Psychopharmacology(1994) 114: 123-130 Psychopharmacology © Springer-Verlag 1994 Atypical antipsychotics, clozapine and sulpiride do not antagonise amphetamine-induced stereotyped locomotion Susan Moore, Paul Kenyon Department of Psychology,University of Plymouth, Drake Circus, Plymouth PL4 8AA, United Kingdom Received: 18 November 1992 / Final version: 20 July 1993 Abstract. An automated tracking system which converted an animal's path between quadrants of a circular open field into a series of trips was used to analyse stereotyped locomotion in amphetamine treated rats. Amphetamine (3.5 mg/kg) increased the horizontal distance moved and the number and proportion of thigmotaxic trips around the perimeter of the apparatus (length 4 trips). To investi- gate the hypothesis that classic antipsychotics, but not atypical antipsychotics, would antagonise the repetitive boundary patrolling associated with amphetamine-in- duced hyperactivity, animals were pretreated with haloperidol (0.01, 0.025, 0.05, 0.075 mg/kg), clozapine (5, 10, 20 mg/kg) or ( +__ )sulpiride (10, 20, 50 mg/kg) 30 min before 3.5 mg/kg amphetamine. The results showed that the classic antipsychotic haloperidol antagonised both hyperactivity and the increased proportion of length 4 trips. In marked contrast, the atypical antipsychotics clozapine and sulpiride antagonised hyperactivity but did not reduce the proportion of length 4 trips. The inability of atypical antipsychotics to reduce the repetitive bound- ary patrolling associated with amphetamine-induced hy- peractivity is consistent with the action of these drugs on other forms of amphetamine-induced stereotyped behav- iour, and indicates that locomotor routes under ampheta- mine are stereotyped. The measurement of trip lengths provides a sensitive tool for examining drug action on the spatial distribution of open field locomotion. Key words: Amphetamine - Locomotor patterns - Stereotyped locomotion - Haloperidol - Clozapine - Sulpiride Antagonism of amphetamine-induced behaviours in ani- mals has been used to study the underlying mechanisms of antipsychotic drug treatment, and to detect novel anti- psychotic agents. Considerable attention has focused on amphetamine-induced stereotyped behaviours such as sniffing, licking and gnawing because these behaviours are reliably antagonised by classic antipsychotics such as haloperidol and chlorpromazine (Szechtman et al. 1988). Correspondence to: S Moore However, it is now clear that a group of clinically effective drugs-so-called atypical antipsychotics-do not antag- onise all the components of the amphetamine-induced syndrome. Tschanz and Rebec (1989) reported that atypical anti- psychotics vary in their ability to antagonise specific am- phetamine-induced behaviours. For example, clozapine blocks sniffing but not the rearing or head bobbing pro- duced by the drug. Paradoxically, several researchers have reported that clozapine and other atypical antipsychotics actually enhance the stereotyped head movements and sniffing induced by 2-5 mg/kg amphetamine (Robertson and MacDonald 1985; Sharp et al. 1986). The conflicting reports of the effects of atypical anti- psychotics on amphetamine-induced stereotyped behavi- ours, and the observation that atypical antipsychotics are less likely to produce Parkinson-like extrapyramidal side effects which are associated with classic antipsychotic drugs, has cast doubt on the utility of amphetamine antag- onism as a screening technique for antipsychotic potential (Robertson and MacDonald 1985; Tschanz and Rebec 1989), and led to the suggestion that antagonism of am- phetamine-induced stereotypy predicts a compound's po- tential to induce unwanted extrapyramidal side effects in humans (Ljungberg and Ungerstedt 1985). However, clas- sic and atypical antipsychotics share the ability to antag- onise amphetamine-induced hyperactivity, and this may form the basis of a more appropriate test for antipsychotic potential (Rebec and Bashore 1984; Ljungberg and Un- gerstedt 1985). At low doses, amphetamine increases open-field loco- motion; with increasing dose the route taken by an animal in the open field becomes increasingly repetitive (Schior- ring 1979; Mueller et al. 1989a; Geyer 1990). Because of this, several authors have argued that locomotion exhib- ited under higher (3-5 mg/kg) doses of amphetamine is stereotyped. We have recently developed a technique for measuring the spatial distribution of open-field loco- motion (Kenyon 1990, 1991; Kenyon et al. 1992), based on the approach described by Mueller et al. (1989a, b). The subject's sequence of movements between adjacent quad- rants of the apparatus is subdivided into a series of "trip lengths" A trip is determined by the extent of forward locomotion without change of direction. A change of