Research ReportCannabinoid type-1 receptor ligands, alone or in combination with cocaine, affect vigilance-related behaviors of marmoset monkeys

- Repeated cocaine exposure induced stereotyped hypervigilance in marmosets.
- CB1r activation also induced hypervigilance, while blockade had no effect on its own.
- Concurrent CB1r blockade prior to cocaine exposure enhanced its hypervigilance effect.
- All effects were independent of changes in motor function.

Endocannabinoids (eCB) have been functionally linked to cocaine׳s rewarding effects. However, results differ at the behavioral level, with few reports in nonhuman primates (NHPs). Here we analyzed whether repeatedly administered cannabinoid type-1 receptor (CB1r) agonist WIN 55-212,2 (WIN) or antagonist AM 251 (AM) induce effects per se and if concurrent pre-treatments affect cocaine-induced changes in marmoset behavior. Six groups were tested: WIN-saline; WIN-cocaine; AM-saline; AM-cocaine; vehicle-cocaine; and vehicle-saline. Subjects were pre-treated with either WIN (1 mg/kg), AM (2 mg/kg) or vehicle and then injected with cocaine (5 mg/kg) or saline. Six exposures were held at 48 h intervals. Behaviors were scored during 15-min in an open-field on days 1 and 6, as well as a withdrawal (WD) trial. Marmosets became hypervigilant during cocaine exposures, which did not condition to the injection context. CB1r activation induced an equivalent response, whereas AM had no effect on its own. However, when given as a pre-treatment to cocaine, CB1r blockade enhanced the former׳s hypervigilance effect and potentially conditioned this response to the exposure context. Enhancement may have resulted from AM׳s inhibition of eCB-potentiated cocaine-induced anxiogenesis and/or its action independent of the eCB system, or even CB1r-mediated changes in synaptic plasticity involved in cocaine reward-learning. All effects were independent of motor function. Thus, changes in CB1r function - alone and in combination with cocaine - affected stereotyped vigilance-related behaviors in this NHP, further implicating the eCB system in the neurobiological mechanisms of cocaine addiction.