Metyrapone and fluoxetine suppress enduring behavioral but not cardiac effects of subchronic stress in rats

Carnevali L, Bondarenko E, Sgoifo A, Walker FR, Head GA, Lukoshkova EV, Day TA, Nalivaiko E. Metyrapone and fluoxetine suppress enduring behavioral but not cardiac effects of subchronic stress in rats. Am J Physiol Regul Integr Comp Physiol 301: R1123-R1131, 2011. First published July 27, 2011; doi: 10.1152/ajpregu.00273.2011.-In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Delta= -23 +/- 3 beats per minute (bpm)] and light/inactive (Delta= -20 +/- 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Delta= -54 +/- 6 counts per hour (cph)]. The brady-cardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methylscopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Delta= -16 +/- 3 bpm, inactive phase Delta= -19 +/- 2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin-and corticosterone-independent.