Uncontrollable shock produces a constellation of behavioral changes that are not observed after equivalent escapable shock. These include interference with escape and potentiation of fear conditioning. The activation of corticotropin-releasing hormone (CRH) receptors within the caudal dorsal raphe nucleus (DRN) during inescapable tailshock (IS) has been shown to be critical for the development of these behavioral changes. CRH binds to two receptor subtypes, both of which are found in the DRN. The present set of studies examined which CRH receptor subtype mediates the effects of IS. Intra-DRN administration of the CRH(2) receptor antagonist anti-sauvagine-30 before IS dose-dependently blocked IS-induced behavioral changes; the CRH(1) receptor antagonist 2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine (NBI27914), administered in the same manner, did not. Moreover, the highly selective CRH(2) receptor agonist urocortin II (Ucn II) dose-dependently caused behavioral changes associated with IS in the absence of shock. Ucn II was effective at doses 100-fold lower than those previously required for CRH. The relationship between CRH(2) receptors and DRN 5-HT is discussed.

Inescapable shock (IS) produces subsequent interference with escape behavior and increased fear conditioning that has been linked to increased activity and release of serotonin (5-HT) from neurons within the caudal dorsal raphe nucleus (DRN) both at the time of IS and later behavioral testing. Extrahypothalamic corticotropin-releasing hormone (CRH) has been implicated in many stress-related phenomena and has recently been shown to increase DRN 5-HT activity in the same caudal DRN area at which IS increases 5-HT activity. The current set of studies therefore examined the role of CRH in mediating the behavioral sequelae of IS. Intra-DRN microinjection of the nonselective CRH receptor antagonist D-Phe CRH (12-41) blocked the ISinduced behavioral changes when administered before IS but not when administered before later behavioral testing. Furthermore, intra-DRN administration of CRH in the absence of IS dose-dependently mimicked the effects of IS and interfered with escape behavior and increased fear conditioning 24 hr later. This effect was specific to injection of CRH into the caudal DRN and was not produced by microinjection into the rostral DRN. Intracerebroventricular CRH produced escape deficits and potentiated fear conditioning 24 hr later at only much higher doses, further confirming the site specificity of the effects. The potential role of the caudal DRN in states of anxiety is discussed.Key words: corticotropin-releasing hormone; dorsal raphe nucleus; learned helplessness; serotonin; rats; shock Corticotropin-releasing hormone (CRH) plays a key role in integrating neural, endocrine, and behavioral responses to stressful stimuli (Dunn and Berridge, 1990;Owens and Nemeroff, 1993). Although endocrine consequences of stressors are mediated by CRH-secreting cells in the hypothalamus, behavioral and neurochemical sequelae of stressor exposure are regulated by extrahypothalamic CRH (Liang et al., 1992;Lee and Davis, 1997).Serotonin (5-HT) systems are also involved in mediating reactions to stressors, and CRH has been shown to interact with 5-HT systems (Kirby et al., 2000;Lowry et al., 2000). There are CRHimmunoreactive fibers associated with 5-HT neurons in the raphe nuclei (Cummings et al., 1983;Austin et al., 1997), as well as CRH receptor mRNA expression, immunoreactivity, and binding (Cummings et al., 1983;DeSouza, 1985;Chen et al., 2000). Although the effects of CRH on 5-HT neuronal firing have been reported to be primarily inhibitory in the rostral dorsal raphe nucleus (DRN; Kirby et al., 2000), Lowry et al. (2000) have recently identified a population of 5-HT neurons in the caudal DRN that are potently excited by CRH.Interestingly, the caudal region of the DRN has been implicated in the behavioral consequences of exposure to uncontrollable stressors that have been called "behavioral depression" (Weiss et al., 1981) or "learned helplessness" (Maier and Seligman, 1976). These terms refer to the general finding that stressors over which an organism has no behavioral control produce changes that do not occu...

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The controllability of stressors modulates many of the consequences of stressor exposure. Here, we used immunohistochemistry to examine neural progenitor cell proliferation and survival and basic fibroblast growth factor-2 in the hippocampus of male rats after controllable or uncontrollable tailshock. A series of identical tailshocks were delivered to yoked pairs of rats. One rat could terminate shocks to both rats of the pair. Reductions in neural progenitor cells were observed at 1-2 days and at 28 days in rats exposed to uncontrollable shock. Controllable shock produced an increase in fibroblast growth factor-2 in the dentate gyrus and CA1 2 h after stress and in the dentate gyrus 24 h after stress. Thus, stressor controllability modulates stress-induced decreases in neurogenesis and increases in fibroblast growth factor-2.

The results indicate that the CORT response to morphine is enhanced in rats that were previously exposed to an uncontrollable stressor, and that this response to the drug, not the stressor, is necessary for the stress-enhanced potentiation of morphine CPP.