Role of state-dependency in memory impairment induced by acute administration of midazolam in mice Leandro Sanday a, 1 , Karina A. Zanin a, b, 1 , Camilla L. Patti a, b , Sergio Tufik b , Roberto Frussa-Filho a, b, ⁎ a Departamento de Farmacologia, Universidade Federal de São Paulo, R. Botucatu, 862, Ed. Leal Prado, 1° andar, 04023062, São Paulo, SP, Brazil b Departamento de Psicobiologia, Universidade Federal de São Paulo, R. Napoleão de Barros, 925, 04021002, São Paulo, SP, Brazil abstract article info Article history: Received 4 August 2011 Received in revised form 18 January 2012 Accepted 28 January 2012 Available online 3 February 2012 Keywords: Anxiety Memory Midazolam Plus-maze discriminative avoidance task State-dependency Although the memory deficits produced by pre-training benzodiazepines administration have been exten- sively demonstrated both in humans and in animal studies, there is considerable controversy about the involvement of the state-dependency phenomenon on benzodiazepines-induced anterograde amnesia. The present study aimed to characterize the role of state-dependency on memory deficits induced by the benzo- diazepine midazolam (MID) in mice submitted to the plus-maze discriminative avoidance task (PM-DAT). This animal model concomitantly evaluates learning and retention of discriminative avoidance task, exploratory habituation as well as anxiety-like behavior and motor activity. Mice received 2 mg/kg MID before training and/or before testing in the PM-DAT. Pre-training (but not pre-test) MID administration impaired the retention of the discriminative avoidance task, which was not counteracted by a subsequent pre-test admin- istration of this drug, thus refuting the role of state-dependency. Conversely, the pre-training administration of MID also led to an impairment of the habituation of exploration in the PM-DAT (an animal model of non- associative memory). This habituation deficit was state-dependent since it was absent in pre-training plus pre- test MID treated mice. Concomitantly, MID pre-training administration induced anxiolytic effects and diminished the aversive effectiveness of the aversive stimuli of the task, leading to an impairment of the acquisition of the discriminative avoidance task. Our findings suggest that pre-training benzodiazepine administration can impair the retention of different types of memory by producing specific deleterious effects on learning or by inducing state-dependent memory deficits. © 2012 Published by Elsevier Inc. 1. Introduction There are many effective benzodiazepines that promote many adverse effects, both in the short- and long-term, such as sedation, ataxy, anterograde amnesia, tolerance and the potential to induce addiction (Akhondzadeh et al., 2002; Allison and Pratt, 2003). Concerning the cognitive side effects of benzodiazepines, there is considerable controversy regarding the involvement of the state- dependency phenomenon on memory deficits induced by their pre-training administration. In this respect, memory can be state- dependent, in that a response that has been acquired in a given (i.e., drug-induced) state may not be retrieved when the organism is in a different state (Ceretta et al., 2008; Colpaert et al., 2001). This state-dependent learning has proven to be involved in the antero- grade amnesia induced by benzodiazepines in mice submitted to the passive avoidance task (Patel et al., 1979), in rats submitted to a food-reward lever pressing task (Colpaert, 1986, 1990; Colpaert and Koek, 1996; Jackson, 1995) and even in chicks submitted to a T-maze task (Gilbert et al., 1989). However, the memory deficits induced by pre-training benzodiazepines administration were not related to state-dependency in pigs (Dantzer et al., 1976), rats (Davis, 1979) and mice (Sanger and Joly, 1985) submitted to conditioned fear tasks. The role of state-dependency was also not corroborated by stud- ies with rats in the passive avoidance task (Nabeshima et al., 1990), Morris water maze (McNamara and Skelton, 1991), or to a delayed known-match-to sample radial-arm maze task (Stackman and Walsh, 1992). As for human studies, the involvement and importance of state- dependency on benzodiazepines-induced anterograde amnesia have been emphasized by some authors (Jensen and Poulsen, 1982; Liljequist et al., 1977) while others have considered state-dependency as contribut- ing relatively little to anterograde amnesia and its observed impairments (Curran, 1986; Lister, 1985). The absence of involvement of state-dependency on the memory deficits induced by the pre-training administration of benzodiaze- pines could be related to a direct effect of these drugs on learning/ Progress in Neuro-Psychopharmacology & Biological Psychiatry 37 (2012) 1–7 Abbreviations: PM-DAT, plus-maze discriminative avoidance task; Av and NAv, aversive and non-aversive enclosed arms, respectively; %Tav, percent time spent in the Av; %TO, percent time spent in the open arms. ⁎ Corresponding author at: Departamento de Farmacologia, UNIFESP, Rua Botucatu, 862-Ed. Leal Prado, 1° andar, 04023062, São Paulo, SP, Brazil. Tel.: +55 11 5549 4122; fax: +55 11 5549 4122 r. 222. E-mail address: frussa.farm@epm.br (R. Frussa-Filho). 1 The first two authors contributed equally to this study. 0278-5846/$ – see front matter © 2012 Published by Elsevier Inc. doi:10.1016/j.pnpbp.2012.01.013 Contents lists available at SciVerse ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp