Intracerebroventricular infusion of CRF increases extracellular concentrations of norepinephrine in the hippocampus and cortex as determined by in vivo voltammetry

Previous studies have indicated that intracerebroventricular (i.c.v.) infus ions of corticotropin-releasing factor (CRF) activate locus coeruleus (LC) noradrenergic neurons and increase the metabolism and extracellular concent rations of norepinephrine (NE) in several brain regions, suggesting increas ed release. To examine the temporal aspects and mechanism of the presumed r elease of NE, CRF was infused i.c.v. and the oxidation current was recorded using carbon fiber voltammetric electrodes placed in rat hippocampus or co rtex. The CRF (1 mu g, i.c.v.) caused a significant increase of oxidation c urrent with a delay of approximately 5 min, and a peak at approximately 35 min. Similar responses were observed in the medial prefrontal cortex, The h ippocampal response was markedly attenuated when CRF was infused into rats pretreated with DSP-4 to deplete NE, suggesting that the observed changes i n current resulted from oxidation of NE, The increase of NE-like current di d not occur when 25 mu g alpha-helical CRF9-41 (ah-CRF) was injected immedi ately before 1 pg CRF, suggesting that the response was mediated by cerebra l CRF-receptors. Subcutaneous pretreatment with the ganglionic blocker, chl orison-damine, at a dose of 3 mg/kg had no effect on the voltammetric respo nse to CRF, but a 6 mg/kg dose completely prevented the response, The P-adr enoceptor antagonists, S-propranolol (5 mg/kg), nadolol (5 and 10 mg/kg), a nd timolol (5 mg/kg) attenuated the NE response to i.c.v. CRF to varying de grees. When chlorisondamine (3 mu g) or nadolol (5 mu g) were given i.c.v. before the CRF, the hippocampal responses were not blocked, These results s uggest peripheral actions of ganglionic and p-adrenergic blockers. We concl ude that peripheral autonomic mechanisms, and probably both central and per ipheral P-adrenoceptors, contribute to the increased secretion of hippocamp al NE in response to i.c.v. CRF. (C) 1998 Elsevier Science Inc.