The Role of the Serotonin Transporter as a Genetic Risk Factor in the Development of Drug Addiction

Drug addiction is a ubiquitous phenomenon worldwide that places tremendous financial and psychological burden on societies, families and the individual. Interestingly, only a small percentage of individuals ( 20%), regardless their drug of choice, go on to develop the compulsive behaviours that define drug addiction. Clinical studies have shown that there is a subset of the population with a genetically determined reduction in the serotonin transporter that may increase vulnerability to developing a variety of psychiatric disorders like depression, anxiety and drug addiction.  To investigate the influence of reduced serotonin transporter function in the laboratory we studied the effects of MDMA (‘ecstasy’) and heroin in a genetically altered animal model: the serotonin transporter (SERT) knockout rat. Homozygous (HOM) animals lack SERT function completely while heterozygous (HET) have about 50% SERT function compared to the wild type (WT). Groups of HOM, HET and WT animals completed MDMA or heroin self-administration experiments. A robust genotype effect emerged for animals self-administering MDMA; facilitation of MDMA self-administration was inversely related to SERT function. HOM animals, without exception, reached acquisition criterion significantly faster than the HET animals; HET animals then showed higher acquisition rates compared to the WT animals. In contrast, there were no differences between the genotypes when animals self-administered heroin. To investigate the driving force behind facilitated MDMA self-administration in animals with reduced SERT function locomotor activity and conditioned taste aversion experiments were undertaken. In contrast to the drug self-administration experiments,MDMA induced hyperactivity was positively related to SERT function. Thus, it was significantly reduced in HOM and HET animals compared to the WT. Again, heroin treatment did not produce differences in locomotion between the genotypes. MDMA induced conditioned taste aversion revealed only a main effect of dose with robust conditioned taste aversion for both drug doses, although a trend indicated that HOM animals may have heightened sensitivity to MDMA. However, heroin treatment failed to produce a conditioned taste aversion effect in any of the groups regardless of dose. Beyond the aforementioned behavioural experiments striatal brain tissue from the animals that had previously self-administered MDMA or heroin was analysed via quantitative reverse transcription polymerase chain reaction; five targets were evaluated to quantify drug induced changes in brain derived neurotrophic factor gene expression (BDNF). Several BDNF isoforms (total BDNF, BDNF III and BDNF IV) were significantly increased in animals that had self-administered MDMA; this effect was true across HOM, HET and WT subjects. Comparatively, animals that had self-administered heroin did not show a difference in BDNF expression compared to untreated control animals.  This suite of experiments provides insight into the influence of a compromised serotonergic system on the development of drug addiction. That is, while reduced SERT function does not appear to augment the addictive properties of drugs like heroin there is reason to suspect that it does confer additional susceptibility to developing addiction to drugs like MDMA, highlighting the hypothesis that different classes of addictive substances act through different neurobiological pathways.