Abstract Rationale: The contradictory amphetamine ef- fects on memory could be due to different protocols of amphetamine administration or the well-known anxio- genic effect of the drug. Objective: The effects of differ- ent protocols of administration of amphetamine were in- vestigated on mice tested in the plus-maze discriminative avoidance task (DAT), which provides simultaneous in- formation about memory and anxiety. Methods: Acutely pre- or post-training, 0.3, 1.0, or 3.0 mg/kg amphet- amine-treated, 10-day chronically 3.0 mg/kg amphet- amine-treated, 0.3 mg/kg amphetamine plus 0.25 mg/kg scopolamine and 3.0 mg/kg amphetamine plus 3.0 mg/kg tacrine-treated mice were conditioned to choose between two enclosed arms (one of which was aversive) while avoiding two open arms. Learning/memory was evaluat- ed by the percentage time in the aversive enclosed arm (PTAV), and anxiety by the percentage time in the open arms (PTO). Results: Given acutely before conditioning, amphetamine significantly decreased PTO in training, suggesting an anxiogenic effect, and significantly in- creased PTAV in the test, suggesting an amnestic action. Given acutely after the conditioning, no action of this drug on memory was found. After repeated treatment, the anxiogenic effect disappeared, while the amnestic effect remained. While no effects of subeffective doses of amphetamine and scopolamine co-administration were detected, tacrine attenuated the amnestic effect of amphetamine. Conclusions: Amphetamine has different effects on DAT when given pre- or post-training. While acute pre-training amnestic action is temporally corre- lated with an anxiogenic effect, there is tolerance to the anxiogenic but not to the amnestic effect after repeated administration. Because this acute amnestic effect of amphetamine is attenuated by tacrine, a possible rela- tionship with cholinergic system cannot be discarded as a mechanism to amphetamine-induced amnesia in DAT. Keywords Avoidance-learning · Anxiety · Amphetamine · Behavior Introduction The plus-maze discriminative avoidance task (DAT) was recently developed in our laboratory (Silva et al. 1997). In this new animal model of learning/memory, mice are conditioned to choose between two enclosed arms (an aversive and a non-aversive arm) while avoiding the open arms of the apparatus. The apparatus employed is an adaptation of the conventional elevated plus-maze, which has been extensively used to assess anxiolytic and anxiogenic effects of drugs since its description and vali- dation for rats and mice (Handley and Mithani 1984; Pellow et al. 1985; Lister 1987). The DAT has shown to be an effective model since the effects of both memory-enhancing and amnesic drugs have been demonstrated in this task. Indeed, the adminis- tration of ganglioside GM1 (a glycosphingolipid be- lieved to play an important role in synaptic plasticity – Bellot et al. 1996, 1997; Silva et al. 1996) was able to improve retention of normal adult mice tested in DAT (Silva et al. 1997). The performance of adult rats in DAT was also improved by neonatal GM1 administration (Silva et al. 2000). In addition, both GM1 and bovine brain phosphatidylserine (proposed as a treatment of Alzheimer’s disease – Crook et al. 1992) were able to attenuate scopolamine-induced amnesia in mice tested in this DAT (Claro et al. 1999; Silva et al. 1999). Besides being a useful model for studying learning/ memory, DAT also provides simultaneous information about anxiety-like behavior of the same animals, evaluat- ed by the time spent in the open arms of the apparatus. The well-known anxiolytic and anxiogenic effects of R.H. Silva ( ✉ ) · R.C. Carvalho · R. Frussa-Filho Departamento de Farmacologia, Universidade Federal de São Paulo, Rua Botucatu, 862 – Edifício José Leal Prado – CEP 04023-062, São Paulo, SP, Brazil e-mail: regina.farm@epm.br Fax: +55-11-55792752 S.R. Kameda · G.S. Rigo · K.L.B. Costa · I.D. Taricano Disciplina de Farmacologia, Universidade de Santo Amaro, Brazil Psychopharmacology (2002) 160:9–18 DOI 10.1007/s00213-001-0948-3 ORIGINAL INVESTIGATION R.H. Silva · S.R. Kameda · R.C. Carvalho · G.S. Rigo K.L.B. Costa · I.D. Taricano · R. Frussa-Filho Effects of amphetamine on the plus-maze discriminative avoidance task in mice Received: 25 September 2000 / Accepted: 30 September 2001 / Published online: 29 November 2001 © Springer-Verlag 2001