u-50488 and Cocaine-Related-Disorders

Kappa opioid receptor (KOR) agonists have known anti-addiction properties and can reduce drug seeking. Their potential for clinical use has largely been daunted by their aversive properties mediated through p38 MAPK signaling. Here we examined the therapeutic potential of the KOR agonist U50,488 (U50) to reduce cocaine seeking in a self-administration model. Following cocaine self-administration and 7 days of forced home-cage abstinence, rats were administered a single dose of U50 (5 mg/kg, i.p.) 30 min prior to the first extinction training session, wherein cocaine and the discrete cocaine-paired cues were no longer available. U50 reduced cocaine seeking on this first extinction session, but did not alter extinction training over subsequent days. 2 weeks after U50 treatment, rats underwent a test of cue-induced reinstatement, and rats that had received U50 reinstated less than controls. Central inhibition of p38 MAPK at the time of U50 administration prevented its long-term therapeutic effect on reinstatement, but not its acute reduction in drug seeking on extinction day 1. The long-term therapeutic effect of U50 required operant extinction during U50 exposure, extended to cocaine-primed reinstatement, and was not mimicked by another aversive drug, lithium chloride (LiCl). These data suggest U50 elicits its long-term anti-relapse effects through a KOR-p38 MAPK-specific aversive counterconditioning of the operant cocaine-seeking response. A single, albeit aversive treatment that is able to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Cues; Drug-Seeking Behavior; Extinction, Psychological; Imidazoles; Infusions, Intraventricular; Lithium Chloride; Male; p38 Mitogen-Activated Protein Kinases; Pyridines; Rats; Receptors, Opioid, kappa; Recurrence; Self Administration

The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) exhibited both dose-dependent antinociception and kappa opioid receptor (KOR) antagonist activity after oral administration. CJ-15,208 antagonized a centrally administered KOR selective agonist, providing strong evidence it crosses the blood-brain barrier to reach KOR in the CNS. Orally administered CJ-15,208 also prevented both cocaine- and stress-induced reinstatement of extinguished cocaine-seeking behavior in the conditioned place preference assay in a time- and dose-dependent manner. Thus, CJ-15,208 is a promising lead compound with a unique activity profile for potential development, particularly as a therapeutic to prevent relapse to drug-seeking behavior in abstinent subjects.

Topics: Administration, Oral; Animals; Cocaine; Cocaine-Related Disorders; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Peptides, Cyclic

Relapse is one of the main challenges facing the current treatment of cocaine addiction. Understanding its neurobiological mechanism is a critical step toward developing effective anti-relapse therapies.. Emerging evidence indicates that glutamate-mediated activation of dopamine (DA) neurons in the ventral tegmental area (VTA) may be critically involved in cocaine-induced relapse to drug-seeking behavior. Activity of VTA DA neurons is modulated by multiple neurotransmitter systems including opioids, serotonin, dopamine, and acetylcholine. Recent studies demonstrated that activation of kappa-opioid receptors (kappaORs) in the rat VTA directly inhibits the activity of a subpopulation of DA neurons projecting to the prefrontal cortex (PFC) and amygdala. Because we previously showed that blockade of DA receptors in the dorsal PFC inhibits cocaine-induced reinstatement of extinguished cocaine-seeking behavior suggesting a critical role of the VTA-PFC DA circuit in this process, we tested the hypothesis that activation of kappaORs in the VTA will block cocaine-induced reinstatement in rats.. Rats were trained to self-administer intravenous cocaine (0.125 mg/infusion) under a modified fixed-ratio five schedule. After extinction of the learned behavior, the effects of activation of VTA kappaORs on cocaine-induced reinstatement were studied.. The kappaOR agonist U50 488 (0-5.6 microg/side) microinjected into the VTA dose-dependently decreased cocaine-induced reinstatement. The effects could not be explained by either a disruption of operant behavior or diffusion of the drug to the areas surrounding the VTA. Moreover, the effect was reversed by norbinaltorphimine.. The VTA DA neurons expressing functional kappaORs are critically involved in cocaine-induced reinstatement in rats.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cocaine-Related Disorders; Conditioning, Operant; Dopamine; Dose-Response Relationship, Drug; Male; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Recurrence; Ventral Tegmental Area

The kappa opioid receptor (KOR) antagonist, JDTic, was reported to prevent stress-induced reinstatement of cocaine-maintained responding and to have antidepressant-like effects.. Our objectives were to determine whether analogs of JDTic retained KOR antagonist activity and whether an orally effective analog prevented footshock-induced cocaine reinstatement.. RTI-194 (i.g. 1-30 mg/kg, s.c. 0.3-10 mg/kg, and i.p. 30 mg/kg), RTI-212 (s.c. 0.3-10 mg/kg and i.p. 30 mg/kg), and RTI-230 (i.g. 3-30 mg/kg and i.p. 1-30 mg/kg) were evaluated for their ability to block diuresis induced by 10-mg/kg U50,488 in rats. RTI-194 was additionally evaluated i.g. (3-100 mg/kg) for its ability to prevent footshock-induced reinstatement of responding previously reinforced with 0.5-mg/kg/inf cocaine.. RTI-194 significantly (p < 0.05) attenuated U50,488-induced diuresis when given i.g., s.c., and i.p. RTI-194s effectiveness increased 1 week following administration. RTI-212 was ineffective. RTI-230 was ineffective when given i.g., but blocked diuresis at 24 h and 8 days (1, 10, and 30 mg/kg), 15 days (10 and 30 mg/kg), 22 and 29 days (30 mg/kg) following i.p. administration. Footshock reinstated responding in vehicle-but not RTI-194 (30 and 100 mg/kg)-treated rats.. RTI-194 and RTI-230 are effective KOR antagonists, and RTI-194 is now included with JDTic as the only reported compounds capable of antagonizing the KOR following oral administration. The failure of stress to reinstate cocaine seeking in rats treated with RTI-194 is consistent with results reported with JDTic, although it had less efficacy in lowering response levels than JDTic, suggesting a diminished overall effectiveness relative to it.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cocaine-Related Disorders; Diuresis; Dose-Response Relationship, Drug; Male; Naltrexone; Pain; Piperidines; Rats; Rats, Long-Evans; Receptors, Opioid, kappa; Self Administration; Tetrahydroisoquinolines

The cyclic peptide zyklophin {[N-benzylTyr(1),cyclo(D-Asp(5),Dap(8))-dynorphin A-(1-11)NH(2), Patkar KA, et al. (2005) J Med Chem 48: 4500-4503} is a selective peptide kappa opioid receptor (KOR) antagonist that shows activity following systemic administration. Systemic (1-3 mg/kg s.c.) as well as central (0.3-3 nmol intracerebroventricular, i.c.v.) administration of this peptide dose-dependently antagonizes the antinociception induced by the selective KOR agonist U50,488 in C57BL/6J mice tested in the 55 degrees C warm water tail withdrawal assay. Zyklophin administration had no effect on morphine- or SNC-80-mediated antinociception, suggesting that zyklophin selectively antagonizes KOR in vivo. Additionally, the antagonism of antinociception induced by centrally (i.c.v.) administered U50,488 following peripheral administration of zyklophin strongly suggests that the peptide crosses the blood-brain barrier to antagonize KOR in the CNS. Most importantly, the antagonist activity of zyklophin (3 mg/kg s.c.) lasts less than 12 h, which contrasts sharply with the exceptionally long duration of antagonism reported for the established small-molecule selective KOR antagonists such as nor-binaltorphimine (nor-BNI) that last weeks after a single administration. Systemically administered zyklophin (3 mg/kg s.c.) also prevented stress-induced reinstatement of cocaine-seeking behavior in a conditioned place preference assay. In conclusion, the peptide zyklophin is a KOR-selective antagonist that exhibits the desired shorter duration of action, and represents a significant advance in the development of KOR-selective antagonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Blood-Brain Barrier; Cocaine-Related Disorders; Consummatory Behavior; Dynorphins; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Peptides; Receptors, Opioid, kappa; Stress, Physiological; Time Factors

Prior activation of the kappa opioid system by repeated stress or agonist administration has been previously shown to potentiate the rewarding properties of subsequently administered cocaine. In the present study, intermittent and uncontrollable footshock, a single session of forced swim, or acute administration of the kappa agonist U50,488 (5 mg/kg) were found to reinstate place preference in mice previously conditioned with cocaine (15 mg/kg) and subsequently extinguished by repeated training sessions without drug.. Stress-induced reinstatement did not occur for mice pretreated with the kappa opioid receptor antagonist norbinaltorphimine (10 mg/kg) and did not occur in mice lacking either kappa opioid receptors (KOR -/-) or prodynorphin (Dyn -/-). In contrast, the initial cocaine conditioning and extinction rates were not significantly affected by disruption of the kappa opioid system. Cocaine-injection also reinstated conditioned place preference in extinguished mice; however, cocaine-primed reinstatement was not blocked by kappa opioid system disruption.. The results suggest that stress-induced drug craving in mice may require activation of the dynorphin/kappa opioid system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Behavior, Animal; Cocaine-Related Disorders; Conditioning, Operant; Disease Models, Animal; Enkephalins; Extinction, Psychological; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Precursors; Receptors, Opioid, kappa; Stress, Psychological; Swimming

Stress contributes to the reinstatement of cocaine-seeking behavior in abstinent subjects. Kappa-opioid receptor antagonists attenuate the behavioral effects of stress, potentially providing therapeutic value in treating cocaine abuse. Presently, the peptide arodyn produced long-lasting kappa-opioid receptor antagonism, suppressing kappa-opioid receptor agonist-induced antinociception at least 3 days after intracerebroventricular administration of 0.3 nmol. C57Bl/6J mice demonstrated cocaine-conditioned place preference, extinction over 3 weeks, and a subsequent reinstatement of place preference. Arodyn pretreatment suppressed stress-induced, but not cocaine-exposed, reinstatement of cocaine place preference. These results verify that arodyn and other kappa-opioid receptor antagonists may be useful therapeutics for cocaine abuse.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Animals; Behavior, Addictive; Behavior, Animal; Cocaine-Related Disorders; Conditioning, Psychological; Dynorphins; Extinction, Psychological; Female; Hot Temperature; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; Pain Measurement; Pain Threshold; Reaction Time; Receptors, Opioid, kappa; Stress, Psychological; Swimming; Time Factors

A series of new N-substituted derivatives of morphinan was synthesized and their binding affinity for the three opioid receptors (mu, delta, and kappa) was determined. A paradoxical effect of N-propargyl (MCL-117) and N-(3-iodoprop-(2E)-enyl) (MCL-118) substituents on the binding affinities for the mu and kappa opioid receptors was observed. All of these novel derivatives showed a preference for the mu and kappa versus delta binding.

Topics: Cocaine-Related Disorders; Drug Combinations; Humans; Morphinans; Narcotic Antagonists; Receptors, Opioid, kappa; Receptors, Opioid, mu