devazepide 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

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.

Topics: Animals; Conditioning, Psychological; Devazepide; Male; Morphine Dependence; Naloxone; Pyrazoles; Rats; Rats, Wistar; Receptors, Cholecystokinin; Sincalide; Spatial Behavior; Substance Withdrawal Syndrome

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 aim of present study was to reveal the role of cholecystokinin (CCK) in the jumping behaviour induced by the opioid antagonist naloxone (30 mg/kg) after the acute administration of morphine (200 mg/kg) in mice. Treatment with caerulein (0.01-1 microg/kg), a nonselective agonist of CCK receptors, induced a large reduction of jumping frequency without parallel suppression of locomotor activity. The CCK(B) receptor agonist CCK tetrapeptide (CCK-4. 0.125-32 mg/kg) caused the same effect, but it happened at much higher doses (above 0.5 mg/kg). Devazepide (1 microg/kg), a preferential CCK(A) receptor antagonist, completely reversed the action of caerulein (0.1 gmg/kg) and CCK-4 (2 mg/kg). A preferential CCK(B) receptor antagonists LY 288,513 at a high dose (4 mg/kg) blocked the action of CCK-4, but not that of caerulein. Acetorphan (16-128 mg/kg), an inhibitor of enkephalin metabolism, did not block naloxone-precipitated jumping behaviour. However, the combination of subthreshold doses of caerulein (0.001 microg/kg) and CCK-4 (0.25 mg/kg) with acetorphan (64 mg/kg) potently antagonized the behaviour induced by naloxone. In conclusion, the antagonism of CCK agonists against naloxone-precipitated jumping behaviour is apparently mediated via the CCK(A) receptor subtype. The stimulation of CCK(A) receptors seems to increase the release of endogenous enkephalins.

Topics: Animals; Ceruletide; Devazepide; Dose-Response Relationship, Drug; Hormone Antagonists; Male; Mice; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Pyrazoles; Receptors, Cholecystokinin; Substance Withdrawal Syndrome; Tetragastrin; Thiorphan

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

In the present study, the effect of cholecystokinin agonists and antagonists on dependence to morphine in mice has been investigated. Mice were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily for 2-4 days, and a last dose of morphine (50 mg/kg) was administered on day 3, 4 or 5. Withdrawal syndrome (jumping) was precipitated by naloxone (2.5, 5 and 10 mg/kg) which was administered intraperitoneally 2 hr after the last dose of morphine. To study the effects of cholecystokinin receptor agonists or antagonists, 10 injection of morphine (3 administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. Cholecystokinin-8 (0.001-0.01 mg/kg), low doses of the cholecystokinin agonists caerulein (0.00001 and 0.0001 mg/kg) and, unsulfated cholecystokinin (but not high doses) as well as the antagonists MK-329 (0.5-1 mg/kg) and L-365,260 (0.5-1 mg/kg) elicit reduction of the nalaxone-induced jumping. The inhibition of jumping induced by caerulein was reduced with the selective cholecystokinin antagonists MK-329 and L-365,260. It is concluded that cholecystokinin mechanism(s) may be involved in morphine dependence, that the agonists may act on a presynaptic receptors and that the antagonists may work on postsynaptic receptors.

Topics: Animals; Benzodiazepinones; Ceruletide; Cholecystokinin; Devazepide; Drug Interactions; Hormone Antagonists; Injections, Subcutaneous; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Receptors, Cholecystokinin; Substance Withdrawal Syndrome

The potent and selective non-peptide cholecystokinin (CCK) antagonist L-364,718 (0.5-2.0 mg/kg s.c.) enhanced the analgesia induced by acute morphine treatment in the rat tail flick test. Chronic treatment with L-364,718 (1.0 mg/kg) prevented the development of tolerance to morphine analgesia (after a 6 day period of morphine treatment) but did not influence the onset of opioid dependence. Since L-364,718 is considerably more potent in inhibiting CCK binding to peripheral tissues than to brain membranes its interaction with morphine is surprising. The exact locus of this interaction, or whether it involves 'peripheral-type' (CCK-A) or 'central-type' (CCK-B) receptors is not known.

Topics: Analgesia; Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Drug Interactions; Drug Tolerance; Male; Morphine; Morphine Dependence; Rats; Rats, Inbred Strains