The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.

The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the ␤2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different ␣ subunit partners of ␤2 (i.e., ␣4 and ␣6), the homo-pentameric ␣7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 g free base/kg/inf) selfadministration was investigated with drug-naive mice deleted (KO) for the ␤2, ␣4, ␣6 and ␣7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice, ␤2-VEC mice with the ␤2 subunit re-expressed exclusively in the VTA, ␣4-VEC mice with selective ␣4 re-expression in the VTA, ␣6-VEC mice with selective ␣6 re-expression in the VTA, and ␣7-KO mice promptly self-administer nicotine intravenously, whereas ␤2-KO, ␤2-VEC in the substantia nigra, ␣4-KO and ␣6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of ␣4␤2-and ␣6␤2-subunit containing nicotinic receptors (␣4␤2*-and ␣6␤2*-nAChRs), but not ␣7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mice.

The present study was designed to explore the relationship between the cannabinoid and opioid receptors in animal models of opioid-induced reinforcement. The acute administration of SR141716A, a selective central cannabinoid CB1 receptor antagonist, blocked heroin self-administration in rats, as well as morphine-induced place preference and morphine self-administration in mice. Morphine-dependent animals injected with SR141716A exhibited a partial opiate-like withdrawal syndrome that had limited consequences on operant responses for food and induced place aversion. These effects were associated with morphine-induced changes in the expression of CB1 receptor mRNA in specific nuclei of the reward circuit, including dorsal caudate putamen, nucleus accumbens, and septum. Additionally, the opioid antagonist naloxone precipitated a mild cannabinoid-like withdrawal syndrome in cannabinoid-dependent rats and blocked cannabinoid self-administration in mice. Neither SR141716A nor naloxone produced any intrinsic effect on these behavioral models. The present results show the existence of a cross-interaction between opioid and cannabinoid systems in behavioral responses related to addiction and open new strategies for the treatment of opiate dependence.