Available online at www.sciencedirect.com Behavioural Brain Research 187 (2008) 185–189 Research report Long-term compulsive exercise reduces the rewarding efficacy of 3,4-methylenedioxymethamphetamine Hsiun Ing Chen a,b , Yu Min Kuo b,c , Chung-Hsien Liao b , Chauying J. Jen a,b , A Min Huang a,b , Chianfang G. Cherng d , Shu-Wen Su e , Lung Yu a,b,e,∗ a Department of Physiology, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, ROC b Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, ROC c Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, ROC d Department of Clinical Psychology, Chang Jung Christian University, Tainan 711, Taiwan, ROC e Institute of Behavioral Medicine, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, ROC Received 11 July 2007; received in revised form 30 August 2007; accepted 7 September 2007 Available online 16 September 2007 Abstract Although exercise has been known to regulate brain plasticity, its impact on psychostimulant reward and the associated mesolimbic dopamine system remained scarcely explored. A psychostimulant, 3,4-methylenedioxymethamphetamine (MDMA), is currently a worldwide abused drug of choice. We decided to examine the modulating effects of long-term, compulsive treadmill exercise on the hedonic value of MDMA in male C57BL/6J mice. MDMA-induced conditioned place preference (CPP) was used as a behavioral paradigm to indicate the reward efficacy of MDMA. We observed that sedentary control mice all demonstrated reliable MDMA-induced CPP with our conditioning protocol. Interestingly, pre-exposure to a treadmill exercise decreased the later MDMA-induced CPP in a running period-dependent manner. Specifically, mice undergoing a 12-week treadmill running exercise did not exhibit any approaching bias toward the MDMA-associated compartment in this CPP paradigm. Twelve weeks of treadmill running did not alter peripheral metabolism of MDMA 30 min following single intraperitoneal injection of MDMA (3 mg/kg). We further used microdialysis technique to study the underlying mechanisms for the impaired MDMA reward produced by the12-week exercise pre-exposure. We found that acute MDMA-stimulated dopamine release in nucleus accumbens was abolished in the exercised mice, whereas an obvious elevation of accumbal dopamine release was observed in sedentary control mice. Finally, the 12-week exercise program did not alter the protein levels of primary dopamine receptors, vesicular or membrane transporters in this area. We conclude that the long-term, compulsive exercise is effective in curbing the reward efficacy of MDMA possibly via its direct effect on reversing the MDMA-stimulated dopamine release in nucleus accumbens. © 2007 Elsevier B.V. All rights reserved. Keywords: Ecstasy; Treadmill exercise; Pavlovian conditioning; Reinforcement; Mouse 1. Introduction Exercise has been shown to promote brain plasticity and functional improvement in normal and compromised conditions [5,23]. Such effects could arise from the impact of exercise on various central neuronal circuits, including both motor and motor-independent systems. Lately, studies have addressed the modulating effects of exercise on central catecholamine syn- ∗ Corresponding author at: Behavioral Neuropharmacology Laboratory, Insti- tute of Behavioral Medicine, National Cheng Kung University College of Medicine, 1 University Road, Tainan 701, Taiwan, ROC. Tel.: +886 6 2353535x5106/5114; fax: +886 6 2095616. E-mail address: lungyu@mail.ncku.edu.tw (L. Yu). thesis [25,26]. Moreover, cumulative evidence indicated that neurotoxin-induced lesions in the dopaminergic motor system were mitigated by physical exercise [7,8,16,20,24]. Given the well-studied modulating effects of exercise on dopaminergic motor system, it was reasonable to suspect that the other central dopaminergic systems, such as dopaminergic motivation system, might also be sensitive to exercise interven- tion. In this regard, mesolimbic dopaminergic system appears to be involved in reward-related motivation [13]. Direct or indirect activation of this dopaminergic system and consequent elevation in terminal dopamine release within the nucleus accumbens have been associated with the hedonic/reward effects of most abused drugs [11]. Thus, this study was undertaken to examine the effects of long-term exercise on the reward efficacy of 0166-4328/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2007.09.014