The Therapeutic Potential of Serotonin 1B Receptor Agonists for Treating Psychostimulant Use Disorders

Serotonin 1B receptor (5-HT1BR) agonists enhance cocaine intake in rats during daily self-administration (SA) sessions, yet decrease cocaine intake after prolonged abstinence. The goal of my dissertation was to examine if 5-HT1BRs are suitable targets for treatment development to attenuate psychostimulant intake. I first investigated if 5-HT1BR agonist effects that had been observed with cocaine generalize across psychostimulants, i.e., methamphetamine. Rats trained to self-administer methamphetamine received either CP 94,253 or the clinically-available but less selective 5-HT1D/1BR agonist, zolmitriptan, prior to tests for effects on SA both before and after a 21-day abstinence period. I found that CP 94,253 and zolmitriptan decreased the reinforcing and incentive motivational effects of methamphetamine, regardless of abstinence, unlike the pre-abstinence increase in cocaine SA observed previously with 5-HT1BR agonists. The attenuating effects of CP 94,253 on methamphetamine were antagonized in a 5-HT1BR-mediated manner. Subsequently, I investigated the efficacy and mechanism involved in effects of zolmitriptan on cocaine SA in male and female rats. Rats trained to self-administer cocaine received zolmitriptan prior to tests for effects on SA before a 21-day abstinence period. I found that zolmitriptan decreased cocaine intake in both sexes regardless of abstinence and without altering sucrose intake. I further demonstrated that the zolmitriptan effects on cocaine SA were mediated by both 5-HT1BRs and 5-HT1DRs. Finally, I examined if the abstinence-induced decrease in cocaine intake observed with the selective 5-HT1BR agonist, CP 94,253, persists during relapse after abstinence or reverts to enhancing cocaine intake, similar to effects observed without an abstinence period. Rats trained to self-administer cocaine resumed daily cocaine SA sessions after the forced abstinence period to investigate the effects of CP 94,253 on cocaine relapse. I found that CP 94,253 attenuated cocaine intake in relapse tests, suggesting that the abstinence-dependent attenuation of CP 94,253 on cocaine SA remains even after resumption of daily cocaine intake. The findings suggest that 5-HT1BR agonists like CP 94,253 and zolmitriptan have clinical potential as treatments for psychostimulant use disorders.