cp-154526 and Cocaine-Related-Disorders

Intermittent exposure to social defeat stress can induce long-term neural plasticity that may influence escalated cocaine-taking behavior. Stressful encounters can lead to activation of dopamine neurons in the ventral tegmental area (VTA), which are modulated by corticotropin releasing factor (CRF) neurons.. The study aims to prevent the effects of intermittently scheduled, brief social defeat stress on subsequent intravenous (IV) cocaine self-administration by pretreatment with a CRF receptor subtype 1 (CRF-R1) antagonist.. Long-Evans rats were submitted to four intermittent social defeat experiences separated by 72 h over 10 days. Two experiments examined systemic or intra-VTA antagonism of CRF-R1 subtype during stress on the later expression of locomotor sensitization and cocaine self-administration during fixed (0.75 mg/kg/infusion) and progressive ratio schedules of reinforcement (0.3 mg/kg/infusion), including a continuous 24-h "binge" (0.3 mg/kg/infusion).. Pretreatment with a CRF-R1 antagonist, CP 154,526, (20 mg/kg i.p.) prior to each social defeat episode prevented the development of stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h "binge". In addition, pretreatment with a CRF-R1 antagonist (0.3 μg/0.5 μl/side) into the VTA prior to each social defeat episode prevented stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h "binge".. The current results suggest that CRF-R1 subtype in the VTA is critically involved in the development of stress-induced locomotor sensitization which may contribute to escalated cocaine self-administration during continuous access in a 24-h "binge".

Topics: Animals; Cocaine; Cocaine-Related Disorders; Locomotion; Male; Neurons; Pyrimidines; Pyrroles; Rats; Rats, Long-Evans; Receptors, Corticotropin-Releasing Hormone; Reinforcement Schedule; Self Administration; Stress, Psychological; Ventral Tegmental Area

We have previously reported that pretreatment with the corticosterone synthesis inhibitor ketoconazole blocks the electric foot-shock-induced reinstatement of cocaine-seeking behavior in rats, suggesting a potential role for the hypothalamo-pituitary-adrenal (HPA) axis in this animal model of relapse.. This experiment was designed to investigate whether or not ketoconazole would also inhibit the reinstatement of cocaine seeking induced by the presentation of a conditioned reinforcer. The effects of the corticotropin-releasing hormone 1 (CRH1) receptor antagonist CP-154,526 were also investigated to further determine the involvement of the HPA axis in this behavior.. Adult male rats were implanted with jugular catheters and trained to self-administer cocaine (0.25 mg/kg per infusion) during daily 2-h sessions. During training, cocaine delivery was paired with the presentation of a tone and the illumination of a house light. Once a stable baseline of cocaine self-administration was observed, lever pressing was extinguished to less than 20% of baseline rates. During reinstatement testing, responding by rats in the contingent group resulted in the presentation of the conditioned reinforcer (i.e., the house light and tone previously paired with self-administered cocaine). Rats in the non-contingent group were presented with the tone/house light compound stimulus once every 5 min, regardless of responding. Rats were pretreated with ketoconazole (25 mg/kg, i.p.) or CP-154,526 (20 mg/kg, i.p.) 30 min prior to testing for reinstatement with the contingent presentation of the conditioned reinforcer to determine the role for the HPA axis in this behavior.. The response-contingent presentation of the conditioned reinforcer reliably reinstated extinguished cocaine-seeking behavior, while the non-contingent presentation of the same stimulus did not. Increases in plasma corticosterone were evident during cocaine self-administration as well as during extinction and reinstatement testing. However, while plasma corticosterone returned to basal levels by the end of the session during extinction, it remained elevated through the end of the session during reinstatement. Pretreatment with ketoconazole reversed the conditioned reinforcer-induced reinstatement of extinguished cocaine-seeking behavior and also attenuated the conditioned increases in plasma corticosterone observed during reinstatement. Pretreatment with CP-154,526 resulted in a similar decrease in cocaine seeking.. These data suggest a potential role for the HPA axis in the ability of environmental cues to stimulate cocaine-seeking behavior.

Topics: Analysis of Variance; Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Corticosterone; Extinction, Psychological; Hypothalamo-Hypophyseal System; Ketoconazole; Male; Pituitary-Adrenal System; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Reinforcement Schedule; Reinforcement, Psychology; Self Administration; Stress, Psychological

Corticotropin-releasing factor (CRF) has been suggested to play an important role in the development of drug dependence and withdrawal. Based on the recent finding that CRF receptor antagonists inhibit the stress-induced relapse to opiate dependence and attenuate anxiety-like responses related to cocaine withdrawal, the present experiment was performed to examine the possible effect of different CRF receptor antagonists on reactivation of cocaine-conditioned place preference induced by cocaine and stress in rats. The results show that a single injection of cocaine (10 mg/kg, i.p.) could reactivate cocaine-conditioned place preference following a 28-day extinction, and pretreatment with i.c.v. 10 microg alpha-helical CRF, a nonspecific CRF receptor antagonist, significantly attenuated this reactivation of conditioned place preference. However, pretreatment with i.p. 1 or 10 mg/kg CP-154,526 (butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethylamine), a specific CRF receptor subtype 1 antagonist, and i.c.v. 1 or 10 microg AS-30 ([D-Phe(11),His(12)]Svg-(11-40)), a specific CRF receptor subtype 2 antagonist, failed to show the same effects. In addition, a single footshock stress also elicited the reactivation of cocaine-conditioned place preference following a 28-day extinction and pretreatment with alpha-helical CRF (10 microg, i.c.v.) and CP-154,526 (1 or 10 mg/kg, i.p.) significantly blocked this effect. In contrast, pretreatment with AS-30 at a dose of 1 or 10 microg (i.c.v.) did not affect the stress-induced reactivation of cocaine-conditioned place preference. The present study demonstrated that CRF receptor type 1, but not CRF receptor type 2, mediates the stress-induced reactivation of cocaine-conditioned place preference. These findings suggest that CRF receptor subtype 1 antagonists might be of some value in the treatment and prevention of stress-induced relapse to drug dependence long after detoxification.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Psychological; Corticotropin-Releasing Hormone; Dopamine Uptake Inhibitors; Hormone Antagonists; Male; Peptide Fragments; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Secondary Prevention; Stress, Physiological

The role for corticotropin-releasing hormone (CRH) receptors in the maintenance of intravenous cocaine self-administration in rats was investigated using the centrally active, small molecule CRH1 receptor antagonist CP-154,526. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine self-administration (0.125, 0.25 or 0. 5 mg/kg/infusion) during daily 2-h sessions. A 1-min timeout separated access to the two reinforcers. Pretreatment with CP-154, 526 produced dose-related decreases in cocaine self-administration without affecting food-reinforced responding, suggesting a specific effect of the antagonist on cocaine-maintained behavior. Drug intake was decreased across several doses of cocaine, with the dose-response curve for cocaine self-administration shifted downward and flattened, suggesting that CP-154,526 decreased cocaine reinforcement. Furthermore, responding on the cocaine lever following CP-154,526 pretreatment was significantly suppressed, even during the first 15 min of the session, a time when rats typically sample the cocaine lever during extinction, suggesting that CRH receptors may also be involved in some of the conditioned effects of cocaine as well. These data are discussed in terms of the role for CRH in the neurobehavioral effects of cocaine.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Food; Male; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Reinforcement, Psychology; Self Administration