Psychopharmacology 64, 45- 54 (1979) Psychopharmacology by Springer-Verlag 1979 Circling Behavior Following Systemic d-Amphetamine Administration: Potential Noradrenergic and Dopaminergic Involvement Larry Kokkinidis ~ and Hymie Anisman 2 1 Departmentof Psychology, Universityof Saskatchewan,Saskatoon, Saskatchewan,Canada z Department of Psychology, CarletonUniversity, Ottawa,Ontario, Canada Abstract. Systemic treatment with d-amphetamine pro- duced a dose-dependent increase in the circling be- havior of normal mice. Treatment with both e-methyl- p-tyrosine (~-MpT) and FLA-63 antagonized the amphetamine-induced circling behavior. Similarly, blockade of B-adrenergic receptors by propranolol and dopamine receptors by haloperidol reversed the circling response elicited by amphetamine. In contrast to c~- MpT and haloperidol, however, neither FLA-63 nor propranolol attenuated the locomotor excitation engendered by amphetamine. Following repeated d- amphetamine injections the circling ordinarily induced by a single injection was abolished, whereas the loco- motor effects of amphetamine remained unaltered. These findings are consistent with earlier work suggest- ing that tolerance may occur in those behaviors that involve a noradrenergic component. Key words: d-Amphetamine - e-Methyl-p-tyrosine - FLA-63 - Haloperidol - Propranolol - Phenoxybenzamine - Circling behavior - Per- severation - Tolerance It is well documented that systemically administered amphetamine produces consistent unidirectional body turning among rats (Jerussi and Glick, 1974, 1976) and mice (Glick et al., 1976). On the basis of behavioral and biochemical data the suggestion was made that circling behavior following systemic injection of d- amphetamine is comparable to that observed after direct injections of dopaminergic agonists to the nigro- neostriatal pathway (Jerussi and Glick, 1974, 1976; Ungerstedt et al., 1969). Presumably, there exists a bilateral imbalance of dopaminergic activity in the nigro-neostriatal system (Glick et al., 1974; Zimmerberg et al., 1974) which is exacerbated follow- ing treatment with d-amphetamine. This imbalance, in turn, results in rotation contralateral to the side of greater stimulation (Glick et al., 1974; Jerussi and Glick, 1974, 1976). The drug induced rational response depends on the amphetamine dosage. Whereas high dosages (15-25mg/kg) produce tight head-to-tail circling, lower dosages (1-5 mg/kg) elicit a running re- sponse in a preferred direction (Kokkinidis and Anis- man, 1977). Thus, the circling behavior after lower dosages is apparent in a spherical rotometer or circular alleyway but not in an open-field situation (Jerussi and Glick, 1974; Kokkinidis and Anisman, t977). Lower dosages of d-amphetamine that engender rotational behavior in a circular alleyway or spherical rotometer also elicit stimulus perseveration when mice are tested in a free-running, spontaneous alternation task (Anisman and Kokkinidis, 1975; Kokkinidis and Anisman, 1976a). That is, when permitted to explore freely in a symmetrical Y-maze following amphetamine treatment, mice tend to visit successively two arms of this maze, i.e., perseveration (Kokkinidis and Anisman, 1976b). In so doing these animals make successive left- right turns at the choice point of the Y-maze. This, of course, contrasts with the unidirectional turning observed in either a spherical rotometer (Glick et al., 1976) or a circular alleyway (Kokkinidis and Anisman, 1977). Kokkinidis and Anisman (1977) have suggested that the rotational behavior observed after systemic treatment with low dosages of amphetamine may be a reflection of a drug-induced perseverative tendency. These authors have argued, as has Robbins (1975), that amphetamine augments unconditioned responses which are high in the organism's repertoire. In fact, although both IP and unilateral intravent.ricular in- jection of amphetamine to either ventricle led to rotational behavior in a circular alleyway, the effects of administration routes could be differentiated from one another in the free-running Y-maze exploratory task. 0033-3158/79/0064/0045/$02.00