Serotonergic agents and alcoholism treatment: a simulation.
BACKGROUND
Those with early-onset alcoholism may better respond to ondansetron (a 5-HT3 receptor antagonist) than to selective serotonin reuptake inhibitor (SSRI) treatment, whereas those with late-onset alcoholism may present the reverse response pattern. Johnson and colleagues proposed a model that attempts to explain the observed treatment response patterns of those with early and late alcoholism onset by focusing on the influence of a common genetic variant in the serotonin transporter regulatory region (5-HTTLPR) on serotonin (5-HT) and dopamine (DA) system function.


METHODS
The present study formalizes and extends Johnson's descriptive model into a computer simulation consisting of differential equations. For each of 16 conditions defined by genotype, drinking status, diagnostic status, and drug treatment, data were generated by 100 simulation runs.


RESULTS
In every condition, the S/_ genotype (S/S and S/L) had higher extracellular 5-HT levels than did the L/L genotype. The S/_ genotype also had higher rates of postsynaptic DA firing than did the L/L genotype with the exception of the SSRI treatment condition, where the firing rates were similar. Drinking generally increased levels of extracellular 5-HT, reduced rates of presynaptic 5-HT firing, and increased rates of postsynaptic DA firing. Drinking produced increases in DA activation that were greater for the L/L genotype in the SSRI treatment condition and for the S/_ genotype in the ondansetron treatment condition.


CONCLUSIONS
Genotype at 5-HTTLPR may influence relative reward of drinking alcohol while a person is under pharmacological treatment for alcoholism. Alternatively, 5-HTTLPR genotype may influence pathways of alcohol craving. Clinical studies should examine these hypotheses.
Stoltenberg
Scott F
SF
University of Michigan, Department of Psychiatry, Addiction Research Center, Ann Arbor 48108, USA. sstolten@umich.edu
D000437:Alcoholism / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D002352:Carrier Proteins / Q000235:genetics*; D003198:Computer Simulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018490:Serotonin Agents / Q000627:therapeutic use*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human