BENZODIAZEPINE RECEPTOR LIGANDS MODULATE ETHANOL DRINKING IN ALCOHOL-PREFERRING RATS

The effects of benzodiazepine receptor ligands with different intrinsi c activity profiles were studied on voluntary ethanol consumption in t he selectively bred alcohol-preferring AA (Alko, Alcohol) rat line, an d 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 p lain 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 e ffects of positive allosteric modulators (agonists) of the gamma-amino butyric acid type A (GABA(A))/benzodiazepine receptor [midazoiam, abec arnil, ethyl yloxy-4-methoxymethyl-beta-carboline-3-carboxylate (ZK 91 296), bretazenil, and dihydro-2-(4-methylphenyl)-3H-pyrazolo[4,3-C]qui no lin-3(5H)-one (CGS 9895)] and of negative allosteric modulators [in verse agonists, ethyl 4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxyla te (Ro 15-4513) and t-butyl azo[1,5-a]thieno[2,3f][1,4]diazepine-3-car boxylate (Ro 19-4603)] were tested after i.p. injections of three diff erent drug doses using saline injections as a control treatment. The b enzodiazepine agonists had rather modest effects on ethanol intake, me asured 1 and 4 h after the injections, whereas the inverse agonists an d naloxone strongly decreased ethanol consumption. Acute citalopram ha d no clear effect on ethanol drinking, but it slightly decreased the c onsumption of novel food during the 4-h session, as did all other benz odiazepine agonists except bretazenil. Neither the inverse agonists no r naloxone had any significant effect on food intake. Three additional groups of rats were repeatedly administered fixed doses of either abe carnil, naloxone (both at 5 mg/kg, i.p.), or saline (1 ml/kg) before f ive consecutive sessions. Naloxone significantly decreased ethanol con sumption 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 dec reased by both compounds. The results suggest that the GABA(A) recepto r may be involved in the regulation of voluntary ethanol drinking in a lcohol-preferring AA rats, but do not indicate that these rats would c onsume ethanol because of its anxiolytic effects in a way that benzodi azepine agonists (full or partial) could substitute for it.