Effects of Exogenous Cholecystokinin Octapeptide on Acquisition of Naloxone Precipitated Withdrawal Induced Conditioned Place Aversion in Rats

Abstract

Cholecystokinin octapeptide (CCK-8), a gut-brain peptide, regulates a variety of physiological behavioral processes. Previously, we reported that exogenous CCK-8 attenuated morphine-induced conditioned place preference, but the possible effects of CCK-8 on aversively motivated drug seeking remained unclear. To investigate the effects of endogenous and exogenous CCK on negative components of morphine withdrawal, we evaluated the effects of CCK receptor antagonists and CCK-8 on the naloxone-precipitated withdrawal-induced conditioned place aversion (CPA). The results showed that CCK2 receptor antagonist (LY-288,513, 10 µg, i.c.v.), but not CCK1 receptor antagonist (L-364,718, 10 µg, i.c.v.), inhibited the acquisition of CPA when given prior to naloxone (0.3 mg/kg) administration in morphine-dependent rats. Similarly, CCK-8 (0.1–1 µg, i.c.v.) significantly attenuated naloxone-precipitated withdrawal-induced CPA, and this inhibitory function was blocked by co-injection with L-364,718. Microinjection of L-364,718, LY-288,513 or CCK-8 to saline pretreated rats produced neither a conditioned preference nor aversion, and the induction of CPA by CCK-8 itself after morphine pretreatments was not significant. Our study identifies a different role of CCK1 and CCK2 receptors in negative affective components of morphine abstinence and an inhibitory effect of exogenous CCK-8 on naloxone-precipitated withdrawal-induced CPA via CCK1 receptor.

Neural circuit mechanisms of the cholecystokinin (CCK) neuropeptide system in addiction

“…However, in contrast to data supporting the anti-opioid hypothesis, experiments on aversive effects of opioid withdrawal indicated that CCK can have pro-opioid actions as well. For example, CCK-8 acted in a CCK1R-dependent manner to attenuate conditioned place aversion (CPA) and anxiety-like behavior resulting from naloxone-induced precipitation of morphine withdrawal [ 75 , 81 ], and CCK restored morphine-induced disruption of hippocampal LTP [ 76 ].…”