3. Conclusion

An important factor that can influence addiction liability is exposure of alcohol and other psychoactive substances during the early life period. Exposure to ethanol, early in life, can have long-lasting implications on brain function and drugs of abuse response later in life.

One of the mechanisms of action of alcohol is the ability to induce vascular spasm, which leads to hypoxia of the developing embryo and affects the retardation of development and growth of the fetus with prenatal effects of alcohol. These changes can lead to the development of fetal alcohol syndrome. Compensatory mechanism in the conditions of this pathology, leading to a decrease in the perimeter of the vessel and the area of the vessel in the cross section, is an increase in the number of vessels in the brain [57]. Alcoholization of the mother, leading to prenatal effects of alcohol on the developing fetus, affects the dynamics of embryonic development of the circulatory system in the human brain, which manifests itself in a change in the vascularization of the growing human brain [23].

The effects of ethanol in the early stages of development can disrupt the signaling mechanisms that regulate synaptogenesis. The result was "dilution" of the structure of elementary membranes and damaged membranes are less able to establish strong contact with each other, which is probably due also to a reduced ability of cells that are in constant contact with ethanol, synthesized mediators filling synaptic vesicles. This significantly violated the formation of neuronal mechanisms underlying the susceptibility and processing of information, which in turn could adversely affect a person's mental activity.

The data obtained by us showed a structured picture of synaptogenesis as one of the most significant periods in the formation and development of the brain, providing its functions and determining the adaptive potential in prenatal alcohol influences. The influence of prenatal ethanol on the development of synaptic structures was expressed in reduction of morphometric parameters, namely slowing the formation of synaptic contacts and reducing their formation in the brain of the embryo and fetus in the early stages of development, in contrast to the normally developing brain, which affects synaptogenesis in the developing brain of a person and can underlie fetal death or serious disorders the child in the future [23, 49, 52–54].

density of CBR in the caudate nucleus and the prefrontal cortex are related to their functional

with mitochondrial membranes in different areas of the human brain in control group (a) and study group (b) (alcoholic

H]PK-11195 binding parameters [Bmax (fmol/mg of protein) – density of binding sites]

The effect of ethanol causes a change in PBR not associated with GABAAR, localized in the mitochondrial membrane, predominantly in glial cells of the brain, and providing cholesterol transfer into the mitochondria [46], thus affecting the regulation of the synthesis of neurosteroids, which are endogenous modulators of GABAA/BzDR in the CNS [42]. Alcohol carries out some of their effects through PBR, regulating the production of neurosteroids and their metabolites, which are critical components of normal brain function [46]. Thus, PBR indirectly affects GABAergic function in the brain, mainly reacting to neurotoxic effects and

The data obtained by us confirm the existence of regulatory mechanisms mediating the relationship between the properties of GABAA/BzDR caused by receptor neuroplasticity and

An important factor that can influence addiction liability is exposure of alcohol and other psychoactive substances during the early life period. Exposure to ethanol, early in life, can have long-lasting implications on brain function and drugs of abuse response later in life.

One of the mechanisms of action of alcohol is the ability to induce vascular spasm, which leads to hypoxia of the developing embryo and affects the retardation of development and growth of the fetus with prenatal effects of alcohol. These changes can lead to the development of fetal alcohol syndrome. Compensatory mechanism in the conditions of this pathology, leading to a decrease in the perimeter of the vessel and the area of the vessel in the cross section, is an

activity in the regulation of emotions and motivated human behavior.

various brain damage [36, 55, 56].

Figure 20. Statistical analysis of [<sup>3</sup>

patients).

94 Drug Addiction

alcohol addiction.

3. Conclusion

On the background of the decrease in the formation of synaptic structures seen here in the fetal brain during gestation under the influence of maternal alcoholism and the simultaneous decrease in the affinity of synaptosomal BzDR, the tendency to an increase in receptor density can be evaluated as neuroplastic features and compensatory reaction directed to adapting the embryo and fetus nervous system to conditions of functional insufficiency of GABAergic neurotransmission. These new data can broaden the understanding of the molecular basis of predisposition not only to alcoholism but also to various disorders associated with PAE. Children and adolescents who were under the influence of alcohol during the period of prenatal development noted functional disorders of neurocognition, self-regulation and adaptive functioning and various neurobehavioral disorders associated with PAE [58]. Plasticity of ion channels and receptors linked to ion channels regulated by neurotransmitters is significant for the realization of adaptive processes in the brain, providing synaptic plasticity for the formation and development of neural network, physiological and pathophysiological processes. Prenatal alcohol exposure (PAE) can cause irreversible physical, neurological and psychiatric impairments that are present at birth and can have lifelong implications [14, 59]. The relationship between prenatal exposure to alcohol and the frequency of behavioral disorders in children and adolescents is established. [60]. The effect remained significant compared to other variables, including environment, maternal psychopathology and some others, and can cause a different mental dysfunction associated with a violation of brain metabolism in children and adolescents in the future [61].

Similar changes in the benzodiazepine receptor binding were identified by us in the brains of patients with alcoholism also. A decrease in the ability of receptors to bind agonist ligands impairs the ligand:receptor protein ratio, leading to decreased binding of the major neurotransmitter GABA and impairment to synaptic transmission. Our results are consistent with other studies that showed a reduction in the function of GABAA/BzDR in the prefrontal cortex in patients with alcohol dependence [36, 55]. Alcohol causes neuroplastic changes in BzDR associated with a decrease in the affinity of the receptors, a change in the conformational state of the GABAA/BzD rector complex, as a result of inhibition of the binding kinetics of BzDR by the polypeptide DBI (Diazepam Binding Inhibitor), as well as its metabolites. The endogenous peptide DBI possesses anxiogenic action and is the inverse agonist of BzDR [62]. Chronic alcohol exposure induces the expression of endogenous DBI interacting with receptors and suppresses binding affinity to [3 H] flunitrazepam.

Author details

Tomsk, Russia

References

2010-0256

10.1111/acer.13261

acer.13232

106.1.51

Tamara V. Shushpanova1

\*Address all correspondence to: shush59@mail.ru

\*, Anatoly Solonskii<sup>1</sup> and Olga V. Shushpanova2

Molecular-Cellular Targets of the Pathogenetic Action of Ethanol in the Human Brain in Ontogenesis…

http://dx.doi.org/10.5772/intechopen.73333

97

1 Department of Clinical Psychoneuroimmunology and Neurobiology, Mental Health Research Institute, Tomsk National Research Medical Center Russian Academy of Science,

2 Department of Child Psychiatry, Scientific Center of Mental Health, Moscow, Russia

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Neuroplastic changes of GABAAR, caused by the influence of ethanol, are associated with a change in the composition of subunits of the receptor complex and change in the pharmacological sensitivity and receptor function associated with the development of tolerance to ethanol and alcohol dependence. High heterogeneity of different isoforms of subunits of the GABAA receptor (α1-α6; β2,β3) in various regions of the brain: nuclei of the basal ganglia, prefrontal cortex and limbic regions of the brain, underlies the functional differentiation of the GABAA receptor complex and provides a varying degree of modulation functions of GABAAR by ethanol in various brain structures [63]. Changes in the expression of neuronal elements induced by alcohol, leading to changes in neurotransmitter function adaptation systems in the brain associated with neuroplasticity [64].

Benzodiazepines, anxiolytics, anesthetics and alcohol are implementing some of its effects through the BzDR "central" and "peripheral" types regulating the synthesis of neurosteroids, which are critical for the provision of brain functions. Ethanol modulates GABAA/BzD receptor complex function by affecting synthesis neurosteroids de novo in the brain, stimulating the mitochondrial receptors of the "peripheral type"—PBR, providing the transfer of cholesterol to mitochondria and synthesizing neurosteroids, independent of the functions of the HPA axis. This mechanism can play a principal role in the central effects of alcohol. Thus, the functional activity of PBR has a modulating effect on GABAergic function in the structures of the brain, reacting to various neurotoxic effects and damage [65].

Alcohol does not have specific receptors in the brain; however, the receptor proteins are exposed to ethanol. The research of a number of authors is aimed at studying long-lasting adaptive changes (neuroplasticity), which contribute to the development of alcohol dependence. Our studies aimed at studying neuroadaptation under the influence of chronic alcohol effects on the benzodiazepine receptor system of the brain have revealed that a low affinity of BzDR can be a marker of disorders of synaptogenesis and regulatory mechanisms mediating the GABAA/BzDR bond that induces receptor neuroplasticity and alcohol addiction [41, 54, 65, 66].

BzDR "central" and "peripheral" types can be a key link to the discovery of new promising therapy for the treatment of compulsive craving for alcohol, alcohol abuse and dependence. The integration of current data and our data is necessary to define the role of GABAAR in modulating the rewarding and aversive effects of ethanol and may lead to the development of pharmacotherapy that targets GABAA/BzD receptors to treat alcoholism in human beings [65–68].
