Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats

Rationale Pathological impulsivity is a prominent feature in several psychiatric disorders, but detailed understanding of the specific neuronal processes underlying impulsive behavior is as yet lacking. Objectives As recent findings have suggested involvement of the brain cannabinoid system in impulsivity, the present study aimed at further elucidating the role of cannabinoid CB1 receptor activation in distinct measures of impulsive behavior. Materials and methods The effects of the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716A) and agonist WIN55,212-2 were tested in various measures of impulsive behavior, namely, inhibitory control in a five-choice serial reaction time task (5-CSRTT), impulsive choice in a delayed reward paradigm, and response inhibition in a stop-signal paradigm. Results In the 5-CSRTT, SR141716A dose-dependently improved inhibitory control by decreasing the number of premature responses. Furthermore, SR141716A slightly improved attentional function, increased correct response latency, but did not affect other parameters. The CB1 receptor agonist WIN55,212-2 did not change inhibitory control in the 5-CSRTT and only increased response latencies and errors of omissions. Coadministration of WIN55,212-2 prevented the effects of SR141716A on inhibitory control in the 5-CSRTT. Impulsive choice and response inhibition were not affected by SR141716A at any dose, whereas WIN55,212-2 slightly impaired response inhibition but did not change impulsive choice. Conclusions The present data suggest that particularly the endocannabinoid system seems involved in some measures of impulsivity and provides further evidence for the existence of distinct forms of impulsivity that can be pharmacologically dissociated

Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal of IV drug self-administration

RATIONALE: The neurobiological mechanisms underlying the persistence of drug craving in detoxified addicts are still poorly understood. OBJECTIVE: The present study was designed to evaluate dopaminergic mechanisms in drug-seeking behaviour following long-term (>3 weeks) extinction of IV drug self-administration in rats. METHODS: To that end, we studied the effects of direct and indirect dopamine (DA) agonists on reinstatement of previously extinguished responding for heroin (50 microg/kg per injection; 14-15 daily 3-h sessions) and cocaine (500 microg/kg per injection; 10-11 daily 2-h sessions). RESULTS: In animals with a cocaine history, priming with cocaine, the selective DA reuptake inhibitor GBR-12909 and the DA D2 receptor agonist quinpirole resulted in robust and selective reinstatement of non-reinforced nose poking behaviour in the previously drug-paired hole. In contrast, the D1 agonist SKF-82958 failed to reinstate responding and the non-selective DA agonist apomorphine even suppressed responding in these animals. In heroin-trained rats, heroin and GBR-12909 strongly reinstated responding, whereas all direct DA agonists were ineffective. Again, the two highest doses of apomorphine decreased responding in these animals. In a parallel study, the ability of DA ligands to express behavioural sensitization in animals pretreated with amphetamine or morphine was evaluated. Interestingly, all agonists that reinstated responding in the present study caused expression of locomotor sensitization and vice versa. CONCLUSIONS: The differences between direct and indirect agonists indicate a clear, but complex, involvement of DA in drug-seeking behaviour long after detoxification. Moreover, the results show an important role of D2 receptor activation in the persistence of cocaine- but not heroin-seeking behaviour. Finally, the results from both studies suggest a relationship between drug-induced reinstatement and drug hyperresponsiveness in long-term abstinent rats