Individual sensitivity to novelty and (+)-3,4-methylenedioxymethamphetamine: Roles for serotonin and GABA neurotransmission

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Drug addiction continues to be a problem in our society, and better understanding of the neuroanatomical and neurochemical alterations that delineate the switch between causal drug use and compulsive drug addiction is needed. Characterizing what makes one individual more vulnerable to the development of compulsive drug-taking behaviors may hold the key to this complex phenomenon. Because individual differences in humans exist to the subjective effects of 3,4-methylenedioxymethamphetamine (MDMA) and these differences are rooted, in part, in individual sensitivity to the drug effects, we utilized two animal models of increased sensitivity in the current studies. First, in a sensitization animal model we examined the mechanisms of increased sensitivity to (+)-MDMA and found a critical role for serotonin (5-HT) neurotransmission, in particular the 5-HT2A receptor (5-HT2AR) in the nucleus accumbens (NAc) and prefrontal cortex (PFC). We then carried this finding into a model of individual difference in which animals are separated based on their differential locomotor response to a novel environment into high responder rats (HR) and low responder rats (LR). In addition to an increased sensitivity to (+)-MDMA, we uncovered basal differences in the 5-HT system between HR and LR rats, an increased level of expression of the 5-HT2AR in the NAc of HR rats in particular. Additionally, we examined the brain structures activated secondary to novelty in HR vs. LR rats and the phenotype-specific behavioral changes after repeated exposure to the environment. Our findings revealed a strong influence of GABA neurotransmission that may underlie the differences between HR vs. LR behavioral phenotypes. These findings lend support to the idea that the neural systems underlying drug-induced and stress-induced behaviors overlap and may help to understand how individual sensitivity to both (+)-MDMA and novelty may confer an increased vulnerability to the development of compulsive drug-taking behavior.

vulnerability, MDMA, drug abuse, DOI, c-Fos, 5-HT2A receptor