Behaviorally active doses of the CB1 receptor antagonist SR 141716A increase brain serotonin and dopamine levels and turnover

Abstract

Large doses (10-40 mg/kg) of the selective cannabinoid CB(1) receptor antagonist, SR 141716A, produce the head-twitch response (HTR) and scratching in rodents and vomiting in the least shrew (Cryptotis parva). Agents that increase brain serotonin (5-HT) levels induce the HTR in rodents, whereas enhancements in either brain 5-HT or dopamine concentrations can lead to production of emesis in vomiting species. The present study was undertaken to demonstrate whether large doses of SR 141716A can (1) induce the HTR and scratching in the least shrew and (2) cause concurrent biochemical changes in brain 5-HT and dopamine concentrations. SR 141716A (0, 1, 5, 10, 20 and 40 mg/kg i.p.) administration induced the HTR, scratching and vomiting. The HTR effect was bell shaped with a maximum frequency occurring at the 20 mg/kg SR 141716A dose, whereas the scratching and vomiting behaviors displayed dose-dependent effects. The selective 5-HT(2A/C) receptor antagonist, SR 46349B (0, 0.1, 0.25, 1, 3 and 6 mg/kg i.p.), differentially attenuated all SR 141716A (20 mg/kg)-induced behaviors because the HTR was relatively more potently and completely blocked. In the shrew forebrain, SR 141716A (20 and 40 mg/kg ip) caused dose- and time-dependent increases in the levels of 5-HT and dopamine and the concentrations of their major metabolites [5-hydroxyindole acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA)] and the turnover of both monoamines. Although the effects of SR 141716A on brainstem concentrations of both monoamines and their metabolites were not always consistent, the CB(1) antagonist did increase the turnover of both 5-HT and dopamine. The present findings suggest that the mechanism and the neurochemical substrate for SR 141716A-induced HTR and scratching behaviors is enhancement of 5-HT release, whereas increased release of 5-HT and dopamine probably contributes to the production of emesis.