Cocaine and Zolmitriptan

Summary

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

Conditions

• Cocaine Use Disorder

Interventions

DRUG

Cocaine

The pharmacodynamic effects of cocaine will be determined during maintenance on placebo and zolmitriptan.

DRUG

Placebo oral capsule

The pharmacodynamic effects of placebo will be determined.

DRUG

Zolmitriptan

The pharmacodynamic effects of zolmitriptan maintenance will be determined.

Sponsors & Collaborators

• National Institute on Drug Abuse (NIDA)

  collaborator NIH

• William Stoops

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

55 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2021-10-15

Primary Completion

2025-01-09

Completion

2025-01-09

FDA Drug

Yes

Countries

• United States

Study Locations