Based on the hypothesis that condensation products of neurotransmitters with aldehydes are involved in the pathogenesis of alcoholism, aromatic beta-carbolines (norharman and harman) were measured in the blood plasma of alcoholics and nonalcoholics. The identity of the extracted compounds was confirmed by various elution conditions of the high performance liquid chromatography (HPLC), newly developed radioreceptor assays, and the mass spectrum of norharman. The levels of norharman and harman in nonalcoholics were unchanged after a load with ethanol (1 g/kg body weight). The norharman levels of the alcoholics were significantly higher than that of the nonalcoholic controls (99.5 +/- 26.6 pg/ml vs. 26.9 +/- 10.7 pg/ml; p less than 0.001) and did not change significantly during a 3-week detoxication period. In the subgroup of alcoholics with delirium or hallucinosis, a slight increase of norharman during detoxication could be detected while in alcoholics with vegetative withdrawal symptoms norharman levels dropped slightly over time (p = 0.07). No difference was found with respect to harman between nonalcoholics and alcoholics. These results suggest disturbed regulatory processes in the formation and/or metabolism of norharman in alcoholics. Further investigations are needed to reveal a possible marker function of norharman in alcoholic patients.
beta-Carbolines occur in man and rat. The concentration in various tissues is about 100 to 1000 times lower than that of classical neurotransmitters. Administration of beta-carbolines in animals induces overlapping but not identical activity profiles. The molecular modes of action differ. For example, harman (1-methyl-beta-carboline) acts as an endogenous inhibitor of monoamine oxidase [E.C. 1.4.3.4.], subtype A, whereas norharman (beta-carboline) probably acts by stimulation of a specific beta-carboline receptor which is different from the benzodiazepine-GABA receptor complex. There is substantial evidence that tetrahydroisoquinolines occur under physiological conditions as well. Whether tetrahydropapaveroline serves as a precursor of morphinanes in mammals, as has been found in opium poppies, remains to be elucidated.
Long-term intake of a psychoactive drug alters brain signal transduction, emotional and motivational factors and behavioral parameters. Some effects that outlast long periods of abstinence are due to the long-term presence of the drug in the organism (tolerance, physical dependence). Withdrawal symptoms, as a consequence of physical dependence, can be protracted, i.e. they persist after long periods of drug deprivation (e.g. a desensitization of the production of cAMP). Further persisting effects include experience-based learning. At least three distinct processes can be differentiated: a memory of drug effects (reflected by a sensitization to drug effects etc.), a memory of drug use (reflected by controlled drug consumption), and a memory of addiction (reflected by a persisting loss of control over drug intake and correlating changes in striatal dopaminergic neurotransmission). The latter probably consists of two components: a general memory of loss of control and a specific memory of the addictive drug (general principles for the development of addiction, specific of the urge for the addictive drug).
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