Behavioural Brain Research 159 (2005) 235–242 Research report Piracetam counteracts the effects of amitriptyline on inhibitory avoidance in CD1 mice Estrella Everss, M. Carmen Arenas, Concepci´ on Vinader-Caerols, Santiago Monle ´ on, Andr´ es Parra ∗ Department of Psychobiology, Faculty of Psychology, University of Valencia, Blasco Ib´ a˜ nez, 21, 46010 Valencia, Spain Received 1 July 2004; received in revised form 29 October 2004; accepted 4 November 2004 Available online 10 December 2004 Abstract The purpose of the present work was to study the effects of amitriptyline on animal cognition in relation to some characteristics of its therapeutic effects. The modulation of acute and chronic effects of amitriptyline on inhibitory avoidance in male and female mice by piracetam was investigated. In Experiment 1, mice were subjected to the training phase of inhibitory avoidance conditioning 60 min after acute piracetam (100 mg/kg) or physiological saline administration. Immediately after the behavioural task, they received a single injection of the tricyclic antidepressant amitriptyline (30mg/kg) or physiological saline. Twenty-four hours later, subjects were tested for avoidance. In Experiment 2, the same doses of amitriptyline and piracetam were chronically administered. Mice were subjected to the training phase of inhibitory avoidance on the 22nd day, and to the test phase 24h later. Forty-five minutes after test, subjects explored the elevated plus-maze for 5min in order to assess whether the effects of amitriptyline on avoidance performance may reflect general behavioural changes. Results obtained were that: (a) acute and chronic amitriptyline impaired inhibitory avoidance of male and female mice, (b) piracetam counteracted the effect of acutely administered amitriptyline on inhibitory avoidance, and (c) piracetam counteracted the effects of chronically administered amitriptyline in males but not females in the same learning task. These effects do not seem to be mediated by non-specific drug effects on spontaneous motor activity or anxiety. © 2004 Elsevier B.V. All rights reserved. Keywords: Amitriptyline; Piracetam; Inhibitory avoidance; Elevated plus-maze; Nootropics; Antidepressants; Sex differences; Mice 1. Introduction Antidepressants are prescribed for a variety of mental dis- orders, in addition to depression [3]. They have clinical bene- fits; but the current armamentarium of antidepressants has an unacceptable lack of efficacy [20]. One of the limitations for designing better antidepressants is a consequence of the fact that their mechanism of therapeutic action is unknown. The pharmacodynamics of antidepressants at molecular, cellular and system levels has been investigated by many authors, e.g. [34,51,52]. Studies on the effects of antidepressants at the cognitive level are less common but likely to be benefi- ∗ Corresponding author. Tel.: +34 963 864 302; fax: +34 963 864 668. E-mail address: andres.parra@uv.es (A. Parra). cial in improving our understanding of these drugs. At this level, the purpose of the present work was to study the ef- fects of amitriptyline on animal cognition in relation to some characteristics of the therapeutic effects of this drug in human beings. Previous studies carried out with the forced swimming test (FST; [8,26,39]) suggested that this test shares some charac- teristics of the short tests used to assess the effects of drugs on memory such as those employed by Ennaceur et al. [9–11], and Platel and Porsolt [41]. FST can be considered as a mem- ory test in which animals learn to be immobile in the first session such that the second session can be used as a reten- tion test [39]. Given that antidepressants impair FST perfor- mance (i.e. animals swim more than controls on the second occasion that they are forced to swim, see Porsolt et al. [44]), 0166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2004.11.004