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Carisbamate, a Novel Antiepileptic Candidate Compound, Attenuates Alcohol Intake in Alcohol-Preferring Rats

Authors

  • Amir H. Rezvani,

    1. From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center (AHR, EDL), Durham, North Carolina; Skipper Bowles Center for Alcohol Studies, University of North Carolina (DHO), Chapel Hill, North Carolina; and Johnson & Johnson Pharmaceutical Research & Development (AHV, BZ), L.L.C., Spring House, Pennsylvania.
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  • David H. Overstreet,

    1. From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center (AHR, EDL), Durham, North Carolina; Skipper Bowles Center for Alcohol Studies, University of North Carolina (DHO), Chapel Hill, North Carolina; and Johnson & Johnson Pharmaceutical Research & Development (AHV, BZ), L.L.C., Spring House, Pennsylvania.
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  • Anil H. Vaidya,

    1. From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center (AHR, EDL), Durham, North Carolina; Skipper Bowles Center for Alcohol Studies, University of North Carolina (DHO), Chapel Hill, North Carolina; and Johnson & Johnson Pharmaceutical Research & Development (AHV, BZ), L.L.C., Spring House, Pennsylvania.
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  • Boyu Zhao,

    1. From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center (AHR, EDL), Durham, North Carolina; Skipper Bowles Center for Alcohol Studies, University of North Carolina (DHO), Chapel Hill, North Carolina; and Johnson & Johnson Pharmaceutical Research & Development (AHV, BZ), L.L.C., Spring House, Pennsylvania.
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  • Edward D. Levin

    1. From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center (AHR, EDL), Durham, North Carolina; Skipper Bowles Center for Alcohol Studies, University of North Carolina (DHO), Chapel Hill, North Carolina; and Johnson & Johnson Pharmaceutical Research & Development (AHV, BZ), L.L.C., Spring House, Pennsylvania.
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Reprint requests: Amir H. Rezvani, Ph.D, Dept. of Psychiatry, Box 3412, Duke University Medical Center, Durham, NC 27710; Fax: 919-681-3416; E-mail: Azadi@duke.edu

Abstract

Background:  Since 1994, when naltrexone (Revia®) was approved by the FDA for the treatment of alcoholism, only 2 other drugs (Campral® and Topamax®) have been approved for alcoholism treatment. However, various experimental drugs, including antiepileptic medications, have been tested in both animal models and in humans with some promising results. The purpose of this project was to study the effect of the novel neuromodulator carisbamate, which is in development for epilepsy treatment, on alcohol intake in selectively bred alcohol-preferring rats.

Methods:  Male alcohol-preferring inbred P rats were allowed to freely drink water or alcohol (10%, v/v) using a 2-bottle choice procedure. After stable baselines for alcohol and water intakes were established, the acute effects of oral carisbamate (0, 10, 30, 45, 60, and 90 mg/kg) were assessed. Then, the chronic effect of the compound (60 mg/kg/day for 14 consecutive days) on alcohol intake was assessed in a separate group of male P rats. In another set of experiments, the effects of carisbamate and naltrexone on alcohol withdrawal-induced elevated drinking of alcohol, an index of craving, were compared. Rats were withdrawn from alcohol for 24 hours and were given vehicle, 20 mg/kg naltrexone or 60 mg/kg carisbamate 30 minutes before re-exposure to alcohol. Alcohol and water intake was measured 6 hours after alcohol re-exposure. To determine the effects of carisbamate on saccharin preference, rats were put on a 2-bottle choice of water versus a solution of 2% saccharin. Then, the effect of the highest dose of carisbamate (90 mg/kg) and naltrexone (20 mg/kg) and the vehicle on saccharin preference was determined.

Results:  Our results showed that there was a selective dose-dependent reduction in alcohol intake and preference in the alcohol-preferring P rat after an acute oral administration of carisbamate. There were no significant effects on food or water intake. Chronic administration of carisbamate significantly reduced alcohol intake and preference initially, but partial tolerance developed after the 10th treatment. The degree of tolerance development was less than that observed for naltrexone. Acute administration of carisbamate was more effective than naltrexone in reducing enhanced alcohol intake after a period of alcohol deprivation. Compared with control vehicle neither carisbamate nor naltrexone had a significant effect on saccharin intake and preference.

Conclusion:  The novel neuromodulator compound carisbamate has a favorable profile of effects on alcohol intake and related measures and should be considered for testing on human alcoholics.

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