Please cite this article in press as: Holmes PV, et al. Chronic exercise dampens hippocampal glutamate overflow induced by kainic acid in rats. Behav Brain Res (2015), http://dx.doi.org/10.1016/j.bbr.2015.02.002 ARTICLE IN PRESS G Model BBR 9402 1–5 Behavioural Brain Research xxx (2015) xxx–xxx Contents lists available at ScienceDirect Behavioural Brain Research jou rn al hom epage: www.elsevier.com/locate/bbr Short communication Chronic exercise dampens hippocampal glutamate overflow induced by kainic acid in rats Philip V. Holmes a,∗ , Jenny I. Reiss a , Patrick S. Murray a , Rod K. Dishman b , Q1 Jessica M. Spradley a a Neuroscience Program, Biomedical and Health Sciences Institute, The University of Georgia, Athens, GA, United States b Department of Kinesiology, The University of Georgia, Athens, GA, United States h i g h l i g h t s • The effects of exercise on seizure-related phenomena in rats were studied. • Glutamate overflow, EEG activity, and behavior were measured after systemic treatment with kainic acid. • Exercise diminished hippocampal glutamate release and seizure-related behaviors. a r t i c l e i n f o Article history: Received 3 October 2014 Received in revised form 14 January 2015 Accepted 2 February 2015 Available online xxx a b s t r a c t Our laboratory has previously reported that chronic, voluntary exercise diminishes seizure-related behav- iors induced by convulsant doses of kainic acid. The present experiments tested the hypothesis that exercise exerts this protective effect through a mechanism involving suppression of glutamate release in the hippocampal formation. Following three weeks of voluntary wheel running or sedentary condi- tions, rats were injected with 10 mg/kg of kainic acid, and hippocampal glutamate was measured in real time using a telemetric, in vivo voltammetry system. A separate experiment measured electroencephalo- graphic (EEG) activity following kainic acid treatment. Results of the voltammetry experiment revealed that the rise in hippocampal glutamate induced by kainic acid is attenuated in exercising rats compared to sedentary controls, indicating that the exercise-induced protection against seizures involves regula- tion of hippocampal glutamate release. The findings reveal the potential benefit of regular exercise in the treatment and prevention of seizure disorders and suggest a possible neurobiological mechanism underlying this effect. © 2015 Published by Elsevier B.V. Q2 Clinical studies in humans as well as basic research in animal models have reliably shown that regular exercise benefits the brain, and changes in hippocampal functions may be particularly rel- evant to its antidepressant, anti-stress, and cognition-enhancing effects [1]. For example, synaptic plasticity in hippocampal neu- rons has been linked to the enhancement in learning and memory caused by exercise [2,3]. This plasticity is mediated in part by exercise-induced increases in the expression of trophic factors such as brain-derived neurotrophic factor (BDNF), nerve growth fac- tor (NGF), and neurotrophin-3 (NT-3), with consequent effects on learning and physiological correlates thereof, such as long term potentiation (LTP) [4–6]. ∗ Corresponding author. Tel.: +1 706 542 3105; fax: +1 706 542 3275. E-mail address: pvholmes@uga.edu (P.V. Holmes). Though the enhanced synaptic plasticity caused by the actions of trophic factors in the hippocampal formation may be benefi- cial for cognitive functions, excess activity in this highly excitable circuitry may render the organism more susceptible to seizures. Indeed, a variety of trophic factor manipulations, such as trans- genic over-expression [7] and intracranial administration of BDNF [8] render the hippocampus more vulnerable to hyperexcitabi- lity and excitotoxicity [9,10]. Consistent with these findings, rats that have experienced a regimen of chronic, voluntary exercise, which reliably elevates hippocampal BDNF gene expression, exhibit increased susceptibility to the excitotoxic effects of kainic acid in hippocampal CA3–CA4 neurons following direct administra- tion into this site in anesthetized subjects [11]. Paradoxically, our laboratory has reported the opposite pattern in awake, freely behaving rats; with reductions in kainic acid-induced seizures evi- dent in chronically exercising rats compared to sedentary controls [12]. http://dx.doi.org/10.1016/j.bbr.2015.02.002 0166-4328/© 2015 Published by Elsevier B.V. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51