NALOXONE IMPROVES IMPAIRMENT OF SPATIAL PERFORMANCE INDUCED BY PENTYLENETETRAZOL KINDLING IN RATS A. OMRANI, a * M. R. GHADAMI, a N. FATHI, a M. TAHMASIAN, a Y. FATHOLLAHI b AND A. TOUHIDI a a Department of Physiology, Kermanshah University of Medical Sci- ences, Kermanshah, Iran b Department of Physiology, School of Medical Sciences, Tarbiat Modarres University, Tehran, Iran Abstract—The role of endogenous opioid peptides in impair- ment of spatial performance due to epileptogenesis was ex- amined. Animals were kindled by repeated injections of pen- tylenetetrazol (PTZ) (40 mg/kg, i.p.) in the presence or ab- sence of the opioid receptor antagonist naloxone. Naloxone in different doses (1, 5 and 10 mg/kg, i.p.) was applied 30 min before each PTZ injection. Behavioral testing was assessed 24 h and 10 days after the last injection in separate groups of animals using Morris water maze. Our results showed that PTZ-induced kindling produced a significant impairment of spatial learning and memory as compared with controls and this effect was not due to the aftereffect of repeated seizures. Naloxone pretreatment in the course of kindling had no effect on seizures development, however it caused an improvement of spatial learning and memory performance in kindled rats. It is likely that the long-lasting changes in neuronal respon- siveness associated with kindling led to a defect in the pro- cessing of spatial information. These data suggest that en- dogenous opioid peptides released in the hippocampus dur- ing kindling are at least in part responsible for impairment of spatial performance in kindled animals. © 2007 IBRO. Pub- lished by Elsevier Ltd. All rights reserved. Key words: endogenous opioid, pentylenetetrazol, kindling, naloxone, learning and memory, Morris water maze. Epilepsy is frequently accompanied by impairment in a number of cognitive functions (Thompson and Corcoran, 1992; Giovagnoli et al., 1997). Epilepsy-related memory impairment has also been demonstrated in animal models of epileptogenesis such as kindling (Becker et al., 1992; Genkova-Papazova and Lazarova-Bakarova, 1995; Letty et al., 1995; Gilbert et al., 1996). Kindling is widely studied in relation to chronic epilepsy and neuronal plasticity. The term “kindling” refers to a process in which repeated ad- ministration of an initially sub-convulsive electrical or chemical stimulus results in appearance and progressive intensification of convulsant activity, culminating in a gen- eralized seizure (Goddard et al., 1969). Among the chem- icals for kindling induction, pentylenetetrazol (PTZ), a non- competitive antagonist of GABA A receptors is extensively used (Mason and Cooper, 1972). PTZ-induced kindling has been associated with a variety of long lasting neuro- chemical, neurophysiological and behavioral alterations (Becker et al., 1992; Schroder et al., 1993, 1994; Ruthrich et al., 1996). Specifically, PTZ-induced kindling results in a worsening of shuttle box learning which is persistent for a long time after kindling completion (Becker et al., 1992; Genkova-Papazova and Lazarova-Bakarova, 1995, 1996). It has been reported that endogenous opioid peptides are involved in memory processes. Acute opioid adminis- tration impairs learning and memory and opioid antago- nists can modulate opioid-induced memory impairment (Izquierdo, 1980; Rigter et al., 1980; Gallagher, 1982; Col- lier and Routtenberg, 1984). Furthermore, epileptic activity has been shown to activate the endogenous opioid system and produce a long-lasting increase in endogenous opioid levels in the brain structures responsible for cognition (Hong et al., 1979, 1980; Vindrola et al., 1984; McGinty et al., 1986). It is suggested that a seizure-activated endog- enous opioid system might be responsible for the learning impairment in kindled rats (Becker et al., 1994; Erdtmann- Vourliotis et al., 1998). This idea is supported by indirect evidence that indicates opioid peptides are released during the course of kindling (Erdtmann-Vourliotis et al., 1998). Although learning impairment has been demonstrated in PTZ-kindled rats, the majority of studies involving learn- ing tasks have been based on electrical shock reinforce- ment (Becker et al., 1992; Genkova-Papazova and Laz- arova-Bakarova, 1995, 1996). Only few studies have con- sidered the spatial performance of PTZ-kindled rats. Furthermore, there are some inconsistencies in the results obtained in these studies. Specifically, Hamm et al. (1995) found spatial learning deficits in PTZ-kindled rats in the Morris water maze (MWM) task whereas Lamberty and Klitgaard (2000) showed that learning performance of kin- dled animals was comparable to that of controls and only spatial memory for place was affected by PTZ kindling. On the other hand, little is known about the contribution of endogenous opioid peptides in learning performance of PTZ-kindled animals in spatial learning tasks. Therefore, the present study was an attempt to further investigate the spatial learning and memory performance of PTZ-kindled rats by using MWM. Additionally, to examine the signifi- cance or contribution of endogenous opioids in this pro- cess, we investigated the effect of naloxone on the PTZ- induced kindling and spatial learning and memory in kin- dled rats. This study may provide further evidence for contribution of endogenous opioids in learning deficits seen in kindled animals. *Correspondence to: A. Omrani, Neurobiology Sector, International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy. Tel: +39-040-3787254; fax: +39-040-3787243. E-mail address: omrani@sissa.it (A. Omrani). Abbreviations: ANOVA, analysis of variance; MWM, Morris water maze; PTZ, pentylenetetrazol. Neuroscience 145 (2007) 824 – 831 0306-4522/07$30.00+0.00 © 2007 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2006.12.049 824