Intra-accumbens rimonabant is rewarding but induces aversion to cocaine in cocaine-treated rats, as does in vivo accumbal cannabinoid CB1 receptor silencing: critical role for glutamate receptors.

Reinforcing effects mediated by accumbal CB(1) receptors (CB(1)R) are controversial, as well as their role in the rewarding effects of cocaine. Accumbal glutamate and glutamate receptors have been proposed to be involved in CB(1)R-mediated effects on cocaine reward. Rewarding effects of cocaine can be evaluated with the conditioned place preference or CPP test. Rimonabant, a cannabinoid CB(1)R ligand, lentiviruses aimed at silencing CB(1)R, and selective glutamatergic ligands are good tools for studying the function of accumbal CB(1) and glutamate receptors. The objectives of the present study were (i) to discern the CPP effects of in vivo gene silencing of accumbal CB(1) receptors by means of lentiviruses containing siRNAs; (ii) to discern the CPP effects of intra-accumbens infusions of the cannabinoid CB(1)R ligand rimonabant, and to evaluate whether effects are due to receptor blockade or inverse agonism; (iii) to discern the role of CB(1)R located within the nucleus accumbens shell in the rewarding effects of cocaine, by means of local infusions of rimonabant, and (iv) to discern the role of glutamate receptors (AMPAR, NMDAR, mGluR2/3) in rimonabant-induced effects on CPP in cocaine-treated rats. The findings revealed that in vivo silencing of accumbal CB(1) receptors with Lenti-CB(1)R-siRNAs induced place aversion to cocaine, but intra-accumbal rimonabant induced place preference in its own right, indicating that this compound seems to act as inverse agonist on the CPP. Glutamate receptors participate in rimonabant-mediated place preference because it was abolished after blocking AMPA glutamate receptors, but not NMDAR or mGluR2/3. Finally, in cocaine-treated rats, local rimonabant induced place aversion to the drug (not place preference), and this effect was mediated by glutamate neurotransmission because it was abolished after blockade of AMPA, NMDA or mGlu2/3 receptors, even though only the blockade of mGlu2/3 autoreceptors restored the emergence of place preference to cocaine.