l-365260 and Substance-Withdrawal-Syndrome

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

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 ability of a pretreatment with the cholecystokininB-receptor (CCK[B]) antagonist L-365,260 to prevent the development of morphine dependence was studied in normal and neuropathic (unilateral peripheral neuropathy) rats. A 4-day pretreatment regimen with two daily s.c. injections of either saline+saline, saline+morphine (3.0 mg/kg) or L-365,260 (0.2 mg/kg)+morphine was used, and withdrawal was precipitated by an injection of naloxone (1.0 or 2.0 mg/kg i.v.) at 24 h after the last pretreatment injection. After pretreatment with morphine alone, physical dependence developed in both normal and neuropathic rats. However, the incidence of teeth chattering and ptosis was higher in neuropathic rats. Pretreatment with the combination of L-365,260 and morphine prevented the expression of teeth chattering, ptosis, diarrhea, writhing and piloerection, but was devoid of effects on the exploratory activity among both groups of rats. These results suggest that endogenous CCK acting on CCK(B)-receptors may be involved in the development of morphine dependence both in normal and neuropathic rats.

Topics: Animals; Benzodiazepinones; Male; Morphine; Naloxone; Narcotic Antagonists; Peripheral Nervous System Diseases; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; 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

The effect of the selective CCKB antagonist L-365, 260 on chlordiazepoxide (CDP) withdrawal-induced hypophagia was assessed in two related studies in rats pretreated for 21 days with CDP at doses escalated from 10 to 30 mg/kg per day (b.i.d). L-365, 260 was studied at doses from 0.001 to 10 mg/kg (b.i.d). There was no evidence that L-365, 260 at any dose alleviated CDP withdrawal-induced hypophagia. These data contrast with reports that CCKB antagonists alleviate behavioural benzodiazepine (BZ) withdrawal symptoms considered to be indicative of "anxiogenesis". Presumably, such positive effects of CCKB antagonists are due to "functional antagonism", with enhanced anxiety during BZ withdrawal being attenuated by anxiolytic actions of CCKB antagonists. Collectively, studies with CCKB antagonists and other agents involving a number of different BZ withdrawal signs suggest that BZ withdrawal is a heterogeneous syndrome, with various different underlying mechanisms. CCKB antagonists appear to alleviate only a subset of possible BZ withdrawal signs.

Topics: Animals; Benzodiazepinones; Chlordiazepoxide; Eating; Female; Phenylurea Compounds; Rats; Rats, Wistar; Receptors, Cholecystokinin; Substance Withdrawal Syndrome

The influence of flumazenil-precipitated diazepam withdrawal on intestinal myoelectric activity and colonic transit was evaluated, in diazepam-dependent rats. Administered intraperitoneally, flumazenil (15 mg kg-1) induced a strong stimulation of the duodenal spiking activity lasting 197 +/- 20 min, and accelerated colonic transit corresponding to a significantly (P < 0.05) increased value of the geometric centre (3.52 +/- 0.23 vs 2.44 +/- 0.1 for the control). Both devazepide and L365260 administered intracerebroventricularly at a dose of 10 micrograms kg-1 abolished the flumazenil-induced withdrawal effect on the duodenum, whereas at a lower dose (1 microgram kg-1) only L365260 was able to antagonize this effect. In the same way, devazepide, loxiglumide and L365260 suppressed the effect of precipitated withdrawal on colonic transit when administered intracerebroventricularly at a dose of 10 micrograms kg-1, whereas similar blockade was obtained at a dose of 5 micrograms kg-1 with L365260, and 10 ng kg-1 with PD135-158. It is concluded that in rats precipitated diazepam-withdrawal altered intestinal motility and colonic transit and that these effects are mediated by central release of cholecystokinin (CCK) or activation of CCK-ergic neurons.

Topics: Animals; Benzodiazepinones; Brain; Cholecystokinin; Devazepide; Diazepam; Flumazenil; Gastrointestinal Motility; Gastrointestinal Transit; Male; Phenylurea Compounds; Rats; Rats, Wistar; Receptors, Cholecystokinin; Substance Withdrawal Syndrome

The effects of the selective CCK-A antagonist L-365,031 and the selective CCK-B antagonist L-365,260 on morphine analgesia and opiate tolerance and dependence in rats were examined. L-365,031 and L-365,260 had no effect on baseline pain thresholds in the radiant heat tail flick test but enhanced analgesia induced by a submaximal dose of morphine (4 mg/kg). Similarly, L-365,260 did not effect pain thresholds in the paw pressure test but enhanced morphine analgesia in this model. Rats injected twice daily for 6 days with incremental doses of morphine became tolerant to the analgesic effects of the drug. Twice daily injections of either 8 mg/kg L-365,031 or 0.2 mg/kg L-365,260 prevented the development of tolerance to morphine analgesia. In contrast, L-365,260 had no influence on the development of opiate dependence in these animals, as assessed by naloxone-precipitated withdrawal. The results of the present study, when considered together with previous data, indicate that the rank order of potency of non-peptide CCK antagonists for enhancing morphine analgesia is L-365,260 greater than MK-329 greater than L-365,031. This rank order correlates well with the potency of the antagonists in blocking CCK-B receptors in rodents and suggests that CCK/opiate interactions in this species are mediated by CCK-B receptors.

Topics: Analgesia; Animals; Benzodiazepines; Benzodiazepinones; Drug Tolerance; Male; Morphine; Naloxone; Pain; Pain Measurement; Phenylurea Compounds; Rats; Rats, Inbred Strains; Reaction Time; Receptors, Cholecystokinin; Substance Withdrawal Syndrome; Substance-Related Disorders