Influence of 5-HT1b Activation on the Abuse Related Effects of Cocaine

Cocaine use disorder continues to be a significant public health concern. Despite strides in our understanding of the neurobiological underpinnings of cocaine addiction in preclinical models, a limited amount of research has translated those findings into clinical populations. Such translation is crucial to identify neurobiological circuits that contribute to the problems posed by cocaine use disorder and to guide treatment based on those clinical neuroscience findings. Cocaine potently inhibits the reuptake of serotonin (5-HT). Increased synaptic 5- HT resulting from this reuptake inhibition activates multiple 5-HT receptor subtypes. Some of these receptor subtypes have been implicated in the abuse-related effects of cocaine, including its primary reinforcing effects (i.e., cocaine taking behavior). 5-HT1b receptors play a particularly important role in cocaine effects, likely because they are highly expressed in the mesocorticolimbic system. Preclinical data show that zolmitriptan, a commercially available selective 5-HT1b agonist migraine medication approved for human use, selectively attenuates the reinforcing and other abuse-related effects of cocaine. The overarching goal of this project is to advance these promising preclinical findings into clinical populations, thereby demonstrating that the 5-HT1b system plays a key role in the effects of cocaine in humans. To this end, 20 non-treatment seeking human subjects meeting diagnostic criteria for cocaine use disorder will sample doses of intravenous cocaine (0, 10 and 30 mg/70 kg) in experimental sessions after 3 days of maintenance on oral zolmitriptan (0, 2.5, 5 and 10 mg). A placebo-controlled, double-blind, within-subjects design will be used such that all subjects experience all dose conditions in random order. The study will require an approximately 1 month admission to our inpatient unit. After sampling a cocaine dose, subjects will make nine choices between that dose and an alternative reinforcer (US$6.00) on a concurrent progressive-ratio choice task that was developed and validated in our laboratory. A battery of subjective drug-effect measures and tasks that assess distinct domains of impulsivity will be completed during the same experimental sessions in which cocaine choice is assessed. The research proposed here will directly translate findings from preclinical research and provide the initial clinical evidence that 5-HT1b activation, achieved through administration of zolmitriptan, reduces the reinforcing and other abuse-related effects of cocaine, as well as cocaine-associated impulsivity. This study will also provide basic science information about the serotonergic mechanisms underlying the pharmacodynamic effects of cocaine in humans. As such, the outcomes will advance our understanding of the clinical neurobiology of cocaine addiction.