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The benzodiazepine inverse agonist RO19-4603 exerts prolonged and selective suppression of ethanol intake in alcohol-preferring (P) rats

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Abstract

The time course of the benzodiazepine (BDZ) inverse agonist RO19-4603 in antagonizing ethanol (EtOH) intake was investigated in alcohol-preferring (P) rats (n=7) maintained on 24-h continuous free-choice access to EtOH (10% v/v), water, and food. After fluid intakes had stabilized over several weeks, animals were injected with Tween-80 vehicle solution or RO19-4603 (0.075, 0.150, and 0.30 mg/kg). EtOH and water intakes were determined at 8- and 24-h intervals. RO19-4603 caused a marked attenuation of EtOH drinking with each of the doses tested. EtOH intake during the 8-h following 0.075, 0.150, and 0.30 mg/kg RO19-4603 was decreased by approximately 36, 74, and 57%, respectively. Intakes during the 24-h interval were similar to the vehicle control condition. However, 32 h post-drug administration, EtOH intakes were reduced to approximately 27, 31, and 29% following the 0.075, 0.150 and 0.30 mg/kg doses, respectively. To further confirm the reliability of the RO19-4603 dose-response effect, and its selectivity for EtOH, the highest dose condition (0.30 mg/kg) was tested twice. The second 0.30 mg/kg dose condition exerted a profile of effects similar to the initial treatment; 8 h following administration, intake was decreased to 60% of the control level, and 32 h post-drug administration intake was decreased to approximately 46% of the controls. These decreases were evidently selective in comparison with water, since water drinking showed compensatory increases which paralleled the decreased EtOH consumption. Dose-response comparisons indicated that 0.150 mg/kg approaches the maximum effective dose, since the 0.30 mg/kg dose of RO19-4603 did not produce an additional decrease in EtOH intake. Furthermore, unlike the lower doses, the 0.30 mg/kg dose failed to yield reliable compensatory increases in water drinking. The results demonstrated that a single acute administration of RO19-4603 produces prolonged and selective suppression of EtOH intake in P rats maintained on 24-h continuous free access to EtOH. While it is not clear at present what properties of the ligand might explain the observed effects on EtOH intake, these findings along with our previous work, clearly suggest that RO19-4603 may modify neuronal processes that promote EtOH self-administration. Neural transmission at the GABAA-BDZ receptor complex may play an important role in mediating EtOH reinforcement.

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Authors and Affiliations

  1. Department of Psychology, Purdue School of Science, Indiana University-Purdue University, 46202, Indianapolis, IN, USA

    Harry L. June, James M. Murphy & Jackie J. Mellor-Burke

  2. Institute of Psychiatric Research and Program in Medical Neurobiology, Indiana University School of Medicine, Indiana University-Purdue University, 46202, Indianapolis, IN, USA

    Harry L. June & James M. Murphy

  3. Department of Medicine, Indiana University School of Medicine, Indiana University-Purdue University, 46202, Indianapolis, IN, USA

    Lawrence Lumeng & Ting-Kai Li

  4. Department of Biochemistry, Indiana University School of Medicine, Indiana University-Purdue University, 46202, Indianapolis, IN, USA

    Ting-Kai Li

  5. VA Medical Center, Indiana University-Purdue University, 46202, Indianapolis, IN, USA

    Lawrence Lumeng

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  5. Ting-Kai Li
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June, H.L., Murphy, J.M., Mellor-Burke, J.J. et al. The benzodiazepine inverse agonist RO19-4603 exerts prolonged and selective suppression of ethanol intake in alcohol-preferring (P) rats. Psychopharmacology 115, 325–331 (1994). https://doi.org/10.1007/BF02245073

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  • DOI: https://doi.org/10.1007/BF02245073

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