Limited effects of zolmitriptan maintenance on the pharmacodynamic profile of intravenous cocaine in humans

Abstract

Serotonin 1b (5-HT 1b ) receptors play an important role in preclinical cocaine effects. Zolmitriptan, a commercially available 5-HT 1b / 1d agonist migraine medication, selectively attenuates the reinforcing and other abuse-related effects of cocaine. This project sought to advance these promising preclinical findings into humans, thereby demonstrating that the 5-HT 1b/1d system plays a key role in the abuse-related effects of cocaine in people with cocaine use disorder (CUD). Twelve nontreatment-seeking individuals (four female human subjects) with CUD participated in this within-subject human laboratory study. Participants were maintained on 0, 2.5, 5, and 10 mg oral zolmitriptan/day in random order. After at least 3 days of maintenance on each target dose, participants completed experimental sessions in which the reinforcing, subjective, physiological, and cognitive-behavioral effects of 0, 10, and 30 mg/70 kg of intravenous cocaine were determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g. increased ratings of 'stimulated' and heart rate). Zolmitriptan produced limited changes in oral temperature after 10 mg/70 kg cocaine. Cocaine administration improved working memory impairments observed under the 5 mg zolmitriptan condition. Zolmitriptan did not alter any other effects of cocaine. Data indicate that activating the 5-HT 1b/1d systems through zolmitriptan maintenance produces limited changes in the pharmacodynamic effects of cocaine in humans, contrasting preclinical findings, suggesting this may not be a promising pharmacotherapeutic strategy for CUD. Failing to translate from preclinical to clinical models could be because of methodological or species differences, suggesting the field needs to better address this translational gap.

Keywords: cocaine; human; self-administration; serotonin; zolmitriptan.

Fig. 1

Dose-response function for cocaine following maintenance on placebo (circles), 2.5 mg zolmitriptan (squares), 5 mg zolmitriptan (triangles) and 10 mg zolmitriptan (diamonds) for Number of Drug Choices out of 5 maximum on the Progressive Ratio Task. X-axis: Intravenous cocaine dose in mg/70 kg. Brackets indicate 1 S.E.M. Filled symbols indicate a statistically significant difference from cocaine placebo for that respective zolmitriptan condition.

Fig. 2

Peak effect dose-response functions for cocaine following maintenance on placebo (circles), 2.5 mg zolmitriptan (squares), 5 mg zolmitriptan (triangles) and 10 mg zolmitriptan (diamonds) for subjective ratings of Like Drug (top left graph), Stimulated (top right graph), High (bottom left graph) and Willing to Take Again (bottom right graph) out of 100 maximum. X-axis: Intravenous cocaine dose in mg/70 kg. Brackets indicate 1 S.E.M. Filled symbols indicate a statistically significant difference from cocaine placebo for that respective zolmitriptan condition. “a” above the 30 mg/70 kg cocaine dose indicates a significant difference between that dose and 10 mg/70 kg cocaine dose for the placebo zolmitriptan condition. “b” above the 30 mg/70 kg cocaine dose indicates a significant difference between that dose and 10 mg/70 kg cocaine dose for the 2.5 mg zolmitriptan condition. “c” above the 30 mg/70 kg cocaine dose indicates a significant difference between that dose and 10 mg/70 kg cocaine dose for the 5 mg zolmitriptan condition. “d” above the 30 mg/70 kg cocaine dose indicates a significant difference between that dose and 10 mg/70 kg cocaine dose for the 10 mg zolmitriptan condition.

Fig. 3

Peak effect dose-response functions for cocaine following maintenance on placebo (circles), 2.5 mg zolmitriptan (squares), 5 mg zolmitriptan (triangles) and 10 mg zolmitriptan (diamonds) for Systolic Blood Pressure (top left graph), Diastolic Blood Pressure (top right graph), Heart Rate (bottom left graph) and Temperature (bottom right graph). X-axis: Intravenous cocaine dose in mg/70 kg. Brackets indicate 1 S.E.M. * indicates a statistically significant difference between the 2.5 and 5 mg zolmitriptan conditions at the 10 mg/70 kg cocaine dose condition. Remaining details are the same as for Fig. 2.

Fig. 4

Dose-response functions for cocaine following maintenance on placebo (circles), 2.5 mg zolmitriptan (squares), 5 mg zolmitriptan (triangles) and 10 mg zolmitriptan (diamonds) for Proportion Correct on the 2-back condition of the n-Back, correcting for baseline performance. X-axis: Intravenous cocaine dose in mg/70 kg. Brackets indicate 1 S.E.M. Filled symbols indicate a statistically significant difference from cocaine placebo for that respective zolmitriptan condition.