cp-154526 and Alcoholism

The alcohol deprivation effect (ADE) is characterized by transient excessive alcohol consumption upon reinstatement of ethanol following a period of ethanol deprivation. While this phenomenon has been observed in rats using both bottle drinking (consummatory behavior) and operant self-administration (consummatory and appetitive "ethanol-seeking" behavior) procedures, ADE studies in mice have primarily relied on bottle drinking measures. Furthermore, the neurochemical pathways that modulate the ADE are not well understood. Therefore, we determined whether the ADE can be observed in C57BL/6J mice using operant self-administration procedures and if expression of the ADE is modulated by the corticotropin releasing factor-1 (CRF-1) receptor.. C57BL/6J mice were trained in a 2-hour operant self-administration paradigm to lever press for 10% ethanol or water on separate response keys. Between operant sessions, mice had access to ethanol in their homecage. Once stable responding occurred, mice were deprived of ethanol for 4 days and were then retested with ethanol in the operant paradigm for 3 consecutive days. Next, to assess the role of the CRF-1 receptor, mice were given intraperitoneal (i.p.) injection (0, 10, or 20 mg/kg) of the CRF-1 receptor antagonist CP-154,526 30 minutes before ADE testing. Additional experiments assessed (i) ADE responding in which the alternate response lever was inactive, (ii) the effects of CP-154,526 on self-administration of a 1% sucrose solution following 4 days of deprivation, and (iii) ADE responding in which mice did not received i.p. injections throughout the experiment.. Mice exhibited a significant increase in postdeprivation lever responding for ethanol with either a water reinforced or inactive alternate lever. Interestingly, i.p. injection of a 10 mg/kg dose of CP-154,526 protected against the ADE while not affecting lever responding for a sucrose solution. Finally, baseline and deprivation-induced increases of ethanol reinforced lever responding were greater in mice not given i.p. injections.. The ADE in C57BL/6J mice can be modeled using the operant self-administration paradigm and increased ethanol self-administration associated with the ADE is modulated by CRF-1 receptor signaling.

Topics: Alcoholism; Animals; Conditioning, Operant; Ethanol; Male; Mice; Mice, Inbred C57BL; Pyrimidines; Pyrroles; Receptors, Corticotropin-Releasing Hormone; Self Administration; Signal Transduction; Substance Withdrawal Syndrome

Drinking in the dark (DID) procedures have recently been developed to induce high levels of ethanol drinking in C57BL/6J mice, which result in blood ethanol concentrations (BECs) reaching levels that have measurable affects on physiology and/or behavior. The present experiments determined whether the increased ethanol drinking caused by DID procedures can be attenuated by pretreatment with CP-154,526; a corticotropin releasing factor type-1 (CRF1) receptor antagonist.. In Experiment 1, male C57BL/6J mice received ethanol (20% v/v) in place of water for 4 hours, beginning with 3 hours into the dark cycle. On the fourth day, mice were given an intraperitoneal injection of one of the 4 doses of CP-154,526 (0, 1, 3, 10 mg/kg) 30 minutes before receiving their ethanol bottle. In Experiment 2, C57BL/6J mice had 2 hours of access to the 20% ethanol solution, beginning with 3 hours into the dark cycle on days 1 to 3, and 4 hours of access to the ethanol bottle on day 4 of DID procedures. Mice were given an intraperitoneal injection of one of the 4 doses of CP-154,526 (0, 1, 3, 10 mg/kg) 30 minutes before receiving their ethanol bottle on day 4. Tail blood samples were collected immediately after the 4-hour ethanol access period on the fourth day of each experiment. Additional control experiments assessed the effects of CP-154,526 on 4-hour consumption of a 10% (w/v) sucrose solution and open-field locomotor activity.. In Experiment 1, the vehicle-treated group consumed approximately 4.0 g/kg/4 h of ethanol and achieved BECs of approximately 30 mg%. Furthermore, pretreatment with the CRF1 receptor antagonist did not alter ethanol consumption. On the other hand, procedures used in Experiment 2 resulted in vehicle-treated mice consuming approximately 6.0 g/kg/4 h of ethanol with BECs of about 80 mg%. Additionally, the 10 mg/kg dose of CP-154,526 significantly reduced ethanol consumption and BECs to approximately 3.0 g/kg/4 h and 27 mg%, respectively, relative to vehicle-treated mice. Importantly, the 10 mg/kg dose of the CRF1R antagonist did not significantly alter 4-hour sucrose consumption or locomotor activity.. These data indicate that CRF1R signaling modulates high, but not moderate, levels of ethanol drinking associated with DID procedures.

Topics: Alcohol Drinking; Alcoholism; Animals; Association Learning; Circadian Rhythm; Darkness; Dose-Response Relationship, Drug; Ethanol; Hypothalamo-Hypophyseal System; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Motor Activity; Pituitary-Adrenal System; Pyrimidines; Pyrroles; Receptors, Corticotropin-Releasing Hormone

Corticotropin-releasing factor (CRF) signaling modulates neurobiological responses to stress and ethanol, and may modulate observed increases in ethanol consumption following exposure to stressful events. The current experiment was conducted to further characterize the role of CRF1 receptor (CRF1R) signaling in stress-induced increases in ethanol consumption in BALB/cJ and C57BL/6N mice.. Male BALB/cJ and C57BL/6N mice were given continuous access to 8% (v/v) ethanol and water for the duration of the experiment. When a baseline of ethanol consumption was established, animals were exposed to 5 minutes of forced swim stress on each of 5 consecutive days. Thirty minutes before each forced swim session, animals were given an intraperitoneal injection of a 10 mg/kg dose of CP-154,526, a selective CRF1R antagonist, or an equal volume of vehicle. The effect of forced swim stress exposure on consumption of a 1% (w/v) sucrose solution was also investigated in an ethanol-naïve group of BALB/cJ mice.. Exposure to forced swim stress significantly increased ethanol consumption by the BALB/cJ, but not of the C57BL/6N, mice. Stress-induced increases in ethanol consumption were delayed and became evident approximately 3 weeks after the first stressor. Additionally, forced swim stress did not cause increases of food or water intake and did not promote delayed increases of sucrose consumption. Importantly, BALB/cJ mice pretreated with the CRF1R antagonist showed blunted stress-induced increases in ethanol intake, and the CRF1R antagonist did not influence the ethanol drinking of non-stressed mice.. The present results provide evidence that CRF1R signaling modulates the delayed increase of ethanol consumption stemming from repeated exposure to a stressful event in BALB/cJ mice.

Topics: Alcohol Drinking; Alcoholism; Animals; Brain; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Pyrimidines; Pyrroles; Receptors, Corticotropin-Releasing Hormone; Signal Transduction; Species Specificity; Stress, Psychological

Intermittent footshock stress reliably reinstates extinguished alcohol-taking behavior in drug-free rats, but the neurochemical events involved in this effect are not known.. We studied here whether two main modulators of stress responses, corticotropin-releasing factor (CRF) and corticosterone, are involved in reinstatement of alcohol seeking induced by the intermittent footshock stressor. METHDOS: Rats were given alcohol in a two-bottle choice procedure (water versus alcohol) for 30 days and were then trained for 60 min per day to press a lever for alcohol (12% w/v) for 24-30 days in operant conditioning chambers. After stable drug-taking behavior was obtained, lever pressing for alcohol was extinguished by terminating drug delivery for 5-8 days. Reinstatement of alcohol seeking was then determined after exposure to intermittent footshock (0.8 mA; 10 min) in different groups of rats that were pretreated with CRF receptor antagonists or underwent adrenalectomy (ADX) to remove endogenous corticosterone from the body.. The CRF receptor antagonists, d-phe-CRF (0.3 or 1.0 microg; ICV) and CP-154,526 (15, 30 or 45 mg/kg; IP) attenuated footshock-induced reinstatement of alcohol seeking in a dose dependent manner. In contrast, the removal of circulating corticosterone by ADX had no effect on footshock stress-induced reinstatement of alcohol-taking behavior. In addition, the prevention of the footshock-induced rise in corticosterone while maintaining basal levels of the hormone by providing adrenalectomized rats with corticosterone pellets (50 mg/kg per day), had no effect on stress-induced reinstatement.. These data suggest that CRF contributes to stress-induced relapse to alcohol seeking via its actions on extra-hypothalamic sites. The present data, and previous data with heroin- and cocaine-trained rats, point to a general role of CRF in relapse to drugs induced by stressors.

Topics: Adrenalectomy; Alcoholism; Animals; Corticosterone; Corticotropin-Releasing Hormone; Electroshock; Extinction, Psychological; Injections, Intraventricular; Male; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Recurrence; Self Administration; Stress, Psychological