1. Introduction

Prenatal alcohol exposure at moderate and higher levels increases the odds of child behavior problems with the dose, pattern and timing of exposure affecting the type of behavior problems expressed [1, 2]. Disruption in the neural activation of the prefrontal cortex (PFC) and neurobehavioral disorders were detected in children with severe prenatal exposure to alcohol (PAE) [3–6]. The developing brain is extremely sensitive to the effects of ethanol [6, 7]. The use of significant doses of ethanol during pregnancy can result in a combination of profound morphological and neurological changes called fetal alcohol syndrome (FAS) [8, 9].

At the molecular-cellular level, changes in the nervous system in the formation of alcohol dependence are associated with activation of the processes of synaptic plasticity. With the development of alcohol dependence, stimulation of neuroplasticity is considered one of the reasons for the rapid formation of a behavioral stereotype—addictive behavior. At the same time, long-term consumption of ethanol leads to a permanent disruption of synaptic plasticity, which can cause cognitive impairment, learning and memory problems, and the formation of alcoholic motivation and obsessive directed behavior in experimental animals and people with

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

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

75

Neurogenesis is the basis for ensuring the plastic function of the brain and is regulated by many factors. Stimulation of neurogenesis is observed in a number of pathological conditions: brain ischemia, trauma, the development of neurodegenerative pathology, the influence of neurotoxic agents, including high doses of alcohol, prolonged use. Neurogenesis is the key adaptive function of the brain, represents one of the most important mechanisms of brain plasticity, which is expressed in an increase in the number of cells involved in the restructuring of neuronal networks. Exposure to ethanol limits early development by delaying or inhibiting the formation of postsynaptic neurons from progenitor neuronal cells (PNA) [19–21, 25].

The effects of ethanol in the early stages of development can disrupt the signaling mechanisms that regulate synaptogenesis. Negative effects of ethanol are associated also with its influences on the lipid component of neuron membranes. As lipotropic agent, ethanol is able to change the essential physico-chemical properties of cell membranes, which is reflected in the current fetal brain synaptogenesis [26, 27]. It has been shown that ethanol triggers apoptotic neurodegeneration [17] in the developing brain, when administered to infant rodents during the period of synaptogenesis, also known as the brain growth spurt period [19, 20]. Prenatal alcohol exposure inhibits neurogenesis [24, 28] and dendritic growth of newborn neurons [18]. The effects of ethanol cause neuronal death, impairment of differentiation, migration of neuronal elements and changes in neuronal plasticity, acting through various receptors and their signaling pathways [29]. Rapidly developing neural networks form synapses, mediate the communication and functioning of a multitude of synapses, through neuromediation part of them associated with a neurotransmitter gamma-aminobutyric acid (GABA), which operates via chloridepermeable GABA type A receptor channels. At an early stage of development, neurons have a high concentration of intracellular chloride, which leads to an outflow of chloride and exciting actions of GABA in immature neurons. Transmission of GABA signals is also established prior to the formation of glutamatergic transmission. Thus, GABA is the main excitatory transmitter in the early stages of development and modulates the cell cycle, the formation of cells and their

The currently accepted position is that the adverse effects of ethanol are also linked with interactions with specific proteins, ion channels and receptors, leading to changes in their functions [17, 34, 35]. The ability of ethanol to interact with receptor proteins was demonstrated, which contributed to a change in neuronal excitability. GABAergic neurotransmission plays an important role in the mechanisms of action of ethanol. GABA receptors fulfill the inhibitory role in the CNS. GABAAR is an oligomeric protein complex, which contains various allosteric binding sites that modulate receptor activity, and these allosteric binding sites are the

prolonged use of alcohol [24].

migration [30–33].

The use of moderate doses of ethanol can cause abnormalities that are not associated with multiple morphological and neurological damage associated with FAS, but are associated with the development of cognitive deficits and more serious consequences in the offspring, which can be particularly pronounced in puberty [10, 11]. This formed the basis for an expanded diagnostic classification of fetal defects and a new category—neurodevelopmental disorders caused by alcohol. There is a complex relationship between the dose, nature and timing of prenatal exposure to alcohol and problems of child behavior in the future. Fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE) are preventable forms of mental retardation and developmental disability caused by heavy prenatal alcohol exposure.

The human brain is arguably one of the most complicated organism living systems. This elaborate structure originates from a simple neural tube, followed by a series of differentiation processes. The possible contributions of PAE to nervous system malformations must be considered in the context of developmental timing. Neural tube defects typically occur during weeks 3–4 of human gestation [12]. Morphometric characterization of the brain at each stage not only aids in understanding this highly ordered developmental process but also provides clues to detecting abnormalities caused by genetic or environmental factors. Some observations have shown that the development of brain abnormalities: brain microencephaly, neural tube defects, hydrocephalus with various etiology and severity and cerebral vascular lesions, is not associated with complications at birth or as a result of prematurity [12].

Alcoholism of the mother can lead to the development of the FAS or FAE, which is apparent as a complex of disorders in the somatic and mental domains, reflecting impaired nervous system development [13, 14]. A number of authors have shown that the development of this syndrome is mainly due to impaired fetal brain development [15–17], starting from the earliest stages of neurogenesis and brain formation structures, which leads to a delay in migration and differentiation of neurons and some disorders of angiogenesis and synaptogenesis [15, 18–21]. The function of the blood-brain barrier (BBB) in the embryonic brain is mediated by cellular elements—endotheliocytes, developing glial cells and pericytes, and also by the noncellular structures of capillary basal membranes. Elements of BBB are under the direct influence of alcohol, with prenatal exposure to it during pregnancy in conditions of mother's alcohol abuse. In the early stages (5–6 weeks of intrauterine development), the neural tube does not have blood vessels. Neuroectodermal structures are fed from a protein-rich fluid into the neural tube. Due to their rapid growth and increase in mass, nutrients enter the newly formed blood vessels [22, 23].

At the molecular-cellular level, changes in the nervous system in the formation of alcohol dependence are associated with activation of the processes of synaptic plasticity. With the development of alcohol dependence, stimulation of neuroplasticity is considered one of the reasons for the rapid formation of a behavioral stereotype—addictive behavior. At the same time, long-term consumption of ethanol leads to a permanent disruption of synaptic plasticity, which can cause cognitive impairment, learning and memory problems, and the formation of alcoholic motivation and obsessive directed behavior in experimental animals and people with prolonged use of alcohol [24].

1. Introduction

74 Drug Addiction

blood vessels [22, 23].

Prenatal alcohol exposure at moderate and higher levels increases the odds of child behavior problems with the dose, pattern and timing of exposure affecting the type of behavior problems expressed [1, 2]. Disruption in the neural activation of the prefrontal cortex (PFC) and neurobehavioral disorders were detected in children with severe prenatal exposure to alcohol (PAE) [3–6]. The developing brain is extremely sensitive to the effects of ethanol [6, 7]. The use of significant doses of ethanol during pregnancy can result in a combination of profound

The use of moderate doses of ethanol can cause abnormalities that are not associated with multiple morphological and neurological damage associated with FAS, but are associated with the development of cognitive deficits and more serious consequences in the offspring, which can be particularly pronounced in puberty [10, 11]. This formed the basis for an expanded diagnostic classification of fetal defects and a new category—neurodevelopmental disorders caused by alcohol. There is a complex relationship between the dose, nature and timing of prenatal exposure to alcohol and problems of child behavior in the future. Fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE) are preventable forms of mental retardation

The human brain is arguably one of the most complicated organism living systems. This elaborate structure originates from a simple neural tube, followed by a series of differentiation processes. The possible contributions of PAE to nervous system malformations must be considered in the context of developmental timing. Neural tube defects typically occur during weeks 3–4 of human gestation [12]. Morphometric characterization of the brain at each stage not only aids in understanding this highly ordered developmental process but also provides clues to detecting abnormalities caused by genetic or environmental factors. Some observations have shown that the development of brain abnormalities: brain microencephaly, neural tube defects, hydrocephalus with various etiology and severity and cerebral vascular lesions, is

Alcoholism of the mother can lead to the development of the FAS or FAE, which is apparent as a complex of disorders in the somatic and mental domains, reflecting impaired nervous system development [13, 14]. A number of authors have shown that the development of this syndrome is mainly due to impaired fetal brain development [15–17], starting from the earliest stages of neurogenesis and brain formation structures, which leads to a delay in migration and differentiation of neurons and some disorders of angiogenesis and synaptogenesis [15, 18–21]. The function of the blood-brain barrier (BBB) in the embryonic brain is mediated by cellular elements—endotheliocytes, developing glial cells and pericytes, and also by the noncellular structures of capillary basal membranes. Elements of BBB are under the direct influence of alcohol, with prenatal exposure to it during pregnancy in conditions of mother's alcohol abuse. In the early stages (5–6 weeks of intrauterine development), the neural tube does not have blood vessels. Neuroectodermal structures are fed from a protein-rich fluid into the neural tube. Due to their rapid growth and increase in mass, nutrients enter the newly formed

morphological and neurological changes called fetal alcohol syndrome (FAS) [8, 9].

and developmental disability caused by heavy prenatal alcohol exposure.

not associated with complications at birth or as a result of prematurity [12].

Neurogenesis is the basis for ensuring the plastic function of the brain and is regulated by many factors. Stimulation of neurogenesis is observed in a number of pathological conditions: brain ischemia, trauma, the development of neurodegenerative pathology, the influence of neurotoxic agents, including high doses of alcohol, prolonged use. Neurogenesis is the key adaptive function of the brain, represents one of the most important mechanisms of brain plasticity, which is expressed in an increase in the number of cells involved in the restructuring of neuronal networks. Exposure to ethanol limits early development by delaying or inhibiting the formation of postsynaptic neurons from progenitor neuronal cells (PNA) [19–21, 25].

The effects of ethanol in the early stages of development can disrupt the signaling mechanisms that regulate synaptogenesis. Negative effects of ethanol are associated also with its influences on the lipid component of neuron membranes. As lipotropic agent, ethanol is able to change the essential physico-chemical properties of cell membranes, which is reflected in the current fetal brain synaptogenesis [26, 27]. It has been shown that ethanol triggers apoptotic neurodegeneration [17] in the developing brain, when administered to infant rodents during the period of synaptogenesis, also known as the brain growth spurt period [19, 20]. Prenatal alcohol exposure inhibits neurogenesis [24, 28] and dendritic growth of newborn neurons [18].

The effects of ethanol cause neuronal death, impairment of differentiation, migration of neuronal elements and changes in neuronal plasticity, acting through various receptors and their signaling pathways [29]. Rapidly developing neural networks form synapses, mediate the communication and functioning of a multitude of synapses, through neuromediation part of them associated with a neurotransmitter gamma-aminobutyric acid (GABA), which operates via chloridepermeable GABA type A receptor channels. At an early stage of development, neurons have a high concentration of intracellular chloride, which leads to an outflow of chloride and exciting actions of GABA in immature neurons. Transmission of GABA signals is also established prior to the formation of glutamatergic transmission. Thus, GABA is the main excitatory transmitter in the early stages of development and modulates the cell cycle, the formation of cells and their migration [30–33].

The currently accepted position is that the adverse effects of ethanol are also linked with interactions with specific proteins, ion channels and receptors, leading to changes in their functions [17, 34, 35]. The ability of ethanol to interact with receptor proteins was demonstrated, which contributed to a change in neuronal excitability. GABAergic neurotransmission plays an important role in the mechanisms of action of ethanol. GABA receptors fulfill the inhibitory role in the CNS. GABAAR is an oligomeric protein complex, which contains various allosteric binding sites that modulate receptor activity, and these allosteric binding sites are the 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 GABA-BzD-receptor complex.

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

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

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

77

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

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

2.1. Vesicles in the human developing brain in conditions of prenatal exposure to alcohol

The rapidly growing neuronal structures of the developing brain of the embryo and fetus are powered by a protein-rich fluid in the lumen of the neural tube. Subsequently, this mechanism becomes inadequate when their mass increases, and the task of delivering nutrients and removing metabolic products falls on blood vessels. It is extremely important to assess the degree of alcohol exposure to vasculogenesis of the developing brain fetus under the influence

influence of chronic alcoholization

pregnancy: influenza, rubella, toxoplasmosis and others.

involved five cases for each age period in the control and study groups.

of prenatal alcohol exposure associated with maternal alcoholism [48].

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 functioning [46, 47].

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 consequences of alcohol abuse and withdrawal.

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 harmful effects of ethanol.
