l-365260 and Morphine-Dependence

Cholecystokinin octapeptide (CCK-8), a brain-gut peptide, plays an important role in several opioid addictive behaviors. We previously reported that CCK-8 attenuated the expression and reinstatement of morphine-induced conditioned place preference. The possible effects of CCK-8 on the negative affective components of drug abstinence are not clear. There are no studies evaluating the effect of CCK-8 on emotional symptoms, such as anxiety, in morphine-withdrawal animals. We investigated the effects of CCK-8 on the anxiety-like behavior in morphine-withdrawal rats using an elevated plus-maze. Morphine withdrawal elicited time-dependent anxiety-like behaviors with peak effects on day 10 (5 days after induction of morphine dependence). Treatment with CCK-8 (0.1 and 1 μg, i.c.v.) blocked this anxiety in a dose-dependent fashion. A CCK1 receptor antagonist (L-364,718, 10 μg, i.c.v.) blocked the effect of CCK-8. Mu-opioid receptor antagonism with CTAP (10 μg, i.c.v.) decreased the 'anxiolytic' effect. CCK-8 inhibited anxiety-like behaviors in morphine-withdrawal rats by up-regulating endogenous opioids via the CCK1 receptor in rats. This study clearly identifies a distinct function of CCK-8 and a potential medication target of central CCK1 receptors for drugs aimed at ameliorating drug addiction.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Benzodiazepinones; Central Nervous System Agents; Devazepide; Dose-Response Relationship, Drug; Male; Morphine; Morphine Dependence; Narcotics; Opioid Peptides; Phenylurea Compounds; Random Allocation; Rats, Wistar; Receptors, Cholecystokinin; Receptors, Opioid, mu; Sincalide; Substance Withdrawal Syndrome

There is evidence that the neuropeptide cholecystokinin (CCK) is important for the rewarding effects of drugs of abuse. However, less is known regarding the role of CCK in drug seeking and craving. The present study investigated whether the CCK(B) antagonist L-365, 260 could block morphine-induced drug seeking using the conditioned place preference paradigm and whether the dopaminergic reward pathway contributes to the effect of L-365, 260 on expression of morphine place preference. We found that systemic administration of the CCK(B) antagonist L-365, 260 attenuates the expression of morphine-induced drug seeking as assessed using conditioned place preference (CPP) and shows that this effect is mediated by CCK(B) receptors in the anterior nucleus accumbens (NAcc). Additionally, we demonstrate that this effect is dependent on D(2) receptor activation in the anterior nucleus accumbens (NAcc). These results indicate that endogenous CCK modulates the incentive-salience of morphine-associated cues and suggest that CCK antagonists may be useful in the treatment of drug craving.

Topics: Animals; Benzodiazepinones; Cholecystokinin; Conditioning, Operant; Male; Morphine; Morphine Dependence; Nucleus Accumbens; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Dopamine D2

The possible effect of different cholecystokinin (CCK) receptor antagonists (MK-329 and L-365260) on the maintenance and reactivation of morphine conditioned place preference (CPP) were investigated in rats, respectively. The results show that the maintenance of morphine CPP could be induced by injection of morphine (10 mg/kg, s.c.) once for 3 days and this effects were significantly attenuated by pretreatment with 1 but not by 0.1 mg/kg L-365260. Furthermore, following a 28-day extinction, the morphine CPP disappeared and then reactivated again by a single injection of morphine (10 mg/kg). Pretreatment with L-365260 (1 and 0.1 mg/kg) significantly blocked this reactivation of morphine CPP. In contrast, pretreatment of MK-329 (1 and 0.1 mg/kg) failed to do so. The present study demonstrated that CCK-B receptor but not CCK-A receptor is involved in the maintenance and reactivation of morphine CPP. These findings suggest that CCK-B receptor antagonists might be of some value in the treatment and prevention of relapse to drug dependence long after detoxification.

Topics: Animals; Benzodiazepinones; Conditioning, Psychological; Devazepide; Extinction, Psychological; Habituation, Psychophysiologic; Male; Morphine Dependence; Phenylurea Compounds; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Recurrence

The possible effect of a cholecystokinin-8 agonist (caerulein) and antagonists (MK-329 and L365,260) on the development of morphine dependence and withdrawal were investigated in rats. Caerulein treatment (0.01 and 0.1 mg/kg) increased the incidence of naloxone-induced withdrawal syndromes and delayed the extinction of morphine-conditioned place preference in morphine-dependent animals. The signs of the morphine withdrawal syndromes and the formation of morphine-conditioned place preference were suppressed by pretreatment with L365,260 (0.1 and 1 mg/kg) and not affected by pretreatment with MK-329 (0.1 and 1 mg/kg). The present study demonstrated CCK, acting on CCK-B receptors, participates in the development of the opiate dependence. These findings suggest that CCK-B receptor antagonists might be of some value in the treatment and prevention the relapse of opiate addicts.

Topics: Animals; Benzodiazepinones; Ceruletide; Conditioning, Psychological; Devazepide; Hormone Antagonists; Male; Morphine Dependence; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Substance Withdrawal Syndrome

The conditioned place aversion paradigm was used to investigate the role of cholecystokinin in the aversive/dysphoric component of morphine abstinence. Several cholecystokinin ligands were chronically administered during the development of morphine dependence: the CCKA antagonist devazepide, the CCKB antagonists PD-134,308 and L-365,260, and the CCKB agonist BC 264. The CCK-B antagonists L-365,260 and PD-134,308 decreased and completely blocked (respectively) the place aversion induced by naloxone in morphine dependent animals whereas BC 264 and devazepide were inactive in this model. No effect was observed in non-dependent animals after chronic administration of these CCK-ligands. These results show a distinct role for CCK receptors in the regulation of the motivational component of morphine abstinence, probably related to their differential effects in the regulation of limbic dopaminergic neurons.

Topics: Animals; Anti-Anxiety Agents; Avoidance Learning; Benzodiazepinones; Cholecystokinin; Conditioning, Classical; Devazepide; Indoles; Male; Meglumine; Morphine Dependence; Peptide Fragments; Phenylurea Compounds; Rats; Rats, Wistar; Substance Withdrawal Syndrome