Behavioural studies indicate that cannabinoid receptors are implicated in cocaine addiction. The synaptic underpinning of cocaine-cannabinoid receptor interaction is however, obscure. We have studied electrophysiologically the sensitivity of cannabinoid receptors modulating synaptic transmission in the striatum of rats exposed to cocaine. One-day treatment with cocaine did not modify the synaptic response to HU210, a cannabinoid CB1 receptor agonist. Seven days cocaine-treatment, conversely, caused conditioned place preference, and sensitized striatal GABAergic synapses to the presynaptic effect of cannabinoid CB1 receptor stimulation. The cannabinoid receptor-induced modulation of glutamate transmission was unaltered by cocaine. Furthermore, the effects of chronic cocaine on cannabinoid-mediated regulation of striatal GABA synapses were attenuated one week after the discontinuation of cocaine, and absent two weeks later, indicating the progressive reversibility of the adaptations of cannabinoid system during abstinence of drug consumption. Our data support the concept that modulation of cannabinoid receptors might be useful against drug abuse.