Pharmacological Research 62 (2010) 450–456 Contents lists available at ScienceDirect Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs Memantine is a useful drug to prevent the spatial and non-spatial memory deficits induced by methamphetamine in rats Jorge Camarasa a,∗ , Teresa Rodrigo b , David Pubill a,1 , Elena Escubedo a,1 a Laboratory of Pharmacology and Pharmacognosy, Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain b Animal Experimentation Unit, Faculty of Psychology, University of Barcelona, 08035 Barcelona, Spain article info Article history: Received 14 April 2010 Received in revised form 19 May 2010 Accepted 20 May 2010 Keywords: Memantine Methamphetamine Learning Memory Object recognition Morris water maze abstract Methamphetamine (METH) is a street drug that is abused by young people. In previous studies, we demonstrated the effectiveness of alpha-7 nicotinic receptor antagonists in preventing the neurotoxicity induced by this amphetamine derivative. The present study seeks to determine whether pre-treatment with memantine (MEM) (an antagonist of both NMDA and alpha-7 nicotinic receptors) counteracts the memory impairment induced by METH administration in male Long Evans rats. Non-spatial memory was tested in the object recognition test and spatial learning memory was tested in the Morris water maze. In our experimental conditions, rats that received the MEM (5 mg/kg, intraperi- toneally) pre-treatment recovered the ability to discriminate between a familiar and a novel object. This ability had been abolished by METH (10 mg/kg, subcutaneously) at 72 h and 1 week after treatment. Moreover, MEM pre-treatment also inhibited the thigmotaxis behaviour induced by METH. Rats treated with METH showed impaired learning in the Morris water maze. The results of the probe trial demonstrated that METH-treated rats did not remember the location of the platform, but this mem- ory impairment was also prevented by MEM pre-treatment. Moreover, MEM by itself improved the learning of the task. Finally, MEM significantly improved the learning and memory impairment induced by METH. Therefore, MEM constitutes the first successful approach to prevent the cognitive deficits induced by amphetamine derivatives which are frequently abused in western countries. © 2010 Elsevier Ltd. All rights reserved. 1. Introduction Methamphetamine (METH) is a highly addictive drug of abuse and addiction to this drug has increased to epidemic proportions worldwide [1]. In humans, METH abuse is associated with neuro- toxicity to frontostriatal brain regions [2] and also cognitive deficits have been reported [3–5]. In rodents, METH decreases multiple indices of dopamine ter- minal integrity, especially in the striatum. The striatal changes produced by extended exposure of rats to METH include long- lasting decreases in dopamine content [6], dopamine metabolites [7], tyrosine hydroxylase activity [8] and loss of dopamine trans- porters [9]. Also, these METH-induced reductions in specific biochemical parameters are accompanied by reactive gliosis, a marker of neuronal injury [10,11]. The development of animal models will be essential for char- acterizing the cognitive deficits induced by amphetamines and ∗ Corresponding author. Tel.: +34 934024530; fax: +34 934035982. E-mail address: jcamarasa@ub.edu (J. Camarasa). 1 Contributed equally to this work. for understanding the neurobiological changes responsible for amphetamine-induced alterations in cognition. Although there are few papers about an animal model that reflects METH-induced alterations of memory processes [12,13], some beneficial effects were reported using baclofen or quetiapine in rats and mice [14,15]. Memantine (MEM) is a non-competitive antagonist of the NMDA receptor and a clinically useful drug to treat moderate to severe Alzheimer’s disease. Moreover, Aracava et al. [16] demon- strated that MEM, at clinically relevant concentrations, blocks alpha-7 nicotinic acetylcholine receptors in a non-competitive manner, and more effectively that it block NMDA receptors. Pre- vious results from our group demonstrated the effectiveness of alpha-7 nicotinic acetylcholine receptors antagonists preventing amphetamine-induced neurotoxicity [17,18]. When neuroprotec- tion was assayed with MEM, an effective improvement in the cognitive deficits was obtained also ahead of serotonergic injury induced by another frequently abused amphetamine derivative, such as MDMA, in rats [18,19]. The aim of this paper is to study the utility of MEM in preventing the learning and memory deficits induced by the administration of METH to rats. These memory deficits were studied by examining the effects of METH and MEM on non-spatial and spatial learning. The 1043-6618/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2010.05.004