Pharmacology Biochemistry & Behavior. Vol. 34. pp. 399-404. ~ Pergamon Press pie, 1989. Printed in the U.S.A. 0091-3057/89 $3.00 + .00 Effect of GAB Aergic Drugs on Motor Impairment From Ethanol, Barbital and Lorazepam in Rat Lines Selected for Differential Sensitivity to Ethanol K. HELLEVUO, K. KIIANMAA ~ AND E. R. KORPI Research Laboratories, Alko Ltd., P.O. Box 350, SF-O0101 Helsinki, Finland Received 3 March 1988 HELLEVUO, K.. K. KIIANMAA AND E. R. KORPI. Effect of GABAergic drugs on motor impairment from ethanol, barbital and Iorazepam in rat lines selected for differential sensitivi~" to ethanol. PHARMACOL BIOCHEM BEHAV 34(2) 399--404, 1989.--The effect of GABAergic drugs on the motor-impairing effects of ethanol, barbital, and lorazepam were studied in the ethanol-sensitive ANT (Alcohol Nontolerant) and ethanol-insensitive AT (Alcohol Tolerant) rat lines, selected for differential ethanol-induced motor impairment on the tilting plane. The basic population from which these rat lines were derived, the mixed (M) line, was also included in the study. The ANT rats were more sensitive to the intoxicating effects of ethanol, barbital, and lorazepam than the AT and M rats at the dose ranges tested. Picrotoxin antagonized motor impairment from all three drugs. Flumazenil (Ro 15-1788) antagonized only the effects of lorazepam, and isoniazid did not modify motor impairment induced by any of the three drugs. These results confirm that the selection of AT and ANT lines has not been specific to ethanol, and that it has increased sensitivity to ethanol, barbital, and lorazepam in the ANT rats rather than decreasing it in the AT rats relative to the M rats. The finding that picrotoxin counteracted motor impairment from ethanol, barbital, and lorazepam support the view that the GABA A receptor complex is important in mediating the intoxicating effects of these drugs. These results also suggest that the genetically-determined difference in sensitivity to ethanol between the rat lines involves GABAergic mechanisms, but it remains to be determined whether any part of the GABAA receptor itself has been affected by the selection program. Ethanol Benzodiazepine Barbiturate GABA Motor impairment Selected lines Ethanol antagonism Picrotoxin Flumazenil (Ro 15-1788) Isoniazid THE ethanol-sensitive ANT (Alcohol Nontolerant) rats show a large performance decrement on the tilting plane after ethanol (2 g/kg), while the ethanol-insensitive AT (Alcohol Tolerant) rats show little motor impairment (6,19). These lines provide a valuable tool for studying the involvement of different neuronal mechanisms in ethanol sensitivity. The ANT rats are also more sensitive than the AT rats to the motor-impairing effects of barbital and lorazepam (12,40), but do not differ in impairment from morphine (40). The line difference in sensitivity cannot be explained by differences in blood ethanol or drug concentrations (6,12). The selection of the AT and ANT rats thus has not been specific to ethanol, but rather has produced changes in the mechanisms of neuronal sensitivity common to ethanol, barbitu- rates, and benzodiazepines. Ethanol, barbiturates, and benzodiazepines also share a com- mon pharmacological profile, being anxiolytic, anticonvulsant, muscle relaxant, and .sedative (2). The primary target of barbitu- rates and benzodiazepines is probably the ~/-aminobutyric acid (GABA)/benzodiazepine receptor/chloride-ionophore complex (GABAA receptor) [see (4, 9, 14, 35, 36, 39)]. In vitro binding studies suggest that this complex has recognition sites for GABA, benzodiazepines, and barbiturates. As the major inhibitory neurotransmitter, GABA is also sus- ceptible to several effects of ethanol [see (17, 21, 44, 45)]. GABA-mediated neurotransmission is potentiated by ethanol in the cerebral cortex and substantia nigra in vivo (30, 32, 33). Behaviorally, GABA agonists have been found to suppress the stimulation of locomotor activity produced by ethanol in mice (5) and GABA antagonists to reduce the motor impairment and the duration of the loss of righting reflex caused by a high dose of ethanol in rats and mice (8, 10, 22, 26). In this study we wanted to clarify the role of GABAergic mechanisms in the genetically-determined differences in sensitiv- ity to ethanol, barbital, and Iorazepam in the AT and ANT rats and also in the mixed (M) line of rats from which they were derived (6). Dose-response curves of the motor impairing effects of ~Requests for reprints should be addressed to Kalervo Kiianmaa, Ph.D., Research Laboratories, Alko Ltd.. P.O. Box 350. SF-00101 Helsinki, Finland. 399