Psychopharmacology 68, 89- 97 (1980) Psychopharmacology 9 by Springer-Verlag 1980 Effects of Gamma-Butyrolactone, Amphetamine, and Haloperidol in Mice Differing in Sensitivity to Alcohol Bruce C. Dudek 1 and Richard J. Fanelli 2 1 Department of Psychology, State University of New York at Albany, 1400 Washington Ave., Albany, NY 12222, U.S.A. 2 Department of Psychology, State University of New York at Binghamton, Binghamton, NY 13901, U.S.A. Abstract. Gamma-butyrolactone (GBL) induced lon- ger loss of righting reflex in mice (LS-line) selectively bred for greater sensitivity to ethanol than in less sensitive SS-line mice. GBL also induced a three-fold greater increase of brain dopamine levels in LS than in SS mice. Among three inbred strains, GBL-induced loss of righting reflex was greater in BALB/c, and greater in DBA/2 than in C57BL/6 mice. A low dose of GBL produced biphasic effects on locomotor activity. Both an initial depressant action and a later increase in activity were greater in LS than in SS mice. These GBL effects on activity were modified in a genotype- dependent fashion by amphetamine. Results of these experiments as well as greater catalepsy-inducing prop- erties of haloperidol in SS mice suggest that genotypic influences on motor reactivity to ethanol may be modeled by GBL effects on brain dopamine systems. Key words: Alcohol - Pharmacogenetics - Dopamine - Gamma-butyrolactone - d-Amphetamine - Halo- peridol In recent years, the field of alcohol research has seen demonstrations of the importance of genetic factors. The use of genes as tools to investigate the action of alcohol (McClearn, 1972) assumes that analysis of physiological differences among genotypes differing in reaction to alcohol will provide knowledge concerning the cellular basis of its actions. For example, genetic influence on the activity of hepatic ethanol- metabolizing enzymes has been demonstrated to affect clearance of ethanol and acetaldehyde from blood (Sheppard et al., 1968). It has been postulated that this biochemical difference may underlie several genotype- dependent behavioral and pharmacological reactions Offprint requests to: B. C. Dndek tO ethanol (Belknap et al., 1972; Horowitz and Whitney, 1975). In other work, McClearn and Kakihana (1973) have selectively bred mice for differ- ences in reaction to the depressant effects of ethanol as measured by durations of loss of the righting reflex after injection of hypnotic doses of ethanol. They produced two lines, long sleep (LS) and short sleep (SS), which are thought to differ in neural sensitivity to ethanol (Heston et al., 1974). Neurophysiological ana- lyses of these mice could lead to specification of the nature of the genetic effects and perhaps suggest physiological loci of ethanol action. Toward this end, Collins et al. (1976) have shown that ethanol is more effective in decreasing brain dopamine (DA) turnover in LS mice than in SS mice; norepinephrine (NE) turnover is not differentially affected in this manner. These investigators also reported higher concentration of DA in the SS line. However, Collins et al. (1976) argue that amine levels are not a good predictor for genotypic influences on alcohol depressant actions, and that measures of turnover are more meaningful. In other research, salsolinol, a DA-acetaldehyde- derived tetrahydroisoquinoline, has behavioral effects that parallel the differential effects of ethanol in these animals. That is, LS mice were shown to be more sensitive to salsolinol than SS mice (Church et al., 1976). Involvement of GABAergic systems in alcohol effects has been demonstrated (Sutton and Simmonds, 1973; Rawat, 1974), but Chan (1976) suggests that this neurotransmitter probably does not play a role in the LS-SS difference. Although available data are sparse, a hypothesis may be formulated that brain DA systems may play a role in the mediation of the LS-SS neurosensitivity differences. Involvement of DA systems, particularly the extensively studied nigrostriatal DA projection, would not be surprising. The behavioral criterion for the original selection program was primarily motor, and the influence of DA on motor behavior is well 0033-3158/80/0068/0089/$01.80