Effect of lithium on morphine state-dependent memory of passive avoidance in mice Mohammad Reza Zarrindast a,b,c, * , Soheila Fazli-Tabaei d , Shamseddin Ahmadi e , Saeid Hosein Yahyavi d a Department of Pharmacology, School of Medicine, Tehran University of Medical Science, P.O. Box 13145-784, Tehran, Iran b Institute for Studies in Theoretical Physics and Mathematics, School of Cognitive Sciences, Tehran, Iran c Institute for Cognitive Science Studies, Tehran, Iran d Department of Physiology, Tehran Medical Unit, Azad University, Tehran, Iran e Department of Biology, Faculty of Science, Tehran University, Tehran, Iran Received 25 July 2005; received in revised form 29 October 2005; accepted 1 November 2005 Abstract In the present study, effects of lithium chloride (LiCl) on morphine induced state-dependent memory of passive avoidance task were examined in mice. One-trial step-down paradigm was used for the assessment of memory retention in adult male NMRI mice. Administration of morphine (5 mg/kg) subcutaneously (s.c.) 30 min before training or testing induced impairment of memory performance. Injection of the same dose of the drug 30 min before testing restored memory retention impaired under pre-training morphine effect. Intraperitoneal (i.p.) injection of lithium, 60 min before training or prior to testing also impaired memory performance. Under the pre-training of morphine, the response of the opioid was restored when animals received LiCl (80 and 160 mg/kg) as pre-test injection. Pre-training administration of lower dose of lithium (20 mg/kg), but not the higher doses of the drug (80 and 160 mg/kg) impaired memory retention in passive avoidance test. LiCl-induced impairment of memory retention was restored by pre-test administration of morphine. In the animals receiving pre-training morphine, combined pre-test morphine and LiCl administration increased the restoration of memory by the opioid. It can be concluded that there may be a cross-state dependency between morphine and lithium. D 2005 Elsevier Inc. All rights reserved. Keywords: Step-down; Latency; Passive avoidance; Retention; State-dependent learning 1. Introduction Lithium is used in the treatment of manic-depressive illness and can potentiate the effects of antidepressant drugs [1–3]. Clinical observations have also suggested that lithium may exert adverse effects on memory [4]. The drug may impair verbal memory [5]. However, a number of studies failed to demonstrate lithium-induced memory deficits [6]. Thus, it appears that the drug has no adverse effects apart from verbal memory impairments. The drug is reported to interact with the opioid system. Many studies suggested an important value of lithium in the treatment of drug addiction [7,8]. It has been proposed that it inhibits morphine withdrawal signs in morphine dependent mice [9], reduces the self-stimulation facilitated by morphine [10] and alters the morphine-induced analgesia in mice [11,12]. Lithium and morphine both produce a conditioned taste avoidance response and suppress schedule-induced polydipsia [13]. Although many interactions have been reported between lithium and morphine, but there is no direct report about their interaction in the state-dependent learning of the step-down passive avoidance task. Learning and memory in laboratory animals are also known to be affected by opioids and their antagonists [14]. A method based on the measurement of step-down latency in passive avoidance has been developed for the study of learning and 0031-9384/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2005.11.005 * Corresponding author. Department of Pharmacology, School of Medicine, Tehran University of Medical Science, P.O. Box 13145-784, Tehran, Iran. Tel.: +98 21 66402569; fax: +98 21 66402569. E-mail address: zarinmr@ams.ac.ir (M.R. Zarrindast). Physiology & Behavior 87 (2006) 409 – 415