ACTIVATION OF NORADRENERGIC LOCUS-CERULEUS NEURONS BY HEMODYNAMIC STRESS IS DUE TO LOCAL RELEASE OF CORTICOTROPIN-RELEASING FACTOR

The present study was designed to determine whether activation of locus coeruleus (LC) neurons by hemodynamic stress is mediated by local release of corticotropin-releasing factor (CRF) within the LC. The ability of local LC injection of the CRF antagonist, alpha helical CRF9-41, to prevent LC activation elicited by i.v. nitroprusside infusion was investigated in halothane-anesthetized rats. Nitroprusside infusion (10-mu-g/30-mu-l/min for 15 min) consistently increased LC spontaneous discharge rate with the mean maximum increase of 32 +/- 5% (n = 8) occurring between 3 and 9 min after the initiation of the infusion. Prior local LC injection of alpha helical CRF9-41 (150 ng), but not of saline (150 nl), prevented LC activation by nitroprusside. Alpha helical CRF9-41 did not alter LC spontaneous discharge rate or LC discharge evoked by repeated sciatic nerve stimulation suggesting that the CRF antagonist selectively attenuates stress-elicited LC activation. In contrast to alpha helical CRF9-41, the excitatory amino acid antagonist, kynurenic acid, did not attenuate LC activation by nitroprusside at a dose (0.5-mu-mol in 5-mu-l, i.c.v.) that prevented LC activation by sciatic nerve stimulation. Taken together, these findings suggest that hemodynamic stress elicited by nitroprusside infusion activates LC neurons by releasing CRF within the LC region. The onset of LC activation by nitroprusside was temporally correlated with electroencephalographic (EEG) activation recorded from the frontal cortex and hippocampus. EEG activation was characterized by a change from low frequency, high amplitude activity to high frequency low amplitude activity recorded from the cortex and theta rhythm recorded from the hippocampus. LC activation usually outlasted the EEG activation. Nitroprusside infusion following local LC injection of alpha helical CRF9-41 was also associated with EEG activation in most rats. However, the duration of hippocampal theta rhythm was shorter in rats administered alpha helical CRF9-41. Thus, LC activation during cardiovascular challenge may play some role in EEG activation but is not necessary for this effect.