Context-specific reversal of cocaine sensitization by the CB1 cannabinoid receptor antagonist rimonabant

The CB(1) cannabinoid receptor is implicated in the rewarding properties of many drugs of abuse, including cocaine. While CB(1) receptor involvement in the acute rewarding properties of cocaine is controversial, CB(1) antagonists such as SR141716 (rimonabant) have clearly been found to prevent cue- and cocaine-elicited reinstatement of cocaine self-administration in rodents. Here we demonstrate the novel involvement of CB(1) receptors in the maintenance of behavioral sensitization to cocaine in C57BL/6 mice. Consistent with previous reports, the induction of locomotor sensitization following repeated daily cocaine was not prevented by systemic pretreatment of either rimonabant, Delta(9)-tetrahydrocannabinol (THC), or a 1:1 mixture of THC and cannabidiol (CBD). In contrast, established cocaine sensitization was markedly disrupted following subchronic treatment with rimonabant alone. This effect was notably context-dependent, in that rimonabant did not diminish established cocaine sensitization if delivered in the home cage, but only if the rimonabant-injected mice were exposed to activity chambers previously paired with cocaine. These findings are consistent with CB(1) receptor involvement in conditioned cocaine-seeking behaviors, and further suggest that endocannabinoid (eCB)-mediated synaptic plasticity may act specifically within drug-paired environments to maintain cocaine-directed behavioral responses.