ISSN 0006-2979, Biochemistry (Moscow), 2024, Vol. 89, No. 11, pp. 1863-1867 © The Author(s) 2024. This article is an open access publication.
1863
MINI-REVIEW
An Intricated pas de deux of Addicted Brain
and Body Is Orchestrated by Stress and Neuroplasticity
Natalia V. Gulyaeva
1,2,a
* and Danil I. Peregud
1,3
1
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485 Moscow, Russia
2
Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department, 115419 Moscow, Russia
3
Federal State Budgetary Institution “V.Serbsky National Medical Research Center
for Psychiatry and Drug Addiction” of the Ministry of Health of the Russian Federation,
119034 Moscow, Russia
a
e-mail: nata_gul@ihna.ru
Received August 13, 2024
Revised August 13, 2024
Accepted August 13, 2024
Abstract— Dependence on psychoactive substances is a phenomenon that is based on the alterations of common
molecular and cellular mechanisms, structures and neuronal networks underlying normal brain functioning
and realizing stress response, reinforcement and aversion, learning and memory. As a result, aberrant neuro-
plasticity states associated with somatic changes are formed, which determine the pathogenesis and symptoms
of dependence and at the same time can be considered as targets for the development of therapies for such
addictions. An integrative scheme of stress and neuroplastic changes participation in the formation of the
vicious circle of substance use disorders based on a holistic approach is presented. This special issue of the
journal focuses on the molecular mechanisms of psychoactive substance use disorders.
DOI: 10.1134/S0006297924110014
Keywords: psychoactive substances, addiction, substance use disorders, brain, stress, neuroplasticity, neuroen-
docrine mechanisms
Abbreviations: HIP, hippocampus; HPA axis, hypothalam-
ic-pituitary-adrenal axis; PAS, psychoactive substance;
PFC, prefrontal cortex; SUD, substance use disorder.
* To whom correspondence should be addressed.
Alcohol kills the nervous cells. All that’s left are the calm ones.
(A phrase attributed to Bernard Shaw)
INTRODUCTION
This issue of Biochemistry (Moscow) focuses on
the molecular mechanisms of substance use disor-
ders(SUDs). Psychoactive substances(PASs) are chemi-
cal compounds with different pharmacodynamic prop-
erties and molecular targets, united by the ability to
induce a sense of satisfaction and euphoria, which
in chronic use may be accompanied by the develop-
ment of pathological dependence [1]. The formation
of dependence on PASs (alcohol, drugs, non-narcotic
PASs) is a chronic relapsing process in biologically
predisposed individuals, in which PASs in the pres-
ence of specific external stimuli cause generally simi-
lar adaptation processes at the molecular, cellular, and
functional levels.
SUBSTANCE USE DISORDERS AS A PART
OF PLASTICITY–PATHOLOGY CONTINUUM:
A CHOLISTIC APPROACH
Adaptation processes in the brain are realized
in the form of neuroplasticity, which encompasses a
variety of processes at the levels from molecules to
neural networks [2]. From the point of view of inte-
grative neurobiology, the concept of the continuum
of neuroplasticity and neuropathology was created.
It is obvious that the commonality and pleiotropy
GULYAEVA, PEREGUD1864
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
of mechanisms at the molecular, synaptic, cellular,
and network levels are associated with high adaptive
plasticity of a number of cerebral regions (e.g., the
hippocampus, HIP) responsible for brain integrative
function, including learning and memory [3]. Im-
portantly, the price of high plasticity is the selective
sensitivity of these structures to the development of
various pathological processes.
Difficulties in the treatment and prevention of de-
pendence on PASs are related to the complexity and
multidimensionality of the mechanisms underlying
development of such dependencies, as well as mul-
tiple states in the continuum of plasticity–pathology,
which develop on the basis of fundamental physiologi-
cal mechanisms of brain functioning, such as stress-re-
sponsiveness, reinforcement and aversion, learning
and memory. The holistic approach (the term “holism”
was introduced in 1926 by J. Smuts) [4], which inte-
grates various mechanisms and aspects of dependence
development, seems to be an adequate analytical tool
that allows taking into account the multifactorial and
multistage nature of the addiction phenomenon and
to understand how brain functioning changes sequen-
tially from alterations in genome activity, biochemi-
cal changes, remodeling of neuronal connections to
transition of behavioral acts to a new level [5].
This approach is all the more important because
the formation of SUDs occurs as a result of close in-
teraction between central and peripheral systems.
The review [6] in this issue presents the current un-
derstanding of the molecular mechanisms that un-
derlie the interaction between visceral systems and
central mechanisms of chemical dependence. SUDs
are associated with altered plasticity of specific brain
structures, with the development of dependence ac-
companied by stress responses, adaptive processes,
learning and memory processes. The realization of
all these changes and events is controlled by the cen-
tral neurohumoral stress-realizing system, the hypo-
thalamic-pituitary-adrenal (HPA) axis. This system is
closely associated with immune responses, inflamma-
tory processes and functions as a key regulator of the
most important events triggering plastic changes in
the brain– systemic inflammatory processes and neu-
roinflammation [7]. This issue presents a review [8],
as well as studies concerning the role of inflammatory
processes in the pathogenesis of alcohol dependence
in clinic [9] and animal model experiments [10, 11].
VICIOUS CIRCLE OF SUBSTANCE USE DISORDERS
Figure 1 presents an integrative scheme of the
involvement of stress and neuroplastic changes in the
formation of the vicious circle of the SUDs resulting
from changes in the plasticity of the main brain struc-
tures implicated. Either directly or indirectly, PASs
stimulate dopaminergic projections of the ventral
tegmental area (VTA) to the striatum (STR) and pre-
frontal cortex (PFC), which is the key mechanism of
reinforcement [12, 13]. PASs affect the reward system,
which is normally targeted by natural stimuli [14], but
the degree of PAS effects is significantly higher [15].
With a combination of external (stress [16]) and in-
ternal (genetic predisposition [17]) factors, voluntary
chronic intoxication becomes possible, which over
time can become uncontrollable and is accompanied
by the development of tolerance and the formation of
stable conditional associative connections [18]. It is be-
lieved that at this stage the stress-reactive HPA axis,
the PFC as a decision-making center, and the HIP as a
key structure for learning and memory are involved.
Changes in expressed gene pattern in specific parts
of the brain, epigenetic alterations, disturbances in the
neurochemical systems of biogenic amines, neuropep-
tides, excitatory and inhibitory amino acids (in this
issue, these aspects are the subject of [19-21]), distur-
bances in trophic regulation of neurons, development
of the inflammatory process, and as a result, active
structural and functional reorganizations of the meso-
corticolimbic system are the basis of the adaptation
processes in the central nervous system underlying its
conversion to functioning under chronic PAS intoxica-
tion [22, 23]. Disorders developing as a result of PAS
abuse are considered as a pathological form of learning
and memory consolidation, accompanied by changes in
the synaptic contact architecture as a result of adap-
tive processes in the intracellular signaling cascades
of dopaminergic neurons, primarily in the cascade of
protein kinase A – transcription factor CREB [24].
The cessation of PAS intake in a dependent per-
son is accompanied by a deficit of positive reinforce-
ment and the development of a painful withdrawal
syndrome, which has both physiological manifesta-
tions and an evident affective component. Withdrawal
state is an additional stressogenic factor and the basis
for the formation of negative reinforcement. The key
role in the development of the affective component of
withdrawal is attributed to the amygdala (amygdalar
complex) and HPA axis [25]. Based on the concept of
addiction as an aberrant form of learning and mem-
ory, the combination of conditional and unconditional
stimuli leads to memory reconsolidation, which is a
trigger for relapse. The amygdala, HIP, and STR are
key structures of this process, and signal cascades ini-
tiated by dopamine and glutamate receptors are its
molecular basis [26]. Relapse has also been associated
with a declining of PFC control [27]. Increase of stress-
or influence, development of depressive symptoms,
which are accompanied by activation of HPA axis,
decrease of trophic regulation and atrophy of frontal
cortical areas are predictors of relapse [28]. The series
INTRICATED pas de deux OF ADDICTED BRAIN AND BODY 1865
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
Fig. 1. Involvement of stress and neuroplastic changes in the formation of the substance use disorders (SUD) vicious circle:
a holistic approach. The development of SUDs is based on fundamental mechanisms of normal brain functioning, includ-
ing stress response, reinforcement (positive and negative), learning, and memory. Various PAS, along with specific effects,
induce typical adaptive and pathological changes in neuroplasticity at the molecular, epigenetic, cellular and functional
levels. During the development of dependence on PAS, the key mechanism of their influence on positive reinforcement
system is the stimulation of dopaminergic projections of the ventral tegmental area (VTA) into the striatum (STR) and the
effect on the prefrontal cortex(PFC). Stressors [their action is mediated by the stress-reactive hypothalamic-pituitary-adrenal
axis (HPA axis; HYP, hypothalamus; P, pituitary; AD, adrenals)] interacting with the amygdala (AMY) nuclei contribute to
voluntary chronic PAS intoxication becoming uncontrollable. This is accompanied by the development of tolerance to PAS
and formation of conditioned associative connections by comprising the system of key structures for learning and memory
(hippocampus, HIP, PFC, and AMY) closely interacting with HPA axis. When dependence on PAS is formed, stopping PAS
intake is accompanied by the development of withdrawal syndrome manifested at both physiological and affective levels
and associated with a decrease in positive reinforcement. Withdrawal becomes a new severe stressor and the basis for
negative reinforcement mediated by HPA axis and AM. HPA axis dysfunction is also associated with the manifestation of
relapse related with weakened PFC control. A physiologic trigger of relapse is memory reconsolidation, and key structures
are AM, HIP, and STR. Neuroplasticity changes associated with the development of addiction span all levels, from epigenetic,
molecular, and synaptic to cellular and network. Chronic PAS intoxication induces both adaptive and pathological changes
in the expression of various genes, alterations in neurotransmitter and trophic factor systems, development of inflammatory
process and, as a result, structural and functional rearrangements of involved structures. Attributable to a healthy brain
functional pleiotropy of brain structures involved in stress, adaptation, learning, and memory, plays a vital role in the for-
mation of SUDs, on the one hand ensuring the adaptation to PAS intoxication, and on the other hand forming pathological
phenotype of addiction. As a result, dependence on PASs is realized on the basis of fundamental mechanisms of normal
brain functioning by inducing aberrant plasticity. The integrative scheme presented is based on the data from [12, 13, 18,
25-28] and uses templates of Servier Medical Art (Servier), provided by Creative Commons Attribution3.0 unported license.
of positive and negative reinforcement shapes asso-
ciative links of dependence and disrupts homeostatic
mechanisms of central nervous system functioning
[29]. Thus, SUD represents a vicious circle consisting
of cycles of intoxication and abstinence involving an-
atomical substrates specific to each act (Fig. 1).
As the duration of abstinence increases, structural
and functional abnormalities in the central nervous
system gradually recover [30]. In other words, if we
exclude PAS intake in the absence of significant or-
ganic damage, the brain will reach, if not the initial
parameters of functioning, then at least maximally
approach them. The key aspect of addiction is the
craving to the substance, which, given a combination
of external circumstances and internal readiness, will
lead to the realization of the motivational act and sub-
sequent relapse. One of the main goals of therapy is to
stabilize remission, prevent memory reconsolidation,
and reduce craving and motivation to use. The de-
velopment of approaches to pathogenetically justified
therapy for SUDs is based, among other things, on un-
derstanding the important role of neurotrophic factor
system alterations in the development of dependence
on PAS [31]. In this issue, we present a paper showing
that low-molecular-weight mimetics of neurotrophin-3
attenuate somatic manifestations of morphine with-
drawal syndrome in rats [32]. On the other hand, an
important problem is the search for new biomarkers
reflecting the processes occurring in the brain during
the formation of dependence on PAS. In this issue,
GULYAEVA, PEREGUD1866
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
a review article on small extracellular vesicles in pe-
ripheral blood is devoted to this aspect [33].
CONCLUSIONS: MULTIPLE DIMENSIONS
OF SUBSTANCE USE DISORDERS
To summarize, we can conclude that SUDs are a
truly amazing phenomenon, which is based on the
usurpation by PAS of common molecular and cellu-
lar mechanisms, structures, and neuronal networks
fundamental to the normal functioning of the brain
and representing the basis for stress response, rein-
forcement and aversion, learning, and memory. As a
result, aberrant plasticity states associated with somat-
ic changes are formed, which underlie the pathogen-
esis and symptomatology of dependence on PAS and,
at the same time, are targets for the development of
therapies. Importantly, common mechanisms of patho-
genesis at the molecular, cellular and network levels
explain the high frequency of comorbidity between
dependence on PASs and many other psychiatric dis-
orders [17, 34, 35].
Contributions. N.V.G. concept, search and analy-
sis of data, final editing of the article; D.I.P. concept,
search and analysis of data, writing the primary text.
Funding. This study was supported by the Mos-
cow Center for Innovative Technologies in Healthcare
(research project no.0702-1/23).
Ethics declarations. This work does not contain
any studies involving human and animal subjects. The
authors of this work declare that they have no con-
flicts of interest.
Open access. This article is licensed under a Cre-
ative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution,
and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s)
and the source, provide a link to the Creative Com-
mons license, and indicate if changes were made.
Theimages or other third party material in this article
are included in the article’s Creative Commons license,
unless indicated otherwise in a credit line to the mate-
rial. If material is not included in the article’s Creative
Commons license and your intended use is not permit-
ted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license,
visit http://creativecommons.org/licenses/by/4.0/.
REFERENCES
1. Ciucă Anghel, D. M., Nițescu, G. V., Tiron, A. T.,
Guțu, C. M., and Baconi, D. L. (2023) Understanding
the mechanisms of action and effects of drugs of
abuse, Molecules, 28, 4969, https://doi.org/10.3390/
molecules28134969.
2. Gulyaeva, N. V. (2017) Molecular mechanisms of
neuroplasticity: An expanding universe, Biochem-
istry (Moscow), 82, 237-242, https://doi.org/10.1134/
S0006297917030014.
3. Gulyaeva, N.V. (2022) Multi-level plasticity-pathology
continuum of the nervous system: functional aspects,
Neurochem. J., 16, 424-428, https://doi.org/10.1134/
S1819712422040092.
4. Smuts, J. C. (1926) Holism and Evolution, Macmillan
and Co., Limited, London.
5. Valentino, R. J., Nair, S. G., and Volkow, N. D. (2024)
Neuroscience in addiction research, J.Neural. Transm.
(Vienna), 131, 453-459, https://doi.org/10.1007/s00702-
023-02713-7.
6. Peregud, D.I., and Gulyaeva, N.V. (2024) Contribution
of visceral systems to the development of substance
use disorders: translational aspects of interaction be-
tween central and peripheral mechanisms, Biochem-
istry (Moscow), 89, 1868-1888, https://doi.org/10.1134/
S0006297924110026.
7. Gulyaeva, N. V. (2023) Glucocorticoids orchestrate
adult hippocampal plasticity: growth points and
translational aspects, Biochemistry (Moscow), 88, 565-
589, https://doi.org/10.1134/S0006297923050012.
8. Mikhalitskaya, E. V., Vyalova, N. M., Bokhan, N. A.,
and Ivanova, S. A. (2024) Alcohol-induced activation
of chemokine system and neuroinflammation devel-
opment, Biochemistry (Moscow), 89, 1889-1903, https://
doi.org/10.1134/S0006297924110038.
9. Prokopieva, V.D., Vetlugina, T.P., Epimakhova, E.V.,
Boiko, A.S., and Bokhan, N. A. (2024) Association of
peripheral markers of oxidative stress with clinical
parameters and inflammatory factors in alcoholic pa-
tients, Biochemistry (Moscow), 89, 1904-1910, https://
doi.org/10.1134/S000629792411004X.
10. Airapetov, M. I., Eresko, S.O., Shamaeva, S.A., Bych-
kov, E.R., Lebedev, A.A., and Shabanov, P.D. (2024)
Study of neuroinflammation in the rat hippocampus
during ethanol exposure and pharmacological correc-
tion with azithromycin: new data and future perspec-
tives, Biochemistry (Moscow), 89, 1911-1921, https://
doi.org/10.1134/S0006297924110051.
11. Shamakina, I.Yu., Anokhin, P.K., Ageldinov, R.A., and
Kokhan, V. S. (2024) Neuroimmune characteristics of
animals with prenatal alcohol intoxication, Biochem-
istry (Moscow), 89, 1922-1929, https://doi.org/10.1134/
S0006297924110063.
12. Cooper, S., Robison, A. J., and Mazei-Robison, M. S.
(2017) Reward circuitry in addiction, Neurothera-
peutics, 14, 687-697, https://doi.org/10.1007/s13311-
017-0525-z.
13. Hayes, A., Herlinger, K., Paterson, L., and Lingford-
Hughes,A. (2020) The neurobiology of substance use
INTRICATED pas de deux OF ADDICTED BRAIN AND BODY 1867
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
and addiction: evidence from neuroimaging and rele-
vance to treatment, BJPsych. Adv., 26, 367-378, https://
doi.org/10.1192/bja.2020.68.
14. Tan,B., Browne, C.J., Nöbauer,T., Vaziri,A., Friedman,
J.M., and Nestler, E.J. (2024) Drugs of abuse hijack a
mesolimbic pathway that processes homeostatic need,
Science, 384, eadk6742, https://doi.org/10.1126/science.
adk6742.
15. Wightman, R.M., and Robinson, D.L. (2002) Transient
changes in mesolimbic dopamine and their associa-
tion with ‘reward’, J.Neurochem., 82, 721-735, https://
doi.org/10.1046/j.1471-4159.2002.01005.x.
16. Ruisoto,P., and Contador, I. (2019) The role of stress
in drug addiction. An integrative review, Physiol.
Behav., 202, 62-68, https://doi.org/10.1016/j.physbeh.
2019.01.022.
17. Miller, A. P., Bogdan, R., Agrawal, A., and Hatoum,
A.S. (2024) Generalized genetic liability to substance
use disorders, J. Clin. Invest., 134, e172881, https://
doi.org/10.1172/JCI172881.
18. Koob, G.F., and Volkow, N. D. (2010) Neurocircuitry
of addiction, Neuropsychopharmacology, 35, 217-238,
https://doi.org/10.1038/npp.2009.110.
19. Peregud, D. I., Shirobokova, N. I., Kvichansky, A. A.,
Stepanichev, M. Yu., and Gulyaeva, N. V. (2024) Pur-
morphamine alters anxiety-like behavior and expres-
sion of hedgehog cascade components in rat brain
after alcohol withdrawal, Biochemistry (Moscow), 89,
1938-1949, https://doi.org/10.1134/S0006297924110087.
20. Vetrovoy, O. V., Potapova, S. S., Stratilov, V. A., and
Tyulkova, E.I. (2024) Prenatal hypoxia predisposes to
impaired expression of the chrna4 and chrna7 genes
in adult Rats without affecting acetylcholine metab-
olism during embryonic development, Biochemis-
try (Moscow), 89, 1950-1960, https://doi.org/10.1134/
S0006297924110099.
21. Sudakov, S.K., Bogdanova, N.G., Nazarova, G.A., and
Zolotov, N. N. (2024) Behavioral features and blood
enzyme activity in offspring of rats conceived from an
alcohol-intoxicated father, Biochemistry (Moscow), 89,
1930-1937, https://doi.org/10.1134/S0006297924110075.
22. Korpi, E.R., den Hollander,B., Farooq,U., Vashchink-
ina,E., Rajkumar,R., Nutt, D.J., Hyytiä,P., and Dawe,
G.S. (2015) Mechanisms of action and persistent neu-
roplasticity by drugs of abuse, Pharmacol. Rev., 67,
872-1004, https://doi.org/10.1124/pr.115.010967.
23. Nestler, E. J., and Lüscher, C. (2019) The molecular
basis of drug addiction: linking epigenetic to synaptic
and circuit mechanisms, Neuron, 102, 48-59, https://
doi.org/10.1016/j.neuron.2019.01.016.
24. Liu,X., Wang,F., Le,Q., and Ma,L. (2023) Cellular and
molecular basis of drug addiction: The role of neuro-
nal ensembles in addiction, Curr. Opin. Neurobiol., 83,
102813, https://doi.org/10.1016/j.conb.2023.102813.
25. Koob, G. F. (2021) Drug addiction: hyperkatifeia/neg-
ative reinforcement as a framework for medications
development, Pharmacol. Rev., 73, 163-201, https://
doi.org/10.1124/pharmrev.120.000083.
26. Milton, A. L. (2023) Drug memory reconsolidation:
from molecular mechanisms to the clinical context,
Transl. Psychiatry, 13, 370, https://doi.org/10.1038/
s41398-023-02666-1.
27. Garavan,H., Brennan, K.L., Hester,R., and Whelan,R.
(2013) The neurobiology of successful abstinence, Curr.
Opin. Neurobiol., 23, 668-674, https://doi.org/10.1016/
j.conb.2013.01.029.
28. Sinha, R. (2011) New findings on biological factors
predicting addiction relapse vulnerability, Curr. Psy-
chiatry Rep., 13, 398-405, https://doi.org/10.1007/
s11920-011-0224-0.
29. Ferrer-Pérez, C., Montagud-Romero, S., and Blanco-
Gandía, M. C. (2024) Neurobiological theories of ad-
diction: a comprehensive review, Psychoactives, 3, 35-
47, https://doi.org/10.3390/psychoactives3010003.
30. Parvaz, M.A., Rabin, R. A., Adams, F., and Goldstein,
R. Z. (2022) Structural and functional brain recovery
in individuals with substance use disorders during
abstinence: a review of longitudinal neuroimaging
studies, Drug Alcohol Depend., 232, 109319, https://
doi.org/10.1016/j.drugalcdep.2022.109319.
31. Peregud, D. I., Baronets, V. Y., Terebilina, N. N., and
Gulyaeva, N. V. (2023) Role of BDNF in neuroplasti-
city associated with alcohol dependence, Biochem-
istry (Moscow), 88, 404-416, https://doi.org/10.1134/
S0006297923030094.
32. Kolik, L. G., Konstantinipolsky, M. A., Nikolaev, S. V.,
Logvinov, I. O., Antipova, T. A., and Gudasheva, T.A.
(2024) Low-molecular neurotrophin-3 mimetics with
different patterns of postreceptor signaling activa-
tion attenuate differentially morphine withdrawal
in rats, Biochemistry (Moscow), 89, 1961-1969, https://
doi.org/10.1134/S0006297924110105.
33. Severtsev, V. V., Pavkina, M. A., Ivanets, N. N., Vin-
nikova, M.A., and Yakovlev, A.A. (2024) Extracellular
vesicles as potential biomarkers in addictive disor-
ders, Biochemistry (Moscow), 89, 1970-1984, https://
doi.org/10.1134/S0006297924110117.
34. Nardi, W. R., Kelly, P., Roy, A., Becker, S., Brewer, J.,
and Sun,S. (2024) A systematic review and meta-anal-
ysis of psychosocial interventions for persons with co-
morbid anxiety and substance use disorders, J.Subst.
Use Addict. Treat., 165, 209442, https://doi.org/10.1016/
j.josat.2024.209442.
35. De Aguiar, A. C. L., and Bloc, L. G. (2024) Transdiag-
nosis of alcohol use and psychopathologies: a system-
atic review, Addict. Behav. Rep., 19, 100543, https://
doi.org/10.1016/j.abrep.2024.100543.
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.
