Activity-wheel running blunts suppression of splenic natural killer cell cytotoxicity after sympathectomy and footshock R.K. Dishman a, *, S. Hong a , J. Soares a,1 , G.L. Edwards b , B.N. Bunnell c , L. Jaso-Friedmann d , D.L. Evans d a Department of Exercise Science, The University of Georgia, Athens, GA 30602-6554, USA b Department of Physiology, The University of Georgia, Athens, GA, USA c Department of Psychology, The University of Georgia, Athens, GA, USA d Department of Medical Microbiology, The University of Georgia, Athens, GA, USA Received 25 January 2000; received in revised form 1 May 2000; accepted 21 June 2000 Abstract We used chemical sympathectomy by 6-hydroxydopamine (6-OHDA) to examine whether adaptation by the sympathetic nervous system (SNS) is a plausible explanation for our prior finding that activity-wheel running blunts the suppression of splenic natural killer cell cytotoxicity after footshock. Male Fischer rats were assigned to treatments using a group (activity wheel vs. sedentary)  treatment (6-OHDA vs. saline)  condition (footshock vs. no shock) design. After 5 ± 6 weeks, rats were injected i.p. with saline or with 40, 80, and 80 mg/kg 6- OHDA on pre experimental days  5,  3, and  1. Half the rats received 6 min of random footshock during a 40-min period. Cytotoxicity was determined by standard 4-h 51 Cr release assay. Sympathectomy reduced splenic [NE] by 72%. After 6-OHDA injection and footshock, percent lysis was 33% lower in sedentary rats compared with activity-wheel runners and home-cage controls, p = 0.048. The results suggest that activity-wheel running leads to adaptations that offset an altered SNS modulation of splenic NK cell cytotoxicity in response to footshock. D 2000 Elsevier Science Inc. All rights reserved. Keywords: Exercise; Immune system; Norepinephrine; Nervous system, autonomic; 6-Hydroxydopamine Acute, intermittent electric shock reliably leads to a 25± 75% suppression of splenic natural killer (NK) cell cytolysis in vitro in rats that persists for 24 to 96 h [9,50,51,57]. We reported that 6 weeks of circadian activity-wheel running blunted the suppression of NK cell cytolysis after footshock with no effects on basal NK cell activity, percentages of splenic cytotoxic lymphocytes, or putative plasma levels of ACTH, corticosterone, and prolactin measured after foot- shock [11]. Mechanisms explaining the effects of exercise on NK cell activity after stress in rat are not known, but several studies suggest a role for the peripheral sympathetic nervous system (SNS). Postganglionic SNS neurons innervate the spleen, and norepinephrine (NE) nerve terminals are directly posi- tioned with lymphocytes in the periarteriolar lymphatic sheath in the spleen of rat [15]. In sedentary rats intrace- rebroventricular, but not systemic, injection of the brain noradrenergic stimulant, corticotropin-releasing factor (CRF), resulted in a dose-dependent suppression of sple- nic NK cell activity [21] and increase in plasma NE that was reversible by sympathetic ganglionic blockade [22]. Similarly, chemical sympathectomy by the neurotoxin 6- hydroxydopamine (6-OHDA) abolished, and nonselective b-adrenoreceptor blockade blunted, the CRF-induced sup- pression of splenic NK cell activity [23], despite increased plasma levels of ACTH and corticosterone. Electrical stimulation of the splanchic nerve suppresses splenic NK cytotoxicity [29]. Also, splenic NK cell suppression after laparotomy under anesthesia was blunted by splenic denervation and restored by electrical stimulation of the cut nerve [28]. The suppression during electric stimulation was blocked by nonselective b-adrenoreceptor blockade. Results of other physiological studies in rat have been mixed. Preganglionic sympathectomy by IgG2b antibody * Corresponding author. Tel.: +1-706-542-9840; fax: +1-706-542- 3148. E-mail address: rdishman@coe.uga.edu (R.K. Dishman). 1 Current address: Department of Neurology, Emory University School of Medicine, Atlanta, GA. 0031-9384/00/$ ± see front matter D 2000 Elsevier Science Inc. All rights reserved. PII:S0031-9384(00)00329-2 Physiology & Behavior 71 (2000) 297 ± 304