Genotype effects on neurodegeneration and neuroadaptation in monoaminergic neurotransmitter systems.
Neuroadaptation and neurodegeneration in central dopaminergic and serotonergic systems are central to vulnerability, process and consequences of addictive behavior. Serotonergic dysfunction has been associated with behavior disinhibition and negative mood states that may predispose to excessive alcohol intake, while alcohol-induced stimulation of dopaminergic neurotransmission may encode the reinforcing properties of alcohol consumption. Chronic alcohol intake induces neuroadaptive reductions in striatal dopamine transporter (DAT) and D2 receptor availability, which were reversible during early abstinence. A polymorphism of the DAT gene (SLC6A3) was associated with the in vivo transporter availability in the putamen of abstinent alcoholics and control subjects. The same genotype was associated with severity of alcohol withdrawal symptoms, hypothetically due to interactions of genotype and alcohol-induced neuroadaptation. Reduction in raphe serotonin transporter (5-HTT) availability was observed in abstinent male alcoholics and it may be the result of neurodegeneration rather than reversible neuroadaptation. Neurotoxic reduction in 5-HTT protein expression seems to be limited to homozygous carriers of a long, more transcriptionally active allele of a promoter repeat polymorphism of the 5-HTT gene (SCL6A4). This genotype was also associated with a low level of acute unpleasant effects of alcohol consumption, a factor predisposing to excessive alcohol intake. The time course of neuroadaptation and recovery of monoaminergic neurotransmission in alcohol intake and withdrawal imply that monoamine transporter genotype could profoundly influence alcohol-induced reinforcement and, perhaps, contribute to neurochemical changes which are long lasting or permanent.
Heinz
A
A
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Mannheim, Germany. heinza@as200.zi-mannheim.de
Goldman
D
D
D000222:Adaptation, Physiological / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics* / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D004298:Dopamine / Q000502:physiology*; D005838:Genotype; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics*; D012701:Serotonin / Q000502:physiology*
D012701:Serotonin; D004298:Dopamine