Reactivation of Cocaine Conditioned Place Preference Induced by Stress is Reversed by Cholecystokinin-B Receptors Antagonist in Rats

The effects of different cholecystokinin (CCK) receptor antagonists (devazepide and L365,260) on cocaine or stress-induced reactivation of cocaine conditioned place preference (CPP) were investigated in rats. After receiving alternate injection of cocaine (10 mg/kg) and saline for 8 consecutive days, the rats spent more time in the drug-paired side (cocaine CPP) on day 9. These animals did not show cocaine CPP on day 31 following saline-paired training daily from days 10 to 30 (21-day extinction). However, a single injection of cocaine (10 mg/kg) or 15 min of intermittent footshock could reinstate CPP on day 32 with significant more time spent in the drug-paired side in comparison with that on day 0. Systemic injection of CCK-A receptor antagonists, devazepide (0.1 and 1 mg/kg, i.p.), 30 min before cocaine priming, significantly attenuated cocaine-induced reinstatement of CPP, while CCK-B receptor antagonist, L365,260 (0.1 and 1 mg/kg, i.p.), did not show a similar effect. In contrast, pretreatment with L365,260 (0.1 and 1 mg/kg, i.p.) but not devazepide (0.1 and 1 mg/kg, i.p.) significantly blocked stress-induced reinstatement of CPP. In another experiment, CCK-A or B receptor antagonists were infused into nucleus accumbens or amygdala to determine which brain area are involved in the role of different CCK receptors in stress or drug-induced relapse to cocaine seeking. The results show that infusion of the devazepide (10 microg) into the nucleus accumbens significantly inhibited the cocaine-induced reinstatement of CPP, while infusion of devazepide (1 and 10 microg) into amygdala did not affect cocaine-induced reactivation of CPP. Interestingly, infusion of L365,260 (1 and 10 microg) into both nucleus accumbens or amygdala significantly attenuated or blocked stress-induced reinstatement of CPP. These findings demonstrate that CCK-A and B receptor have different roles in relapse to drug craving and further suggest that the brain areas involved in the CCK receptors on reinstatement of drug seeking are not identical. CCK-B receptor antagonists might be of some value in the treatment and prevention of relapse to stress-induced to drug craving following long-term detoxification.