UC Santa Barbara

Self-administration of cocaine produces an initially euphoric or “high” state, following shortly after by an aversive, anxiogenic “crash”. Although there has been extensive research into the neurobiology of cocaine’s rewarding effects, less attention has focused on understanding the mechanisms of the drug’s aversive component. Recent research has identified regions like the Bed Nucleus of the Stria Terminalis (BNST) and Lateral Habenula (LHb) as key structures that contribute to aversive effects in humans and animals. The specific intent of this dissertation is to investigate the role of serotonin (5-HT) signaling in these two regions as it contributes to the negative effects of cocaine. Three main studies were designed and executed to address this question. First, to assess the role of 5-HT perturbations within the BNST on the development of approach-avoidance retreat behavior in animals trained to run an alley for cocaine. Next, the same methods were used to investigate the role of 5-HT signaling within the LHb, as animals learned about cocaine’s negative effects. Finally, the third study used selective lesions of serotonin fibers in both the LHb and BNST to determine a more precise mechanism of the observed serotonergic effects. Altogether, the experiments described in this thesis support a role for 5-HT signaling, in both regions, in mediating the behavioral consequences of cocaine’s aversive properties.