Effect of the NMDA antagonist MK-801 on latent inhibition of fear conditioning Luis M. Traverso, Gabriel Ruiz, Luis G. De la Casa ⁎ Department of Experimental Psychology, University of Seville, Spain abstract article info Article history: Received 22 March 2012 Received in revised form 22 May 2012 Accepted 19 June 2012 Available online 23 June 2012 Keywords: MK-801 Latent inhibition Fear conditioning N-methyl-D-aspartate (NMDA) receptors seem to play a central role in learning and memory processes in- volved in Latent Inhibition (LI). In fact, MK-801, a non-competitive NMDA receptor antagonist, has proved its effectiveness as a drug for attenuating LI when administered before or after stimulus preexposure and conditioning stages. This paper presents three experiments designed to analyze the effect of MK-801 on LI when the drug is administered before (Experiment 1A) or after (Experiment 1B) preexposure and condition- ing stages with a conditioned emotional response procedure. Additionally, we analyze the effect of the drug when it was administered before preexposure, before conditioning or before both phases (Experiment 2). The results show that the effect of the drug varied as a function of the dose (with only the highest dose being effective), the moment of administration (with only the drug administered before the experimental treatments being effective), and the phase of procedure (reducing LI when the drug was administered only at preexposure, and disrupting fear conditioning when administered at conditioning). These differences may be due to several factors ranging from the role played by NMDA receptors in the processing of stimuli of different sensorial modalities to the molecular processes triggered by drug administration. © 2012 Elsevier Inc. All rights reserved. 1. Introduction Latent Inhibition (LI) is generally defined as a retardation in learn- ing that results from previous non-reinforced exposure to the to-be-Conditioned Stimulus (CS). LI has traditionally been considered the result of a failure in the acquisition of the CS–Unconditioned Stim- ulus (US) association after preexposure due to: i) a reduction in CS associability (e.g., Mackintosh, 1975; Pearce and Hall, 1980), ii) the formation of an association between the preexposed stimulus and the contextual cues (e.g., Wagner, 1981), iii) the conditioning of an inattentional response (e.g., Lubow, 1989), or iv) the reduction of CS novelty (e.g., Schmajuk et al., 1996). More recently, an alternative set of theories has proposed that LI reflects a retrieval failure at the time of testing rather than an associative deficit (Miller et al., 1986; Bouton, 1993). This view implies that a CS–nothing association is formed at preexposure, and an independent CS–US association is established during conditioning. Both associations would compete to obtain behavioral expression at the time of testing, producing a weaker CR (conditioned response) to the CS. A very influential model of LI, that combines psychological and physiological points of view, is the so-called switching model (Weiner, 1990, 2003; Weiner and Feldon, 1997; Weiner and Arad, 2009) that integrates the evidence available from LI in animal and human experi- ments. The switching model proposes that the dopaminergic system is the main responsible for producing LI, and its predictive capacity has been demonstrated in the analysis of the effects on LI of some drugs commonly used in the treatment of schizophrenia (e.g., Weiner et al., 1988). Recent developments in this area have led to greater interest in the study of the glutamatergic system (e.g. Rivas-Vazquez and Resnick, 2003), because it is based on a new pharmacological model of LI that complements the dopaminergic model, although the available experi- mental results are not entirely consistent. Specifically, LI seems to be abolished with aversive conditioning procedures when a NMDA antag- onist that impedes normal glutamatergic activity is administered at pre- exposure stage, regardless whether the drug is administered before or after stimulus exposure (Aguado et al., 1994; Gallo et al., 1998; Traverso et al., 2003; Lewis and Gould, 2004). However, these results may be seen as a consequence of a state dependent learning and the resulting contextual change that it involves (e.g., Siegel, 1988). In fact, when the NMDA antagonist is administered at both preexposure and conditioning stages, the results are apparently contradictory. Some ex- periments have resulted in intact LI despite drug administration (Weiner and Feldon, 1992; Aguado et al., 1994; Gaisler-Salomon and Weiner, 2003) while other reports have shown complete LI abolition (Turgeon et al., 1998, 2000; Traverso et al., 2003). On the other hand, fear conditioning is a prominent model of aver- sive conditioning, that has been frequently used to study LI. In fear conditioning, the effect of MK-801 (a non-competitive NMDA receptor antagonist agent) on LI is far from clear. A summary of the reported effects of MK-801 on LI appears in Table 1. The contradictory results Pharmacology, Biochemistry and Behavior 102 (2012) 488–494 ⁎ Corresponding author at: Dpt. Psicologia Experimental, Facultad de Psicologia, C/Camilo Jose Cela, s/n, 41018 Sevilla, Spain. Tel.: +34 954557682; fax: +34 954551784. E-mail address: delacasa@us.es (L.G. De la Casa). 0091-3057/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2012.06.014 Contents lists available at SciVerse ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh