Original article 79 Effect of subchronic caffeine treatment on MK-801-induced changes in locomotion, cognition and ataxia in mice R. V. de Oliveira a , O. P. Dall’Igna a , A. B. L. Tort a , J. F. Schuh a , P. F. Neto a , M. W. Santos Gomes a , D. O. Souza a and D. R. Lara b N-Methyl-D-aspartate (NMDA) receptor antagonists cause hyperlocomotion and cognitive deficits in rodents, and caffeine-tolerant mice show diminished locomotor response to NMDA receptor antagonists. The aim of this study was to evaluate the effect of subchronic caffeine treatment on MK-801-induced hyperlocomotion, ataxia and cognitive deficits, as well as amphetamine-induced hyperlocomotion in mice. Mice were treated subchronically with caffeine (0, 0.1, 0.3 and 1 mg/ml and 1, 3 and 7 days) and evaluated for locomotor activity, working memory (delayed alternation test), long-term memory (inhibitory avoidance task) and ataxia. Hyperlocomotion induced by MK-801 (0.25 mg/kg i.p.) was diminished after 3 days and almost abolished after 7 days of caffeine treatment at the 1 mg/ml dose, and this effect was also dose-dependent. Ataxia induced by 0.5 mg/kg MK-801 was not affected by caffeine treatment, but a short-lived hyperlocomotor effect was observed. Performance deficit in the inhibitory avoidance task induced by MK-801 (0.01 mg/kg) was prevented in mice treated with caffeine for 7 days at 1 mg/ml, and perseverative errors in the T-maze by MK-801 (0.4 mg/kg) were attenuated. The locomotor effect of amphetamine (5 mg/kg) was unaffected by subchronic caffeine treatment. The findings that hyperlocomotion and cognitive effects induced by MK-801 can be specifically influenced by reduced adenosinergic activity agree with a model of adenosine hypofunction in schizophrenia, since NMDA receptor antagonists are pharmacological models for this disorder. Behavioural Pharmacology 16:79–84  c 2005 Lippincott Williams & Wilkins. Behavioural Pharmacology 2005, 16:79–84 Keywords: adenosine, MK-801, NMDA, caffeine, tolerance, schizophrenia, locomotion, mouse a Departamento de Bioquı ´mica, ICBS, UFRGS, Porto Alegre and b Faculdade de Biocie ˆ ncias, PUCRS, Porto Alegre, Brazil. Sponsorship: This study was supported by PRONEX (Grant # 41960904-366/ 96), CNPq and FAPERGS. Correspondence and requests for reprints to Diogo R. Lara, Faculdade de Biocie ˆ ncias, PUCRS, Av. Ipiranga, 6681 Pd 12A, Porto Alegre, RS, Brazil, 90619-900. E-mail: drlara@pucrs.br Received 5 November 2004 Accepted as revised 22 December 2004 Introduction Caffeine, a non-selective adenosine receptor antagonist, increases locomotor activity apparently from an additive effect of A 1 (A 1 R) and A 2A (A 2A R) receptor blockade (Karcz-Kubicha et al., 2003). According to Svenningsson et al. (1999), chronic caffeine treatment is well known to produce tolerance to its locomotor effect in animals, probably due to functionally relevant adaptations and alterations in gene expression in the hippocampus and striatum. As shown by Karcz-Kubicha et al. (2003), the acute motor-activating effects of 10 but not 30 mg/kg caffeine in rats undergo complete tolerance after chronic caffeine exposure (1 mg/ml in drinking water). This treatment also leads to complete cross-tolerance to specific A 1 R antagonists, but not to A 2A R antagonists, which still produced significant motor activation. Thus, A 1 R blockade might be mostly responsible for the tolerance to the motor-activating effects of caffeine, whereas a residual motor-activating effect of caffeine in tolerant animals seems to be mostly due to A 2A R blockade. N-Methyl-D-aspartate (NMDA) receptor antagonists, considered one of the best pharmacological models of schizophrenia, produce both hyperlocomotion and cogni- tive deficits in rodents (Angelucci et al., 1999; Krystal et al., 1999). The activation of NMDA receptors increases adenosine release (Hoehn and White, 1989; Craig and White, 1992, 1993; Manzoni et al., 1994), whereas adenosine agonists prevent neurophysiological and beha- vioural actions of NMDA receptor antagonists (Browne and Welch, 1982; Fraser et al., 1997; Popoli et al., 1997). In addition, both caffeine and NMDA receptor antagonists induce glutamate and dopamine release in the nucleus accumbens (Adams and Moghaddam, 1998; Solinas et al., 2002). In accordance with such common mechanisms, Dall’Igna et al. (2003) have recently shown that subchronic caffeine treatment (1 mg/ml for 7 days) causes cross-tolerance to the effect of NMDA receptor antag- onist MK-801 on locomotion, but not for cognitive impairments, as evaluated with the inhibitory avoidance task and spontaneous alternation. Importantly, in that study the dose of MK-801 in all behavioural tests was 0.25 mg/kg. This is a typical dose used for studies with locomotion, which is a behavioural parameter regarded as a model for psychotic symptoms in rodents (Angelucci et al., 1999). Finally, Sukhotina et al., (2004) showed that 0955-8810  c 2005 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.