Can serotonin transporter genotype predict craving in alcoholism?

Abstract

Background: We hypothesize that functional control of the serotonergic system is regulated in part by differential expression of the serotonin (5-HT) transporter (5-HTT). Alcohol-dependent individuals with the LL/LS genotype (L-carriers), compared with those with the SS genotype, have a lower 5-HT neurotransmission, which we hypothesize would be associated with higher craving for alcohol among L-carriers. We hypothesize further that acute peripheral depletion of tryptophan (5-HT's precursor), while further reducing 5-HT function, might decrease auto-inhibition of 5-HT neuronal firing, thereby increasing 5-HT neurotransmission transiently and lowering alcohol craving.

Methods: We tested these hypotheses by examining whether in 34 Hispanic alcohol-dependent individuals subjective and physiological cue craving for alcohol differed by genotype, age of onset of problem drinking, and tryptophan availability.

Results: On subjective "urge to drink" and "crave for a drink," we found a significant (p < 0.05) main effect of genotype and cue, as well as an interaction among genotype, age of onset of problem drinking, and tryptophan depletion. For the physiological measure of pulse, there was a main effect of genotype. L-carriers had higher craving than their SS counterparts, an effect that decreased under tryptophan depletion. While craving in L-carriers increased with an earlier age of onset of problem drinking, the opposite effect was seen in those with the SS genotype.

Conclusion: These results not only provide support for the hypothesis that alcoholics who are L-carriers have greater alcohol craving and possibly greater propensity for drinking but also propose that there is an important 5-HTT gene-by-environment interaction that alters cue craving response for alcohol.

Figure 1

Effect of genotype on the mean difference ± standard error in “urge to drink” for response to cue exposure. Estimated average cue exposure response is calculated using the following formula: (t4 to t5) – (t1 to t3), or post-cue minus pre-cue craving scores between the alcohol and control cues, which represents the change from baseline both with and without tryptophan depletion.

Figure 2

Effect of genotype on the mean difference ± standard error on “urge to drink” for response to cue exposure. Estimated average cue exposure response is calculated using the following formula: (t4 to t5) – (t1 to t3), or post-cue minus pre-cue craving scores between the alcohol and control cues, which represents the change from baseline by age of problem drinking onset. Participants comprised: 11 LL early-onset alcoholics (EOAs), 1 LL late-onset alcoholic (LOA), 6 SS EOAs, 3 SS LOAs, 9 LS EOAs, and 4 LS LOAs. This figure is shown to describe the direction of the interaction between genotype and age of problem drinking onset. Inferential statistics were conducted using age of problem drinking onset as a continuous, not a dichotomous, variable. The purpose of the figure dichotomizing early onset from late onset is for visual display only.