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Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone, and in combination with Ro15-1788 (flumazenil)

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Abstract

Recent work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine (BDZ) agonist, decreases ethanol (ETOH) self-administration in rodents under fluid deprivation conditions. The present study further examined the effects of Ro15-4513 (2.5 and 5.0 mg/kg) alone and in combination with Ro15-1788, (flumazenil) (8.0 and 16.0 mg/kg), a BDZ receptor antagonist on ETOH self-administration in freely feeding and drinking rats. Animals were trained to consume ETOH (11% v/v) using a limited access procedure. Measurements were taken at 10- and 60-min intervals. Ro15-4513 (2.5 and 5.0 mg/kg) markedly attenuated ETOH consumption at both intervals. The antagonistic actions of Ro15-4513 were completely blocked by the higher dose of flumazenil at both intervals; the lower dose failed to antagonize the Ro15-4513-induced reduction of ETOH intake. When flumazenil was given alone, both doses reduced ETOH self-administration at 60 min; although the magnitude of the antagonism was comparable to that of Ro15-4513 only with the highest does of flumazenil (16.0 mg/kg). Neither Ro15-4513 nor flumazenil alone or in combination significantly altered water intake at any of the tested doses. Rats pretreated with Ro15-4513 showed a substantial reduction in blood ethanol concentration (BEC) compared with the Tween-80 vehicle condition at the 10-min interval. However, the BEC of animals given Ro15-4513 in combination with flumazenil were similar to rats given Tween-80 vehicle. The present study extends our previous research by demonstrating that Ro15-4513 and flumazenil attenuate ETOH self-administration in non-food or water deprived rats. These studies suggest that the suppressant effects of Ro15-4513 and flumazenil on ETOH self-administration are associated with actions at the BDZ site of the GABAA receptor complex. These data are discussed in relation to the possible mechanism(s) by which Ro-15-4513 and flumazenil exert their antagonism on ETOH self-administration.

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Author notes

  1. Harry L. June

    Present address: Dept of Psychology, Indiana University - Purdue University at Indianapolis, 402 North Blackford Street, LD 3124, 46202, Indianapolis, IN, USA

  2. Michael J. Lewis

    Present address: Neurobehavioral Laboratory, Dept of Psychology, Temple University, 1300 Cecil B. Moore Avenue, 19122, Philadelphia, PA, USA

Authors and Affiliations

  1. Neurobehavioral Laboratory, Department of Psychology, C. B. Powell Building, Howard University, 20059, Washington, DC, USA

    Harry L. June, Roger W. Hughes, Holly L. Spurlock & Michael J. Lewis

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  1. Harry L. June
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  2. Roger W. Hughes
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  3. Holly L. Spurlock
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  4. Michael J. Lewis
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Additional information

Portions of this work were presented at the Annual Meeting of the Research Society on Alcoholism under the symposium entitled “GABA/BDZ Receptor Update,” Marco Island, FL, June 10, 1991.

We would like to dedicate this paper to the late Dr. Richard G. Lister, a friend, teacher, colleague and exceptional scientist who contributed substantially to the area of alcohol abuse and alcoholism. Over the past years, Dr. Lister investigated the interactions of alcohol with inverse benzodiazepine agonists and benzodiazepine receptor antagonists. His seminal and more recent papers played an important role in delineating the GABA benzodiazepine systems in the neurobehavioral actions of alcohol. Richard, we will miss you.

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June, H.L., Hughes, R.W., Spurlock, H.L. et al. Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone, and in combination with Ro15-1788 (flumazenil). Psychopharmacology 115, 332–339 (1994). https://doi.org/10.1007/BF02245074

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  • DOI: https://doi.org/10.1007/BF02245074

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