The CCKB antagonist PD-134,308 facilitates rewarding effects of endogenous enkephalins but does not induce place preference in rats

The interaction between cholecystokinin and endogenous opioid systems on rewarding responses was examined. Motivational effects induced by peripheral administration of a complete inhibitor of enkephalin catabolism, RB 101 or the CCK_B antagonist PD-134,308, and by both compounds in combination were evaluated in the conditioned place preference test in rats. RB 101 (5, 10, 20, 40 and 80 mg/kg, IP, and 20 mg/kg, IV) given alone produced a bell-shaped dose-effect function. A significant increase of the preference for the drug-associated compartment was only observed at doses of 10 and 20 mg/kg (IP). The effect observed with morphine was stronger, and all the doses used of this compound (1.25, 2.5 and 5 mg/kg, SC) were found to be active. These results suggest that the inhibitor of enkephalin catabolism has weak rewarding properties. Pretreatment with the CCK_B antagonist PD-134,308 (0.1, 0.3, 1 and 3 mg/kg, IP) alone failed to produce a reliable aversion or preference on the paradigm studied. When PD-134,308 (0.3 mg/kg, IP) was coadministered with a subthreshold dose of morphine (0.6 mg/kg, SC) or RB 101 (5 mg/kg, IP), a conditioned place preference was observed, indicating that the CCK_B antagonist facilitated the motivational responses induced by endogenous enkephalins as compared to morphine. This suggests that endogenous cholecystokinin, acting through CCK_B receptors, modulates the rewarding effects of endogenous enkephalins.