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...

Uncontrollable or inescapable shock (IS) produces behavioral changes that are characterized by a sensitized fear system and a deficit in fight-flight responding. These behavioral changes have been argued to represent an anxiety-like state produced by the uncontrollability of the stressor. The bed nucleus of the stria terminalis (BNST) has been implicated in the mediation of long-duration responses to unpredictable stressors, which have also been argued to represent anxiety. In the present study, the effects of BNST chemical lesion on the IS-induced sensitization of freezing to an environment previously paired with shock and the IS-induced impairment of escape responding were investigated. BNST chemical lesion blocked the potentiation of freezing and the increases in escape latency that normally follow IS.The bed nucleus of the stria terminalis (BNST) is adjacent to the anterior commissure in the basal forebrain and makes up the rostral part of the continuum known as the extended amygdala. The BNST has been strongly implicated in mediating the responses to stimuli that contain an affective salience, so that (a) BNST activation produces neuroendocrine (Dunn, 1987) and behavioral (Casada & Dafny, 1991) responses that resemble those produced by stress, and (b) BNST inactivation decreases the neuroendocrine and behavioral responses to stress (Gray et al., 1993), and blocks some forms of unconditioned fear (Davis, Walker, & Lee, 1997;Fendt, Endres, & Apfelbach, 2003; and the effects of centrally injected corticotropin-releasing hormone (CRH; . Furthermore, stressors increase BNST levels of stress-related neurotransmitters and neuropeptides, including CRH (Chappell et al., 1986;Makino et al., 1999;Stout, Mortas, Owens, Nemeroff, & Moreau, 2000) and norepinephrine (NE;Pacak, McCarty, Palkovits, Kopin, & Goldstein, 1995). In addition, the release of these substances within the BNST has been shown to mediate, in part, some of the behavioral consequences of stressor exposure (Cecchi, Khoshbouei, Javors, & Morilak, 2002;.Although the BNST mediates many responses to stressors, its function is not always critical (Gewirtz, McNish, & Davis, 1998;Hitchcock & Davis, 1991;LeDoux, Iwata, Cicchetti, & Reis, 1988;Treit, Aujla, & Menard, 1998). A consideration of the circumstances in which the BNST is, or is not, involved in the mediation of the consequences of stressor exposure has led Davis and colleagues to suggest that the BNST mediates long-duration responses to unpredictable threatening or aversive stimuli, while the anatomically related central nucleus of the amygdala (CeA) mediates short-term responses to stimuli that are predictable in nature Walker, Toufexis, & Davis, 2003). Davis and colleagues called these long-duration, BNST-mediated responses "anxiety," and the short-duration, CeA-mediated responses "fear."Exposure to uncontrollable or inescapable shock (IS) produces a constellation of behavioral changes that are not observed if the shock is controllable or escapable (ES). These behavioral responses have been called "le...