolites into the CNS [116-118]. This creates a direct

pathway for peripheral inflammatory load to microg-

lia and astrocytes, triggering neuroinflammatory cas-

cades.

Adipose tissues, often underestimated in al-

cohol dependence, act not just as a system for re-

serve energy storage but as an active endocrine and

SKRYABIN et al.858

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

immune unit. In the individuals with long-term al-

cohol abuse and patients with alcohol-associated

liver disease, adipose insulin resistance, increased

expression of CCL2, TNF-α, IL-6, and inflammasome

components in adipocytes and tissue macrophages,

as well as shift in macrophage polarization from

the anti-inflammatory M2 subtype to the pro-inflam-

matory M1 phenotype are detected [119-123]. These

pro-inflammatory signals additionally affect liver and

brain, enhancing the overall neuroimmune–metabolic

stress (Fig.  2).

Metabolic reprogramming that develops within

this axis deserves special attention. Changes in the

microbiota lead to the decrease in production of the

short-chain fatty acids (SCFAs)– butyrate, propionate,

and acetate– which normally support integrity of the

intestinal barrier, modulate microglia, and participate

in maintaining energy metabolism in astrocytes and

neurons  [124,  125]. In the alcohol-associated dysbi-

osis, decrease in the SCFA levels contributes to the

further increase in the intestinal permeability, LPS

translocation, and activation of the TLR4-dependent

pathways, whereas under normal conditions, activa-

tion of the SCFA receptors (GPR41/GPR43, or FFAR3/

FFAR2) plays a key role in regulating vascular endo-

thelium, immune cells, and glial activity [117, 126,

127]. At the same time, hepatic dysfunction leads

to accumulation of ammonia and other neurotoxic

metabolites, which disrupt neuronal metabolism, en-

hance oxidative stress, suppress mitochondrial func-

tion, and are associated with subclinical cognitive

impairments even at the preclinical stage of hepatic

encephalopathy [110, 128].

A fundamental question remains about the rela-

tive contribution of systemic inflammation (of hepatic

and intestinal origin) compared to the direct neuro-

toxic effect of ethanol on glia and neurons. Direct

comparative data are scarce, but a number of obser-

vations allow preliminary conclusions to be drawn.

Studies using ethanol labeled with stable isotopes

show that ethanol and acetaldehyde directly penetrate

the BBB and activate microglial TLR4 independently

of systemic inflammation. At the same time, the study

using antibiotics that suppress intestinal microbiota

and reduce endotoxemia demonstrates a significant

reduction in the neuroinflammatory markers  [72],

indicating substantial peripheral contribution.

Apparently, the direct and systemic pathways interact

additively or synergistically: the direct effect of etha-

nol triggers priming of microglia, lowering threshold

for their activation, while systemic endotoxemia pro-

vides a sustained chronic stimulus. This distinction

has practical significance: therapeutic interventions

aimed only at the intestine (prebiotics, probiotics)

would be insufficient without simultaneous effects

on central neuroinflammatory cascades.

Collectively, the available data allow us to build

an integrative scheme: microbiota → intestinal bar-

rier → liver → systemic inflammation and metabolic

stress → BBB → brain. In this scheme, the brain is

not a passive recipient of signals; it responds with

restructuring of neurotransmitter systems, disruption

of synaptic energy, and plasticity. It is this multi-or-

gan circuit – the gut–liver–brain axis – that becomes

a key in explaining why patients with addictions so

often exhibit cognitive impairments, sleep disorders,

emotional lability, and high frequency of relapses

[109, 112, 129]. This approach emphasizes that for

effective therapy of addictions, not only neuropsy-

chiatric but also gastro-hepato-metabolic interven-

tions are necessary including correction of micro-

biota, enhancement of liver detoxification function,

restoration of barrier functions, and normalization

of energy metabolism [13, 111, 112].

CONCLUSION

Modern concept on the role of neuroinflamma-

tion in addictions moves the mechanism of patho-

genesis beyond the traditional neurotransmitter

model and emphasizes the role of complex interac-

tion of immune, metabolic, and neuron–glial process-

es. The data from recent years convincingly show

that chronic use of psychoactive substances initiates

sustained shifts in the functioning of microglia and

astrocytes, accompanied by activation of the NLRP3

inflammasome, restructuring of the cytokine profile,

impaired glutamate clearance, energy supply defi-

cits to neurons, and changes in synaptic plasticity.

These processes are not isolated: they are integrat-

ed into a general metabolic circuit linking intestine,

liver, adipose tissue, and brain. Translocation of

bacterial products, early activation of Kupffer cells,

changes in the microbiota composition, and reduced

production of short-chain fatty acids form a sus-

tained systemic pro-inflammatory background that

disrupts barrier functions of the brain endothelium

and modulates the work of glia.

At the CNS level, these changes lead to a typi-

cal pattern: enhanced glutamatergic excitation, weak-

ened GABAergic inhibition, reduced dopaminergic

tone, and shift of the tryptophan metabolism toward

the kynurenine pathway. A state is formed in which

the neuronal networks responsible for reward, ex-

ecutive control, and stress reactivity are function-

ing under conditions of chronic inflammation and

energy limitation. In the clinical phenotype, this is

manifested as cognitive vulnerability, sleep disor-

ders, anxiety-depressive symptomatology, increased

probability of relapse, and severity of withdrawal

syndrome.

NEUROINFLAMMATION, GLIA–NEURON CROSSTALK, ENERGY METABOLISM 859

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

The data obtained in recent years indicate that

the key target for translational approaches is not so

much an individual cytokine or signaling molecule

but rather an integrated inflammatory–metabolic

system disrupted in addictions. Correction of micro-

biota, restoration of intestinal barrier function, reduc-

tion of systemic inflammatory stress, normalization

of glial metabolism, and stabilization of glutamate

exchange form a basis for the complementary thera-

peutic strategies.

Development of biomarker panels to identify pa-

tients with pronounced neuroinflammatory burden

is one of the most promising translational directions.

Based on the data of this review, the following mini-

mal set of candidate blood biomarkers could be sug-

gested:

1. KYN/TRP ratio (kynurenine/tryptophan) – an in-

tegral marker of IDO activation and shift of the

serotonin/kynurenine metabolism; its increase is

associated with the severity of withdrawal syn-

drome and cognitive impairments.

2. Serum GFAP (glial fibrillary acidic protein) –

a marker of astrocytic damage and reactive as-

trocytosis; its level reflects the degree of structur-

al brain distress.

3. Neopterin (or neopterin/biopterin ratio)– amark-

er of macrophage/microglia activation and re-

duced BH4 synthesis, directly reflecting dopami-

nergic vulnerability.

4. Short-chain fatty acid profile (primarily butyrate

and propionate) in plasma – an integral marker

of intestinal barrier status and microbiota com-

position.

5. IL-6 or its soluble receptor (sIL-6R)– a marker of

systemic inflammatory load with a proven link

to neuroinflammation in AUD.

As additional, more accessible surrogate markers

of the inflammatory–oxidative phenotype, protein car-

bonyls and TBARS-reactive products in plasma could

be considered, increase of which has been demon-

strated in the patients in the early post- abstinent

period and partially persists after detoxification.

In contrast, the level of 8-OH-dG in this clinical win-

dow did not show comparable sensitivity, making it

a less convincing candidate for a minimal primary

screening panel.

Such panel would allow identification of the sub-

groups of patients with dominant neuroinflammato-

ry phenotype, for whom immunomodulatory therapy

(minocycline, NAC, TLR4 antagonists) may be partic-

ularly effective; this would differentiate them from

the patients with predominantly metabolic or micro-

biota deficits.

The possibility that the alcohol-induced neuroim-

mune shifts may form long-term vulnerability even

at the stage of brain development deserves special

attention. In the experimental model of prenatal al-

coholization, sex-dependent changes in the cytokine

profile in the prefrontal cortex were detected in the

adult offsprings: in males, but not in females, the

levels of TNF-α, IL-1β, IL-3, IL-6, and IL-9 decreased,

indicating not so much a simple increase in inflam-

mation but a sustained dysregulation of neuroim-

mune homeostasis  [130]. These data emphasize that

the alcohol-associated neuroimmune pathology could

have not only acute and chronic but also program-

ming characteristics.

Based on the systematized data of this review,

the following testable hypotheses are formulated,

which determine the priority research agenda:

Hypothesis  1. Restoration of GLT-1/EAAT2 function

(e.g., using ceftriaxone or β-lactam antibiotics) com-

bined with suppression of TLR4 signaling (TAK-242

or analogs) could provide a more pronounced and

sustained reduction in alcohol consumption than

monotherapy with each of these agents, due to the

mutually reinforcing nature of neuroinflammation

and glutamate imbalance.

Hypothesis  2. Normalization of the short-chain

fatty acid profile (using prebiotics or fecal microbiota

transplantation) could reduce severity of the changes

in the neuroinflammatory markers (GFAP, neopterin,

KYN/TRP) and decrease symptomatology of the with-

drawal syndrome more strongly in the subgroup of

the patients with initially increased intestinal per-

meability (determined by the zonulin/occludin ratio)

than in the subgroup with normal barrier function.

Hypothesis  3. Mitochondria-targeted therapy (e.g.,

MitoQ or SS-31) in combination with antioxidant sup-

port (NAC) could prevent specific energy deficit in-

crease during the withdrawal period (measured by

31P-MRS) and accelerate recovery of cognitive func-

tions in the first 4  weeks of remission compared to

the standard therapy.

Abbreviations

ANLS astrocyte–neuron lactate shuttle

AUD alcohol use disorder

BH4 tetrahydrobiopterin

BBB blood–brain barrier

DHA docosahexaenoic acid

EAAT2/GLT-1 excitatory amino acid transporter  2/

glutamate transporter  1 (in rodents)

GABA gamma-aminobutyric acid

HPA hypothalamic–pituitary–adrenal

IDO indoleamine-2,3-dioxygenase

IL interleukin

KYN/TRP kynurenine/tryptophan ratio

LPS lipopolysaccharide

LTP long-term potentiation

NF-κB nuclear factor kappa  B

NLRP3 NLR family pyrin domain-containing  3

SKRYABIN et al.860

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

PS psychoactive substances

ROS reactive oxygen species

SCFA short-chain fatty acids

TLR4 toll-like receptor  4

TSPO translocator protein (18  kDa)

TNF-α tumor necrosis factor alpha

Contributions

V.  Yu.  Skryabin, S.  I.  Sokolova, and A.  V.  Masyakin:

Concept of the review; V.  Yu.  Skryabin and S.  I.  Sokolo-

va: Writing the text; A.  V.  Masyakin: Editing the arti-

cle text.

Funding

This work was financially supported by the ongoing

institutional funding. No additional grants to carry

out or direct this particular research were obtained.

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man and animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

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