NEUROBIOLOGICAL BASES OF ALCOHOL ADDICTION.

Alcohol addiction is a heterogeneous psychiatric disorder according to both phenotype and etiology. Difference in phenotype characteristics manifests in the manner the addiction arises, history of the alcoholic and history of drinking, comorbid disorders, and the phenomenon of abstinence difficulties. Concerning the etiology of alcoholism, the disease itself is considered to be a consequence of an interactive influence of the environment and genetic factors. Numerous researches conducted in the last decades discovered many aspects of the biochemical, cell and molecular bases of alcohol addiction, leading to a conclusion that alcoholism is, like many other addictions, a brain disease. By recognizing alcoholism as a disease which basically implies changes of the neurobiological mechanisms, as well as a clear genetic basis, it was supposed that the disease, having its basis solely in the symptomatology, is essentially heterogeneous. By trying to solve the problem of a clinically heterogeneous nature of the disease during the last fifty years, various sub-classifications of such patients have been suggested. According to Cloninger, subtypes of alcoholism differ also according to changes in the brain neurotransmission systems, i.e. it is supposed that patients suffering from alcoholism type 1 have a more pronounced dopaminergic transmission deficit, while dopaminergic transmission is not disturbed significantly in patients diagnosed with alcoholism type 2, who, however, have a significant lack of serotonergic transmission. In such a way, Cloninger actually presented the basis of the so-called neurobiological alcoholism model. Since he has connected differences in neurotransmission with differences in personality characteristics, this model is also known as the psychobiological model of alcoholism. The characteristic of alcoholism type 1 is avoiding damage (Harm Avoidance, HA) decreased dopamine transmission and increased serotonin transmission, while the significant characteristic of alcoholism type 2 is seeking for excitement (Novelty Seeking, NS), unchanged dopamine transmission and decreased serotonin transmission. These neurochemical differences among alcoholism subtypes represent the basis for a different therapy approach. Intake of alcohol changes different gene expression in the human brain. The inheritance model of alcoholism is not fully explained, however, it is considered that the disease is connected to a larger gene number included in neurotransmission, cell mechanisms and general metabolic function, with a simultaneous influence of the environment. The contribution of genetic factors is stronger in certain types of alcoholism and thus we have been confronted in the last years of alcoholism research with studies researching the connections of some alcoholism subtypes with the polymorphism phenomenon in the genes coding the synaptic proteins included in the alcoholism etiology. The primary role of monoamine oxidase (MAO) in the brain is catalysis of deamination of the oxidative neurotransmitter amines, i.e. serotonin, adrenaline, noradrenaline and dopamine. Thus, this enzyme is the key factor for maintaining cytoplasmic concentration of various neurotransmitters and for regulation of the neurotransmitting synaptic activity. Taken this MAO function into consideration, MAO is the enzyme included in the etiology and pathogenesis of various neuropsychiatric and neurological disorders. The finding of the decreased platelet MAO activity in various psychiatric disorders has brought us to the assumption that this enzyme may be a constitutional/genetic indicator (trait marker) or an indicator of disease condition (state marker) in biologic psychiatry. There are only a few studies of alcohol addiction researching the connections of the MAO coding gene polymorphism and alcoholism; however, these studies are primarily related to the variable number of tandem repeats (VTNR) polymorphism in the regulatory gene region for MAO-A, considered to influence the transcription activity/functionality of the enzyme.

Alcohol dependence and polymorphisms of serotonin-related genes: association studies.

Variations in 5HT-related genes contribute to the alterations of serotonergic neurotransmission, which is implicated in the etiopathology of alcoholism. In this preliminary study we have tested polymorphisms of genes involved in 5HT transport and turnover for their association with alcohol dependence. A case group of males with type 2 alcoholism (N=59) and a control group of healthy males (N=282), both of Croatian origin, were analyzed for the frequency distribution of polymorphisms in 5HT transporter (5HTT-VNTR2, 5HTT-LPR), monoamine oxidase A (MAOA-uVNTR) and B (MAOB-A/G) and tryptophan hydroxylase 1 (TPH1 A218C) and 2 (TPH2 G-703T) genes. An increase in the frequencies of 10-repeat allele (p = 0.010; OR = 1.73; 95% CI = 1.14-2.60) and 10/10 genotype (p = 0.006; OR = 2.57; 95% CI = 1.32-5.00) of the 5HTT-VNTR2 polymorphism was found in alcoholic patients. No differences between case and control groups were observed for the other tested polymorphisms. Present results support earlier studies implicating the role of 5HTT gene in alcoholism. The increase of sample size (in progress) is expected to enable search of more subtle differences, as well as re-evaluation of these preliminary findings.

Increase of serum triiodothyronine concentration in soldiers with combat-related chronic post-traumatic stress disorder with or without alcohol dependence.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a relatively new psychiatric disorder with three clusters of symptoms: trauma re-experiencing, avoidance, and increased arousal. The condition develops after a person sees, is involved in, or hears of an extreme traumatic stressor such as war, torture, natural catastrophe, assault, rape, or serious accident. PTSD is also often comorbid with other psychiatric disorders, especially with alcohol dependence. Several hormonal alterations have been reported in veterans with combat-related PTSD, including elevations in certain thyroid hormones, e.g., total T3; however, previous studies have not controlled for alcohol dependence, a common comorbid psychiatric disorder in this population. OBJECTIVE: The first aim of our study was to assess possible differences in basal serum levels of free triiodothyronine (FT3), total triiodothyronine (TT3), free thyroxine (FT4), total thyroxine (TT4), and thyroid stimulating hormone (TSH) in Croatian soldiers with combat-related chronic PTSD alone or comorbid with alcohol dependence and in healthy controls. The second purpose of the study was to determine any correlation between duration of combat activities, number of combat traumas, intensity and duration of PTSD symptoms, and serum levels of TT3, FT3, TT4, FT4, and TSH in this sample. METHOD: We analyzed basal serum FT3, TT3, FT4, TT4, and TSH concentrations in soldiers with combat-related chronic PTSD (N=43), combat-related chronic PTSD comorbid with alcohol dependence (N = 41), and in healthy controls (N = 39) using a luminoimmunochemical assay. RESULTS: Soldiers with chronic combat-related PTSD with or without comorbid alcohol addiction had significantly higher values of TT3 than the control group (F = 19.556, p<0.01). There was a significant correlation between TT3 levels and number of traumatic events in both the PTSD group (r=0.663, p<0.01) and those with PTSD comorbid with alcohol dependence (r=0.836, p<0.01). There was also a significant correlation between TT3 levels and symptoms of increased arousal in both PTSD (r=0.419, p<0.01) and PTSD comorbid with alcohol dependence (r=0.516, p<0.01). CONCLUSION: Elevated concentrations of serum TT3 are associated with combat-related PTSD, regardless of its comorbidity with alcohol dependence, and also with the number of traumatic events and symptoms of increased arousal. Given that current pharmacotherapy for PTSD is inadequate, reduction of TT3 may be a new strategy for pharmacologic intervention that could contribute to more effective treatment of this disorder.

Comorbid alcohol addiction increases aggression level in soldiers with combat-related post-traumatic stress disorder.

The aim of this study was to compare aggressive behavior in soldiers with combat-related post-traumatic stress disorder (PTSD), PTSD comorbid with alcohol addiction and alcohol addiction only. Three groups of male combat experienced soldiers with PTSD (n=43), PTSD comorbid with alcohol addiction (n=41) and alcohol addiction (n=39) were compared by Aggression rating scale A-87. PTSD was diagnosed according to DSM-IV criteria and Watson's PTSD rating scale. Alcohol addiction was diagnosed according to DSM-IV criteria and CAGE Questionnaire. Combat-experienced soldiers with alcohol addiction as well as soldiers with combat-related PTSD comorbid with alcohol addiction have a high level of verbal latent aggression (VLA), (F=26.65; P<0.001), physically latent aggression (PLA), (F=37.86; P<0.001), indirect aggression (INA), (F=56.94; P<0.001), verbal manifest aggression (VMA), (F=18.35; P<0.001), and physically manifest aggression (PMA), (F=43.22; P<0.001), vs. soldiers with combat-related PTSD without comorbid conditions. Alcohol addiction is a severe factor in increasing aggression levels in soldiers with PTSD.

Factores biológicos en pacientes con Trastorno de Estrés Postraumático (PTSD) y Alcoholismo

Los acontecimientos traumáticos que sobrepasan la experiencia humana normal, tales como las situaciones que ponen en peligro la vida o la integridad física o la exposición de personas próximas a un peligro similar, pueden producir determinados problemas psicológicos en el individuo, que se describen en el marco de un trastorno denominado Trastorno de Estrés Postraumático. La exposición a numerosos acontecimientos e influencias estresantes produce, como resultado de numerosos factores, el que el organismo desencadene una serie de mecanismos de defensa, en los que juega un papel fundamental el Sistema Nervioso Central, pero también el sistema suprarrenal y el cardiorespiratorio. Cuando la homeostasis interna está en peligro, se activa el sistema endocrino y su respuesta al peligro depende de la intensidad del agente causante del estrés, de la duración de la exposición y de la capacidad del sistema para compensar el estrés. La exposición al estrés y el efecto directo del agente causante de estrés desencadena además otro mecanismo de defensa, cual es el aumento del consumo de alcohol a modo de automedicación y bajo la influencia directa del agente causante de estrés. Tanto el PTSD como el alcoholismo conducen de forma gradual a la afectación del sistema neuroendocrino. En nuestro estudio hemos incluido dos grupos de pacientes, concretamente el grupo de pacientes que padecen de PTSD y de alcoholismo y el grupo de pacientes que padecen únicamente de PTSD. Hemos llevado a cabo la evaluación de los niveles de cortisol en suero y en la orina de 24 horas, el test de supresión de la dexametasona y los niveles en suero de ACTH, TSH, T3, T4, testosterona, prolactina y hormona del crecimiento. Los resultados obtenidos llevan a considerar la presencia de alteraciones en los ejes neuroendocrinos en los dos grupos de esta investigación, alteraciones que se presentan más marcadas en el grupo de sujetos que presentan comorbilidad de PTSD y alcoholismo (AU)