Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans

Abstract

Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine's reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine.

Trial registration: ClinicalTrials.gov NCT01651377.

Keywords: Cocaine use disorder; Drug reinforcement; Drug reward; Peak effects; Stimulants; Substance use disorder.

Conflict of interest statement

Conflicts of interest

The authors declare no relevant conflict of interest or financial interests to declare relating to this study.

Published by Elsevier Ireland Ltd.

Figures

Fig. 1

CONSORT flow diagram.

Fig. 2

Mean (+SEM) subjective effects ratings for “HIGH” (A), “ANY DRUG EFFECT” (B), “GOOD DRUG EFFECT” (C) and “LIKE DRUG” (D) following 0, 20 and 40 mg cocaine from participants treated with placebo (pramipexole 0 mg) and pramipexole (3 mg). *p < 0.05, ** <0.01.

Fig. 3

Mean (+SEM) peak VAS ratings obtained within the 30 min test session between placebo and pramipexole treated groups following different doses of cocaine (0 mg, 20 mg and 40 mg). Asterisks represent significant difference between groups (*p < 0.05, **p < 0.01).