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Little et al., 1993Little et al., , 1999Staley et al., 1994), accompanied by up-regulation of dopamine uptake (Mash et al., 1997). Such functional alterations could be important, perhaps contributing to cocaine-induced binging, withdrawal symptoms, or craving. Beyond drug self-administration, dopamine neurons play a role in other rewarding phenomena, including sex (Everitt, 1990) and eating (Phillips et al., 1993), suggesting that regulatory alterations in DAT function could have interesting implications for understanding the dynamics of a number of motivational and appetitive processes. Recent experiments in cell culture have determined that phosphorylative treatments (Pristupa et al., 1998;Daniels et al., 1999;Melikian and Buckley, 1999) or exposure to the stimulant d-amphetamine (Saunders et al., 2000) dynamically regulate DAT function by changing DAT cellular localization, perhaps invoking mechanisms that might be related to those activated by cocaine.Understanding the mechanisms involved in DAT binding site changes is important because 1) binding site alterations are the primary alterations documented in postmortem brain from cocaine users; 2) DAT inhibitors/ligands are being developed extensively as both therapeutic and imaging agents for both the DAT as well as dopamine neurons; and 3) DAT regulation may provide broader insights into the pharmacological effects of drugs on transporter binding sites. In addition to our need to uncover cocaine's neurochemical effects that provoke symptoms associated with its dependence, it is possible that new therapeutic or imaging agents (many of which are often DAT uptake inhibitors) might themselves induce adaptations in DAT function, as well as alter cocaine's effect on dopamine uptake. Also, potentially, DAT inhibitor binding sites could be altered through some mechanism that is independent of changes in DAT concentration or function.

A functional polymorphism in the regulatory region of the serotonin transporter gene (5‐HTTLPR) is considered to be a plausible candidate gene for anxiety‐related personality traits and for alcoholism. Empirical support for the association between 5‐HTTLPR and psychological traits has been somewhat inconsistent; however, observations of the functional dominance of the low‐activity s‐allele over the l‐allele have been more consistent. When studying the influence of particular genes on psychological traits, it seems useful also to assess more biological intermediate traits that may mediate the effects of those genes on the traits of interest. The present study examined relationships between 5‐HTTLPR genotype, whole blood serotonin (5‐HT) level, and platelet 5‐HT binding in 150 Caucasian subjects from 50 biological families. Individuals with the s‐allele had lower average platelet 5‐HT binding availability than those with the l/l genotype (P < 0.025). Whole blood 5‐HT level was not associated with 5‐HTTLPR genotype. In adult men, those with the s‐allele had higher mean scores on the NEO‐FFI personality trait of openness than did those with the l/l genotype (P = 0.002). The effect was not statistically significant in women (P = 0.42), although it was in the same direction. Our findings do not support an association of 5‐HTTLPR genotype with alcoholism diagnosis, alcoholism subtype, or the personality trait of neuroticism. The results of this pilot study suggest that further work should examine the mediation of the genetic effects on personality traits by biochemical measures and their moderation by gender. © 2002 Wiley‐Liss, Inc.

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Cocaine exposure has a marked effect on DAT function, but the mechanisms involved may be complex.