2. Neuroplastic features of vascular development, synaptic contacts and formation of benzodiazepine receptors in the developing human fetal brain under conditions of prenatal exposure to alcohol. Adaptive changes in the benzodiazepine receptor system of the human brain under the influence of chronic alcoholization

targets for various agents, including benzodiazepines (BzD) and ethanol. Benzodiazepines, which bind to the specific sites—benzodiazepine receptors (BzDR) on the GABA receptor complex, change its conformation and affinity [35–37]. Sedative and anxiolytic effects of alcohol and benzodiazepines are based on the potentiation of inhibitory effects of GABA by the inactivation of GABAA receptors. In the experiment, it was shown that the acute effect of ethanol enhances the gain of GABAergic transmission, but chronic alcoholization increases the binding of inverse BzDR agonists and reduces GABAergic function [38, 39]. Recent data point to the existence of a relationship between the actions of ethanol and the functioning of the

One of the theories of alcoholism involves a shift in the general excitability of the brain as a result of reduced inhibition processes. GABAAR are modulated by the main inhibitory neurotransmitter in the central nervous system—GABA, are potential targets for alcohol and mediate the effects of ethanol [40–44]. Alcohol can activate GABAAR, possesses anxiolytic properties, and in connection with its use of this ability is a form of self-medication by patients. Decrease of GABAergic functioning was found in patients with alcoholism and persons with a high risk of alcohol addiction development [44, 45]. The sedative and anxiolytic effects of alcohol and BzD are associated with potentiating of the inhibitory effect of GABA [41, 43]. At current time has not been revealed endogenous ligands for BzDR, as for opiate receptors and others, but their role is very significant in neuropharmacology of inhibitory processes in the CNS. There are cross-reactions (tolerance and dependence)

between alcohol and BzD, which confirm the interaction of ethanol with BzDR [38].

In addition to BzDR "central" type (CBR) that associated with GABAAR and having synaptic localization, known BzDR "peripheral" type (PBR), not associated with GABAAR and localized in the mitochondrial membrane, more of them are located in the glial cells of the brain.

These receptors make very important function—transfer of cholesterol into the mitochondria; this is limited step in the regulation of the neurosteroids biosynthesis. Neurosteroids are endogenous modulators of the GABAA/BzDR in the CNS [46]. BzD, anxiolytics, anesthetics and alcohol are implementing some of its effects through the PBR and regulating production of neurosteroids and their active metabolites, which are very significant for normal brain func-

Understanding of the basic signaling mechanisms that regulate the excitability and inhibition of brain processes involved in the formation of alcohol addictive behavioral, the determination of the target of alcohol effects can contribute to the creation of new pharmaceutical preparations to influence these targets and to develop a potentially effective therapies to prevent the

In this regard, it is impossible to overestimate the importance of further studying the processes associated with angiogenesis and synaptogenesis and the formation of receptor systems in the developing human brain, in particular, the GABA-benzodiazepine receptor system under conditions of chronic effects of ethanol, their role in the development of alcohol dependence, which may contribute to further clarification of the etiopathogenesis of the disease and the search for new medications necessary for pharmacotherapeutic correction, and prevention of

GABA-BzD-receptor complex.

76 Drug Addiction

tioning [46, 47].

harmful effects of ethanol.

consequences of alcohol abuse and withdrawal.

The study of the effect of mother's alcoholism on the developing fetal brain (prenatal exposure to alcohol) was carried out in the brain tissue of embryos and human fetuses at the 7–15 week of pregnancy in accordance with the requirements of the Ethics Committee and with the consent of patients during abortion procedures under strict medical indications. About 33 embryos and fetuses were obtained from female, suffering from alcoholism and constituted the main study group. The age of women who suffered from alcoholism was 26–39 years old, and the duration of the disease was from 3 to 13 years. In all cases, according to ICD-10 criteria, alcoholism of grade II was diagnosed (ICD-10 F10.201, F10.202). The diagnosis of alcoholism was established in the Department of Addictive Conditions, the Institute of Mental Health, Tomsk National Scientific Medical Center Russian Academy of Science (RASci). The control group included samples of the brain tissue of embryos and fetuses obtained from healthy women who do not have a history of neurological or mental diseases comparable in age. Exclusion criteria were cases of adverse effects on brain development of embryos, namely exposure to radiation, chemicals, certain pharmacological agents and maternal diseases during pregnancy: influenza, rubella, toxoplasmosis and others.

Ultrastructure of synaptic contacts and vessels of the brain tissue from embryonic and fetal brain were examined under JEM-100B and JEM-100CX electron microscopes. Electron microscopy studies addressed the intermediate layer of the wall of the forebrain, which is an accumulation of neuroblast and glioblast (including microglial cells), between which blood vessels start to grow. Morphometric analysis was performed using photographic prints from 6 to 9 cm negatives obtained from the electron microscopes. Some negatives were digitized with the scanner without intermediate paper prints. Scion Image for Windows, developed at the National Institutes of Health by Scion Corporation, was used to assess the areas of presynaptic terminals, their perimeters and the lengths of postsynaptic densities. Quantitative assessments by computerized morphometric analysis were performed by subdividing electron micrographs of embryo brain synapses into four groups, according to the period of embryo development: 7–8, 9–10, 10–11 and 11–12 weeks. This was performed in both the study group and the control group. Analyses involved five cases for each age period in the control and study groups.
