Benzodiazepine receptor ligands modulate ethanol drinking in alcohol-preferring rats

Abstract

The effects of benzodiazepine receptor ligands with different intrinsic activity profiles were studied on voluntary ethanol consumption in the selectively bred alcohol-preferring AA (Alko, Alcohol) rat line, and compared to those of an opiate antagonist, naloxone, and a serotonin uptake inhibitor, citalopram. The rats were first allowed to develop a strong preference for 10% (v/v) ethanol solution in tap water over plain water until their ethanol consumption stabilized. Thereafter, the period when ethanol solution was available for the rats was gradually reduced to 4 h, 3 times a week, every second working day. The acute effects of positive allosteric modulators (agonists) of the γ-aminobutyric acid type A (GABA A)/benzodiazepine receptor [midazolam, abecarnil, ethyl 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylate (ZK 91296), bretazenil, and 2 2,5-dihydro-2-(4-methylphenyl)-3 H-pyrazolo[4,3-C]quinolin-3(5 H)-one (CGS 9895)] and of negative allosteric modulators [inverse agonists, ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4 H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (Ro 15-4513) and t-butyl 5,6-dihydro-5-methyl-6-oxo-4 H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate (Ro 19-4603)] were tested after i.p. injections of three different drug doses using saline injections as a control treatment. The benzodiazepine agonists had rather modest effects on ethanol intake, measured 1 and 4 h after the injections, whereas the inverse agonists and naloxone strongly decreased ethanol consumption. Acute citalopram had no clear effect on ethanol drinking, but it slightly decreased the consumption of novel food during the 4-h session, as did all other benzodiazepine agonists except bretazenil. Neither the inverse agonists nor naloxone had any significant effect on food intake. Three additional groups of rats were repeatedly administered fixed doses of either abecarnil, naloxone (both at 5 mg/kg, i.p.), or saline (1 ml/kg) before five consecutive sessions. Naloxone significantly decreased ethanol consumption at 1-h and 4-h measuring points, whereas abecarnil tended to increase the drinking at 4 h. Food consumption at 4 h was slightly decreased by both compounds. The results suggest that the GABA A receptor may be involved in the regulation of voluntary ethanol drinking in alcohol-preferring AA rats, but do not indicate that these rats would consume ethanol because of its anxiolytic effects in a way that benzodiazepine agonists (full or partial) could substitute for it.