Pharmacology Biochemistry& Behavior, Vol. 33, pp. 667-678. ¢ Pergamon Press plc, 1989. Printed in the U.S.A. 0091-3057/89 $3.00 + .00 Genetic Influences on Nicotine Responses MICHAEL J. MARKS,t JERRY A. STITZEL AND ALLAN C. COLLINS Institute for Behavioral Genetics and School of Pharmacy University of Colorado, Boulder, CO 80309 Received 8 August 1988 MARKS, M. J., J. A. STITZEL AND A. C. COLLINS. Genetic influences on nicotine responses. PHARMACOL BIOCHEM BEHAV 33(3) 667-678, 1989.--Male mice from 19 inbred strains were tested for the effects of nicotine on six responses: respiratory rate, acoustic startle response, Y-maze crosses, Y-maze rears, heart rate and body temperature. Dose-response curves were constructed for each strain on each test in a multitest battery. Results indicated that the responses were strongly influenced by the genotype of the animal. Comparison of the results from the six tests measured in this study and the results previously reported for nicotine-induced seizures in these same strains indicated that the responses could be grouped into two major classes: a set characterized by Y-maze crosses, Y-maze rears and body temperature and a set characterized by seizure sensitivity and seizure latency. Responses observed for respiratory rate and startle response shared characteristics with both of these sets, while nicotine effect on heart rate was fairly unique. The results have identified strains of mice which are differentially sensitive to the effects of nicotine. Nicotine Pharmacogenetics Respiratory rate Acoustic startle response Locomotor activity Heart rate Body temperature ADMINISTRATION of nicotine to rodents affects, among other responses, locomotor activity, body temperature, heart rate, res- piration, and, at high doses, causes convulsions (1-3, 7-9, 14, 18, 22, 24, 26, 28-30). Not only does nicotine interact with specific receptor sites in the central nervous system and periphery, it also has biphasic effects on its receptors. Langley and Dickinson (13) were the first to note that low doses of nicotine will stimulate autonomic ganglia while higher doses will induce blockade. Nicotine induces a transient stimulation of electrical activity which is followed by a longer lasting blockade (12). This phenomenon is referred to as desensitization of the nicotinic receptor. Genotype apparently affects the sensitivity of an animal to nicotine. The influence of genotype on the effects of nicotine on locomotion have been most thoroughly studied in both rats (3, 7, 8, 26) and mice (2, 10, 14, 17). Other responses have been less well studied, but genotype also influences nicotine-induced hypo- thermia (14, 16, 18), bradycardia (18), respiratory stimulation (14,18), acoustic startle response (14,18) and convulsions (22, 23, 26). Genotype also influences the extent of tolerance development with chronic nicotine treatment (15,19). Although these results indicate that genotype influences sensitivity to nicotine, very little is known about the genetic architecture that regulates sensitivity to nicotine, perhaps because most of the studies that have been published, to date, have employed a relatively small number of inbred strains. Because of the complexity of nicotine response, the ability to measure several different parameters is of value in fully assessing the effects of this drug. To accomplish this purpose, a test battery consisting of six measures (respiratory rate, acoustic startle re- sponse, Y-maze crosses, Y-maze rears, heart rate and body temperature) has been developed (18). This battery allows the measurement of these responses in an individual animal with no measureable intertest interactions. The availability of this test battery makes efficient use of experimental subjects possible such that a more extensive analysis of genetic influences on nicotine response is feasible. This paper presents the results of such an analysis. Nineteen inbred mouse strains have been tested for the effects of nicotine using the test battery. A full dose-response curve has been constructed for each strain to determine whether qualitative or merely quantitative differences in response occur. Since several measurements of nicotine effects were obtained, further analyses of the results obtained in this paper, and those on nicotine-induced seizures (23), have been made to determine if a relationship among the various responses exists. Several of the strains used in the current study are closely related, while others are thought to derive from substantially different populations. This design was chosen to determine the stability of nicotine sensitivity (from similarity of related stocks) and to maximize the likelihood of identifying widely divergent responses (by testing mice of different origins). METHOD Animals Male mice of 19 inbred strains were used in this study. Mice of 1Requests for reprints should be addressed to Dr. Michael J. Marks, Institute for Behavioral Genetics, Campus Box 447, University of Colorado, Boulder, CO 80309. 667