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, which are
autoreceptors on 5-HT nerve endings that regulate 5-HT release and heteroreceptors that also
mediate other neurotransmitter release, play a particularly important role in cocaine
effects, likely because they are highly expressed in the mesocorticolimbic system. The 5-HT1b
system displays profound dysregulation during both active cocaine use and abstinence. Initial
preclinical research showed that selective 5-HT1b agonists enhanced the reinforcing and
locomotor effects of cocaine during ongoing cocaine administration, but subsequent research
showed that these agents robustly attenuated reinstatement of cocaine- and cue-primed cocaine
seeking behavior. These findings have been replicated in rigorously conducted studies using
multiple schedules of reinforcement and negative sucrose reinforcement controls across
laboratories. Notably, though, these preclinical studies used compounds not approved for use
in humans, hindering translation. Recently published data show that zolmitriptan, a
commercially available selective 5-HT1b agonist migraine medication, also selectively
attenuates the reinforcing and other abuse-related effects of cocaine, regardless of stage of
use (i.e., ongoing or extinguished cocaine self-administration).
Although a robust preclinical literature supports the premise that 5-HT1b activation reduces
a number of cocaine-associated behaviors (e.g., self-administration, cocaine seeking), this
area remains unstudied in humans. The overarching goal of this project is to advance these
promising preclinical findings, specifically those with zolmitriptan, to a clinical
population, thereby demonstrating that the 5-HT1b system plays a key role in the effects of
cocaine in humans