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.

Corticotropin-releasing factor (CRF) has been implicated in the mediation of the stress-like and negative affective consequences of withdrawal from drugs of abuse, such as alcohol, cocaine, and opiates. This study sought to determine whether brain CRF systems also have a role in cannabinoid dependence. Rats were treated daily for 2 weeks with the potent synthetic cannabinoid HU-210. Withdrawal, induced by the cannabinoid antagonist SR 141716A, was accompanied by a marked elevation in extracellular CRF concentration and a distinct pattern of Fos activation in the central nucleus of the amygdala. Maximal increases in CRF corresponded to the time when behavioral signs resulting from cannabinoid withdrawal were at a maximum. These data suggest that long-term cannabinoid administration alters CRF function in the limbic system of the brain, in a manner similar to that observed with other drugs of abuse, and also induces neuroadaptive processes that may result in future vulnerability to drug dependence.

Animal models have revealed that psychoactive cannabinoids induce both anxiolytic and anxiety-like reactions which are dose- and context-dependent. In the present study we examined the acute actions of the CB1 cannabinoid receptor antagonist SR 141716A in both the defensive withdrawal test and the elevated plus-maze in rats. Acute administration of SR 141716A (0.1, 1 and 3 mg kg-1) induced defensive responses in both anxiety tests, at a dose of 3 mg kg-1. This dose had no effect on horizontal locomotor activity and did not activate the hypothalamus-pituitary-adrenal axis, although several cannabinoid withdrawal-like behavioural symptoms were observed. These results demonstrate that blockade of the endogenous cannabinoid tone might induce anxiety-like responses in rats.

Cocaine is a powerfully addictive substance and new strategies are needed to treat its abuse. Generating an active immunization to cocaine offers a means of blocking the actions of the drug by preventing it from entering the central nervous system, and should have fewer side effects than treatments based on manipulation of central neurotransmitter function. The design and preparation of a cocaine immunogen requires special regard for the stability of cocaine both free and as a haptenic determinant. Immunochemistry and a well defined behavioural model were brought together to address the problem of inactivation of the psychostimulant actions of cocaine. We report here that active immunization with a new, stable cocaine conjugate suppressed locomotor activity and stereotyped behaviour in rats induced by cocaine but not by amphetamine. Moreover, following acute injection of cocaine, levels of cocaine in the striatum and cerebellum of the immunized animals were lower than those of control animals. These results suggest that immunopharmacotherapy may be a promising means by which to explore new treatments for cocaine abuse.