EFFECTS OF VOLUNTARY EXERCISE ON HIPPOCAMPAL LONG-TERM POTENTIATION IN MORPHINE-DEPENDENT RATS H. MILADI-GORJI, a,b A. RASHIDY-POUR, b * Y. FATHOLLAHI, a  S. SEMNANIAN a AND M. JADIDI b,c a Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran b Laboratory of Learning and Memory, Research Center and Department of Physiology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran c Department of Medical Physics, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran Abstract—This study was designed to examine the effect of voluntary exercise on hippocampal long-term potentiation (LTP) in morphine-dependent rats. The rats were randomly distributed into the saline–sedentary (Sal/Sed), the depen- dent–sedentary, the saline–exercise (Sal/Exc), and the dependent–exercise (D/Exc) groups. The Sal/Exc and the D/Exc groups were allowed to freely exercise in a running wheel for 10 days. The Sal/Sed and the morphine–sedentary groups were kept sedentary for the same extent of time. Morphine (10 mg/kg) was injected bi-daily (12 h interval) dur- ing 10 days of voluntary exercise. On day 11, 2 h after the morphine injection, the in vivo LTP in the dentate gyrus of the hippocampus was examined. The theta frequency primed bursts were delivered to the perforant path for induc- tion of LTP. Population spike (PS) amplitude and the field excitatory post-synaptic potentials (fEPSP) slope were mea- sured as indices of increase in synaptic efficacy. Chronic morphine increased the mean basal EPSP, and augmented PS–LTP. Exercise significantly increased the mean baseline EPSP and PS responses, and augmented PS–LTP in both saline and morphine-treated groups. Moreover, the increase of PS–LTP in the morphine–exercise group was greater (22.5%), but not statistically significant, than that of the Sal/Exc group. These results may imply an additive effect between exercise and morphine on mechanisms of synaptic plasticity. Such an interaction between exercise and chronic morphine may influence cognitive functions in opiate addicts. Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: voluntary exercise, morphine exposure, long-term potentiation, hippocampus. INTRODUCTION Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity that proposed as a cellular substrate of learning and memory (Bliss and Collingridge, 1993). Previous studies, using in vivo and in vitro methods, have shown that chronic morphine can reduce LTP in rat hippocampal synapses (Pu et al., 2002; Salmanzadeh et al., 2003a; Bao et al., 2007). In contrast, other studies have shown that chronic morphine exposure augments in vivo LTP in Schaffer collateral–CA1 synapses (Mansouri et al., 1997, 1999), and in vivo LTP in the lateral perforant bath (PP)- granule cell synapses of the rat dentate gyrus (DG) (Ito et al., 2001; Lu et al., 2010b). The conflicts between these studies could be due to the fact that, different experimental protocols such as the pattern of stimulation, the time points of synaptic responses recording after the morphine injection, and the site of stimulation might be involved in the modulation of synaptic responses. For example, Pu et al. (2002) showed that chronic exposure of rats to morphine markedly reduced the capacity of hippocampal CA1 LTP during the period of drug withdrawal (9–12 h after the termination of chronic treatment), while Mansouri et al. (1997, 1999) demonstrated the augmented LTP in the Schalleral-CA1 synapses of the hippocampal slices taken from dependent, but not withdrawn rats. Many studies have assumed that abused drugs can hijack synaptic machinery that are dedicated to plastic changes in the excitability of principal hippocampus circuits (Robbins and Everitt, 1999; Wolf, 2002; Bao et al., 2007; Kauer and Malenka, 2007), and may induce maladaptive plasticity in this structure (Eisch et al., 2000). Such maladaptive plasticity in the hippocampus and other brain structures may underline learning and memory impairment induced by chronic morphine (Miladi-Gorji et al., 2008, 2011; Lu et al., 2010a). Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of relapse and other related disorders (Wolf, 2002; Lu et al., 2010a). 0306-4522/13 $36.00 Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuroscience.2013.09.056 * Corresponding author. Address: Laboratory of Learning and Mem- ory, Research Center and Department of Physiology, Semnan University of Medical Sciences, 15131-38111 Semnan, Iran. Tel: +98-09121140221. E-mail addresses: Rashidy-pour@sem-ums.ac.ir (A. Rashidy-Pour), fatolahi@modares.ac.ir (Y. Fathollahi).   Co-corresponding author. Address: Department of Physiology, School of Medical Sciences, Tarbiat Modares University, PO Box 14115-111, Tehran, Iran. Abbreviations: ANOVA, analysis of variance; AP, Anterior-Posterior; BDNF, brain-derived neurotrophic factor; D/Exc, dependent–exercise; DG, dentate gyrus; D/Sed, dependent–sedentary; DV, Dorssal-ventral; fEPSP, field excitatory post-synaptic potentials; I/O, input/output; LTP, long-term potentiation; ML, Medial-lateral; NMDA, N-methyl- D-aspartate; PBs, primed bursts; PP, perforant bath; PS, population spike; Sal/Exc, saline–exercise; Sal/Sed, saline–sedentary; TrkB, tyrosine kinase B. Neuroscience 256 (2014) 83–90 83