Low doses of corticotropin-releasing hormone injected into the dorsal raphe nucleus block the behavioral consequences of uncontrollable stress

Abstract

The behavioral consequences of uncontrollable stress that are collectively called learned helplessness (LH) are mediated in part by increased levels of serotonin (5-HT) activity in the dorsal raphe nucleus (DRN) and it’s projection regions. Recently, corticotropin-releasing hormone (CRH) within the DRN has been implicated in the development of LH because intra-DRN CRH produces LH at very high doses, and because intra-DRN antagonists for the CRH 2 receptor (CRHR2) block LH. Since these behavioral effects are mediated by both 5-HT excitation and CRHR2 activation, we have suggested that CRHR2 mediates excitation of DRN 5-HT neurons. However, CRH has been shown to inhibit DRN 5-HT neurons at low doses that are expected to bind to CRHR1. Since CRHR1 antagonists were ineffective in blocking LH, we have further suggested that CRHR1 might mediate the inhibition of DRN 5-HT neurons. In support of this hypothesis, although low doses of CRH that preferentially bind CRHR1 inhibit DRN 5-HT activity, higher doses at which CRH would be expected to bind both receptor subtypes no longer inhibit DRN 5-HT. In addition, high doses of CRH are required to produce LH, which is known to be mediated by 5-HT excitation, and the CRHR2 agonist urocortin II (UCN II) produces LH at much lower doses than does CRH. The present studies show that intra-DRN CRH microinjection blocks the behavioral effects produced by DRN UCN II, but only at doses that have been shown to inhibit DRN 5-HT activity. Indeed, a higher dose of CRH that has been shown to no longer inhibit DRN 5-HT activity did not affect the behavioral consequences of DRN UCN II. In a separate experiment, the effective dose of CRH blocked the usual behavioral consequences of uncontrollable stress.