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Example research essay topic: Substance Abuse Neuro Transmission - 2,526 words

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PHYSIOLOGICAL MECHANISMS OF SUSCEPTIBILITY TO PSYCHOACTIVE SUBSTANCE DEPENDENCE Physiological Mechanisms of Susceptibility To Psychoactive Substance Dependence Abstract The scholars enter into controversy concerning the genetic susceptibility to psychoactive substance dependence. Currently some evidence has been advanced which confirms that patients suffering from opiomania often report hereditary characters of alcoholism. The paper examines a chance of fundamental uni city of central mechanisms of psychoactive substance dependence, in order to prove the hypothesis that congenital insufficiency of activity in the cerebral system of reward, predominantly stipulated by the deficit of dopamine neurotransmitter system may be examined as one of the main neurophysiological prerequisites of high motivation for psychoactive substance abuse. Introduction On the modern level, the fact of genetic susceptibility to psychoactive substance dependence is well-known. Currently some evidence has been advanced which confirms that patients suffering from opiomania often report hereditary characters of alcoholism (49 per cent of patients have at least one family member suffering from alcohol abuse).

Under these conditions 59 % of patients reported alcohol abuse prior to drug consumption. Different types of pre morbid pathologies were discovered: pathological state of mothers pregnancy and postnatal stage of development, enuresis, symptoms of minimal cerebral dysfunction, and symptomatic psychical infantilism, etc. Thus, susceptibility to psychoactive substance dependence is predominantly observed in patients with hereditary characters of alcohol abuse and other hereditary malfunctions of central nervous system. Neuro chemical researches allow making conclusion concerning a fundamental uni city of central mechanisms of psychoactive substance dependence. In this connection it should be noted that, probably, genetic mechanisms of susceptibility also can be common. All substances able to provoke the dependence syndrome, have a common link of pharmacological action, - a peculiar impact on catecholamine neuro transmission in limbic structures of cerebrum, in particular, in the system of reward (reinforcement).

The influence of psychoactive substances causes intensive ejection of neurotransmitters CA group (catecholamine) from depots (primarily, dopamine), or directly activates dopaminergic receptors. In its turn, it leads to significantly stronger reward system agitation. Such agitation is often followed by positively colored emotional experiences. Experiments on animals allowed coming to conclusion that congenital insufficiency of activity in the cerebral system of reward, predominantly stipulated by the deficit of dopamine neurotransmitter system may be examined as one of the main neurophysiological prerequisites of high motivation for psychoactive substance abuse.

Taking into account that the changes in dopamine neuro transmission are the key elements of formation of psychoactive substance dependence, it is reasonable to suppose that the search for neuro chemical and genetic mechanisms of congenital susceptibility to psychoactive substance dependence should be based on its examination and further research. Peculiarities of circulating load of dopamine in blood in patients suffering from alcohol abuse with burdened familial history and those having no familial anamnesis records According to the results of researches, there are significant differences in functioning dopamine system in patients suffering from alcohol abuse with burdened familial history and those having no familial anamnesis records. Along with changes in functions of catecholamine neurotransmitter system, characteristic for all patients reporting alcohol abuse, there were discovered dysfunctions of catecholamine neurotransmitter systems activity, peculiar exceptionally to patients with burdened familial history for this disease. Dysfunctions, characteristic for patients with burdened familial history for alcohol abuse, are as follows: significant decrease in free dopamine concentration in blood serum, tendency to decrease the level of noradrenaline, followed by abrupt decrease in dopamine/ noradrenaline coefficient, low dihydroxy phenylalanine concentration, and high level of dihydroxyphenylphenol acid. Patients with no familial anamnesis records on psychoactive substance abuse reported completely opposite results: concentration of free forms of noradrenaline and dopamine in blood serum exposed the tendency to increase; dihydroxy phenylalanine level was high, while dihydroxyphenylphenol acid concentration was low. Patients with familial anamnesis records on psychoactive substance abuse during the remission period also reported significantly low activity of dopamine beta hydroxylase in blood.

The analysis of obtained data allows making conclusion that patients suffering from alcohol abuse with familial anamnesis records on psychoactive substance abuse report system dysfunction of dopamine system function, first of all deficit in free forms of dopamine, which acts as neurotransmitter. The cause of the deficit may, probably, serve a decreased dopamine synthesis and its intensified desalinization (low dihydroxy phenylalanine concentration and high dihydroxyphenylphenol acid level). Low dopamine beta hydroxylase activity, emerging even during the remission periods, witnesses of dysfunctions in other chains of dopamine system. Experiments on mice with different level of susceptibility to voluntary psychoactive substance consumption also report interdependence between high motivation for psychoactive substance consumption with lo activity of the cerebral reward system and deficit of dopamine neuro transmission in limbic systems. Dopamine System genetic polymorphism The examination of genetic nature of alcohol and psychoactive substance abuse is of the utmost practical importance for prevention and treatment. Discovering genetic markers of susceptibility to psychoactive substance abuse will allow determining the biological risk group and undertaking effective preventive measures.

Congenital deficit of dopamine neuro transmission in cerebral reward system is the main prerequisite for susceptibility to depressions, permanent feeling of dissatisfaction, and emotional instability. The patients with deficit of dopamine neuro transmission are characterized by a consistent search for newness, and disposition to run risks (Noble, 2000). Understanding the physiological and genetic basis for susceptibility to psychoactive substance abuse will allow developing new genetic therapy methods. Yet, in order to realize the intervention on a genetic level, it is necessary to know the genetic address, e. g. to discover genes responsible for susceptibility to psychoactive substance abuse as well as their structural peculiarities.

The psychoactive substance dependence is a poly genic disease therefore the discovery of genes responsible for susceptibility is a matter of significant difficulties. Evidently, the search should be conducted within the framework of functional approach. The above-listed facts support the hypothesis that the search for genes responsible for for susceptibility to psychoactive substance abuse should be conducted by examining genes regulating dopamine neuro transmission. The examinations of structural peculiarities in genes responsible for different chains of dopamine system genetic polymorphism (the gene of key enzyme of the dopamine and noradrenaline synthesis, tyrosine hydroxylase, dopamine beta hydroxylase, dopamine receptors (DR 2, DR 4), gene of dopamine transporting protein, andthe gene of enzyme responsible for dopamine destruction catechol ortho methyl transferase). The research has been conducted by means of comparison of two groups the group of patients suffering from alcohol abuse with familial anamnesis records on psychoactive substance abuse, and the group of patients with no prior familial anamnesis records.

In addition, there was a difference in clinical characteristics of disease. The first group of patients reported early onset of disease, grave clinical course and unsatisfactory results of treatment. Screening group included healthy donors with no psychoactive substance abuse and no mental disorders. The screening group was statistically homogenous to the group of patients with dependence by age, sex and ethnic origin. During the process of comparison and analyzing obtained data the groups of patients both with and without prior familial anamnesis records by frequency of occurrence 12 of possible non minor genotypes tyrosine hydroxylase by locus HUMTH 01 were discovered two genotypes with different frequency of occurrence, - 9 / 10 - 1 and 7 / 8 correspondingly. Genotype 9 / 10 - 1 occurred in the group of patients with prior familial anamnesis records at a frequency rate of 0. 15 % vs. 0. 05 % in the group of patients with no prior familial anamnesis records.

The frequency rate made up 11 % in the control group that corresponds to intermediate value for the groups of patients. The differences in frequency of occurrence for genotype 9 / 10 - 1 between the control group and two groups of patients, apparently, were invalid, while the differences between groups with and without prior familial anamnesis records displayed a steady trend close to the reliability threshold by criterion hi 2 (hi 2 = 2, 31; p = 0, 12). The patients with 9 / 10 - 1 genotype (group 9 / 10 - 1) were compared to the group of patients with other genotypes. Group 9 / 10 - 1 reported considerable decline in quantity of patients with continuous sluggish clinical course of alcoholism (0. 067 vs. 0. 49; Chi 2 = 9, 83; p = 0, 0017) and increased quantity of patients with average-progressive clinical course of alcoholism (0. 47 vs. 0. 15; hi 2 = 9, 14). Quantity of patients with high level of prior familial anamnesis records made up 60 % vs. 14. 5 % in the other group (Chi 2 = 17, 37; p = 0, 0001) (see table 1). In such a way, the patients with 9 / 10 - 1 genotype are characterized by significant level of prior familial anamnesis records and unsatisfactory clinical course of alcoholism with few cases of continuous sluggish clinical course of disease.

This data confirms the relationship of 9 / 10 - 1 genotype and prior familial anamnesis records on alcoholism. 7 / 8 genotype was discovered only in group of patients with no prior familial anamnesis records on alcoholism. The usage of two-tailed Fishers test showed consistency of differences (p = 0, 001). Other genotypes failed to show statistical reliability of data. All patients with 7 / 8 genotype were belonging to the group of patients with no prior familial anamnesis records on alcoholism. Consequently, this fact allowed making an assumption that 7 / 8 genotype by locus HUMTH 01 of tyrosine hydroxylase gene has negative association with prior familial anamnesis records on alcoholism. Probably involvement of this variant of polymorphic locus of tyrosine hydroxylase gene confirms the results of reversed analysis, according to which 60 % of patients with 9 / 10 - 1 genotype reported prior familial anamnesis records on alcoholism.

Dopamine transporting protein is one of the most important proteins of dopamine system, which allows occurring reverse mediator capture by presynaptic terminal. 40 - nucleotide tandem repeat in 3 - untranslated region is of the utmost importance for the researchers. The quantity of repeat may fluctuate from 3 to 11. According to the researches, patients with prior familial anamnesis records on alcoholism report increased occurrence of 9 / 10 genotype dopamine transporting protein (0. 41) compared to control group and patients with no prior familial anamnesis records on alcoholism (Table 2). Patients suffering from opiomania reported a predominance of homozygote's 10 / 10 with frequency rate 0. 69 as well as heterozygote's 9 / 10 with frequency 0. 24. During the comparative analysis of frequency of genotype distribution between group of patients and control set reliable differences were discovered (Chi 2 = 11, 42; p = 0, 006) due to reliable increase of the share of homozygote genotype 9 / 9 (Chi 2 = 7, 38; p = 0, 008).

Both representative samples reported a prevalence of gene allele 10 (0. 81 and 0. 79); gene allele 9 was the second most abundant allele. Probably, gene allele 9 should be examined as risk allele for alcohol and psychoactive substance abuse. This assumption can be supported by facts of functional role of the given polymorphism, particularly, its influence on expression of gene-transporter dopamine. Dopamine receptors subtype 2 (DRD 2) (auto receptors) are located at afferent nerve fibers endings in ventral cerebral surface. DRD 2 gene is located at chromosome 11 q 22 -q 23 and contains several polymorphic sites (Bloom 2000). DRD 4 gene is located at chromosome 11 p, being one of the most variable by its structure.

Such diversity can be explained by presence of polymorphic site in 3 rd exon. Numerous researches report that A 1 allele DRD 2 prevails in patients suffering from psychoactive substance abuse compared to average population. However, the present research discovers no reliable differences in distribution A 1 allele DRD 2 in all groups (Table 3). Table 4 shows increase in share of homozygote genotype C/C and allele C in two groups of patients. This increase is followed by decline in heterozygote genotype T/C, in contrast to control group.

Patients suffering from substance abuse also report the increase in homozygote C/C genotype and C allele. Those having prior familial anamnesis records on alcoholism report an increase in homozygote genotype LL. In such a way, the research confirms the hypothesis that patients suffering from substance abuse have a tendency to increase in quantity of homozygote genotypes with L allele. Therefore, in the basis of susceptibility to psychoactive substance dependence may lay both polymorphism of one of the genes dopamine system, and polymorphism of several genes, which in combination lead to weakening dopamine neuro transmission in the cerebral reward system. Therefore, some patients suffering from substance abuse may have polymorphism of different genes coding different chains of dopamine neuro transmission. References Blum, K. , Cull, J.

G. , Braverman, E. R. , & Comings, D. E. (1996). Reward Deficiency Syndrome. American Scientist, 84, 132 - 145. Comings, D. (1996).

Both genes and environment play a role in antisocial behavior. Politics and the Life Sciences, 15, 84 - 86. Comings, D. (1996). Genetic factors in drug abuse and dependence. In W. G.

Glantz (Ed. ), Differences in the Bio behavioral Etiology of Drug Abuse (pp. 16 - 38). Washington, D. C. : National Institut on Drug Abuse. DJ, V. (2000). Am J Med Genet, 96, 678 - 83. Noble, E. (2000).

Addiction and its reward process through polymorphisms of the D 2 dopamine receptor gene: a review. European Psychiatry, 15 (2), 79 - 9. Table 1 The relative frequency tyrosine hydroxylase gene allele by polymorphic locus HUMTH 01 Group Characteristics n tyrosine hydroxylase gene all 10 - 1 Control group Healthy 113 0. 21 0. 19 0. 09 0. 17 0. 33 All patients Substance abuse 143 0. 22 0. 16 0. 06 0. 21 0. 33 Group A With prior familial records 66 0. 19 0. 13 0. 06 0. 24 0. 38 Group B No prior familial records 38 0. 28 0. 21 0. 07 0. 17 0. 26 Table 2 Genotype (%) frequency characterized by presence of 9 -, 10 - and 11 -fold VNTR repeats in dopamine transporting protein gene Group Genotype 9 / 10 10 / 10 9 / 9 11 / 9 Control group 24, 5 67, 9 6, 6 1, 0 Patients (substance abuse) All patients 36, 6 53, 3 6, 9 0, 9 Group A 41, 3 (p< 0, 05 Chi 2) 51, 8 6, 4 0, 5 Group B 28, 0 65, 4 5, 6 1, 0 Table 3. Distribution of genotype and alleles of locus Take gene DRD 2 frequencies group n Genotype frequency Alleles frequency 1 / 1 1 / 2 2 / 2 1 2 Control group 30 0, 2 0, 1 0, 7 0, 25 0, 75 Patients 25 0, 0 0, 6 0, 4 0, 30 0, 70


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