Pharmacology Biochemistry & Behavior, Vol. 31, pp. 871-875. ©PergamonPress plc, 1989. Printedin the U.S.A. 0091-3057/88$3.00 + .00 Locomotor Activity and Stereotypy in Rats Following Repeated Apomorphine Treatments at 1-, 3-, or 7-Day Intervals BRUCE A. MATTINGLY, JAMES E. GOTSICK AND CARLOS MARIN Department of Psychology, Morehead State University, Morehead, KY40351 Received 9 December 1987 MATTINGLY, B. A., J. E. GOTSICK AND C. MARIN. Locomotor activity and stereotypy in ratsjbllowing repeated apomorphine treatments at I-, 3-, or 7-day intervals. PHARMACOL BIOCHEM BEHAV 31(4) 871-875, 1988.--In two experiments, the effects of repeated intermittent administration of a relatively high dose of apomorphine (5 mg/kg) on locomotor activity and/or stereotypic behavior in rats was determined. In Experiment 1, male rats were given ten sub- cutaneous (SC) injections of apomorphine or vehicle and tested for locomotor activity and stereotypy. The first nine injection test sessions were given at 3-day intervals and the tenth injection test session was given 18 days following the ninth session. In Experiment 2, male rats were tested for locomotor activity following ten SC injections of apomorphine or vehicle with either a one- or seven-day interval between injections. Major findings were as follows: a) apomorphine produced progressively greater increases in locomotor activity with each succeeding injection (i.e., sensitization); b) sensitization to the locomotor activity stimulating effects of apomorphine developed with interinjection intervals of one, three, and seven days; c) the sensitization effect was maintained over the 18-day drug-free break; and d) the effect of apomorphine on stereotypic behavior did not significantly change with repeated injections. These findings indicate that even a single dose of apomorphine induces relatively long-lasting neurobiological changes. Moreover, these findings are consistent with the view that separate neural pathways mediate locomotor activity and stereotypy in rats. Apomorphine Dopamine Locomotor activity Stereotypy Sensitization Rats REPEATED treatments of rats with dopamine antagonists (e.g., haloperidol) produce a behavioral supersensitivity to dopamine agonists (e.g., apomorphine) (3). This increased sensitivity to dopamine agonists appears to be mediated, in part, by an increase in the number of dopamine receptors (3, 6, 12). Paradoxically, repeated treatments with dopamine agonists also result in a behavioral supersensitivity to dopamine agonists. This enhanced sensitivity to dopamine agonists with repeated exposure has been referred to as "reverse-tolerance," "up-regulation," and "sensitization," and has been demonstrated using several agonists (2, 5, 7, 16, 18, 21). Research in our laboratory has also revealed a very strong sensitization effect in rats following repeated treatments with the dopamine agonist apomorphine. Indeed, the second ad- ministration of this drug in doses greater than 1.0 mg/kg often produces twice the effect on locomotor activity as does the first injection with a three-day interval between injections, and this progressive increase in activity continues to grow larger for up to 10-12 administrations of the drug (11). Unlike the chronic antagonist-induced behavioral supersensitivity, the neural mechanisms responsible for behavioral sensitiza- tion following repeated agonist treatments are unknown. Al- though an agonist-induced increase in receptor number or sensitivity would appear likely, available evidence indicates that striatal dopamine receptor sites either decrease in number or do not change following repeated agonist treat- ments (4, 12, 13, 18). Thus, receptor supersensitivity would not appear to account for the behavioral supersensitivity. EXPERIMENT 1 Besides locomotor activity, acute injections of apomor- phine also induce specific stereotypic behaviors in rats in- cluding repetitive sniffing, licking, and chewing responses (10). The main purpose of Experiment 1 was to determine whether apomorphine-induced stereotypy, like locomotor activity, would significantly change with repeated treatments with apomorphine. For this reason, two groups of rats were given nine injections of either apomorphine or vehicle with a 72-hr interval between injections. Following each injection, all rats were tested for stereotypy and locomotor activity. In addition, all rats were retested 18 days following the last regular test session to determine the relative permanence of the sensitization effect. METHOD Subjects Eighteen male Wistar albino rats were experimentally naive and approximately 90 days old at the beginning of test- ing. All rats were housed individually and maintained on ad lib food and water. All behavioral testing was conducted during the light phase of the 12-hour light-dark cycle. 871