To reiterate a point made earlier, it is not simply exposure to aversive events that ultimately propagates stress in an individual, but also the anticipation of aversive events. The anticipation of aversive events may include learned associations that are formed across the life span as well as species-specific innate responses to biologically hard-wired threats. For instance, learned associations between fearful stimuli and the context where those stimuli are encountered are readily formed. Certain other fears appear to be unlearned such as the fear of open spaces in rodent species. Regardless of whether these fears are learned or innate, exposure to stimuli that elicit such fear will ultimately lead to activation of stress responsive systems. Common experimental paradigms used to examine the neural substrates of learned and innate fears (i.e., the anticipation of aversive events) include contextual and cue-elicited fear conditioning in the rat and exposure to predator cues such as fox feces and feline odors. The interesting point to be made here is that the anticipation of aversive events leads to mobilization of stress responsive systems. However, when sustained anticipation occurs over a prolonged period of time, the resources necessary for effective coping with such stressors eventually become depleted, and deleterious health consequences are likely to ensue. Indeed, the ultimate cost to the individual of prolonged negative anticipation has been conceptualized as "allostatic load" (McEwen, 2000; Schulkin et al., 1994). Thus, it is advantageous to look toward animal models of fear and anxiety for an understanding of the neuroanatomical and neurochemical basis of learned fears (see Chapter 16), which should in turn help elucidate how chronic anticipation of aversive events may predispose individuals toward psychiatric illness. Indeed, one of the most provocative advances in stress research over the past decade has been the demonstration that CRH in brain regions other than the paraventricular nucleus of hypothalamus that controls pituitary ACTH secretion (referred to as extrahypothalamic CRH systems) may play a critical role in stress-related disorders. Thus, we will now turn our discussion toward specific evidence supporting the important role for extrahypothalamic CRH.
Corticotropin-releasing hormone is a 41-amino-acid peptide initially identified as a hypothalamic factor responsible for stimulating ACTH from the anterior pituitary (Vale et al., 1981). As discussed in the previous section, stressors induce the synthesis and release of CRH from cells of the paraventricular nucleus into the portal blood, initiating the HPA response to stressors. CRH is also involved in mediation of the normal autonomic and behavioral consequences of exposure to stressors. For instance, the intracerebroventricular (icv) administration of CRH produces autonomic activation and many of the same behavioral (Koob and Britton, 1990), neurochemical (Dunn and Berridge, 1990), and electrophysiological (Valentino et al., 1983) alterations that are produced by stressors. Furthermore, the icv administration of CRH antagonists such as a-helical CRH9-41 and D-Phe CRH12-41 can blunt or block these stress-induced alterations in behavior and autonomic activity (e.g., Korte et al., 1994). Many of these effects can be obtained by infusing CRH or its antagonists into nonhypothalamic sites such as the locus coeruleus and amygdala (Butler et al., 1990), and persist in hypophy-sectomized and dexamethasone-treated subjects (Britton et al., 1986).
These facts together with the wide extrahypothalamic distribution of high-affinity CRH receptors and CRH-like immunoreactivity suggest that CRH functions as a neuro-transmitter as well as a hormone, and that it mediates stress-related behavioral responses by action at extrahypothalamic sites (Dunn and Berridge, 1990; Koob, 1990). Given the widespread involvement of extrahypothalamic CRH in mediating the consequences of stressor exposure, these systems have been proposed as key mediators of anticipatory stress. Thus, a review of the relationship between extrahypothalamic CRH systems and learned fear as a model of anticipatory stress will provide further evidence to this end.
Brain CRH systems have been shown to be important in mediating the fear responses observed in fear conditioning experiments. Rats and other organisms freeze when placed in an environment in which they have previously received an aversive stimulus such as foot shock, and freezing has been shown to be a measure of fear conditioned to the environment by the aversive stimulus (Fanselow and Lester, 1988). The term fear conditioning refers to the fact that both discrete and contextual cues that are present during exposure to a stressor such as foot shock can elicit behavioral and physiological responses such as freezing, inhibited appetitive behavior, potentiated startle, increased autonomic and HPA activity, and the like (Davis, 1992). It is to be noted that freezing is not simply an absence of movement, but rather an active defensive response consisting of no movement beyond that required for respiration including the absence of vibrissae movement, typically accompanied by a hunched posture and muscular rigidity. Importantly, icv a-helical CRH reduces the freezing that occurred when rats were exposed to the environment in which they had received foot shock, and it also reduces the potentiation of startle produced by a light that had previously been paired with shock (Swerdlow et al., 1989). These data suggest that extrahypothalamic CRH is important for the normal expression of fear-related behavior.
The amygdala plays a key integrative role in both the induction of fear conditioning and the expression of fear-related behavior. Lesions in basolateral regions of the amygdala (Campeau and Davis, 1995) or microinjection of N-methyl-D-aspartate (NMDA) antagonists (Fanselow and Kim, 1994) in this region prevent the induction of fear conditioning. In contrast, infusions of NMDA antagonists into the central nucleus of the amygdala do not retard fear conditioning (Fanselow and Kim, 1994), even though electrolytic lesions of that structure are effective (Campeau and Davis, 1995). NMDA antagonists, injected either into the amygdala (Miserendino et al., 1990) or icv (Kim et al., 1992) have no effect on the expression of fear that has been previously conditioned. This pattern of data has led to the view that the association between the sensory cues that precede the stressor and the stressor itself are formed in basolateral regions of the amygdala and critically involves NMDA receptors. The information then flows to the central nucleus of the amygdala, which functions in the behavioral expressions of fear via a final common path that integrates the bodily manifestations of fear (Davis, 1992), and it is likely that unconditioned psychological (affective) fear responses are also so induced (Chapter 16). In sum, NMDA receptors that mediate learning of fear do not appear to be essential in the central nucleus expression mechanisms.
The amygdala contains CRH immunoreactive cells and fibers (Swanson et al., 1983), and both the type 1 and type 2 CRH receptor are widely distributed in both the basolateral region and central nucleus (Chalmers et al., 1995). Exposure to a stressor has been reported to increase CRH messenger ribonucleic acid (mRNA) in the amygdala (Kalin et al., 1994), and microinjection of a-helical CRH into the central nucleus decreases the expression of conditioned fear (Swiergiel et al., 1993) as well as other stressor-induced behavioral changes (Heinrichs et al., 1992). Thus previous research has implicated NMDA-related processes in the basolateral amygdala in the induction but not expression of fear conditioning, and CRH in the central nucleus in the expression of fear. The potential role of CRH in the induction of fear conditioning has only recently been explored, and the results suggest that CRH is important in both induction and expression of conditioned fear (Deak et al., 1999). Clearly, it would be of interest to determine whether the critical site of CRH action in the induction of fear is the basolateral amygdala.
Implications for Biological Psychiatry. The evidence described above clearly points to CRH transmission within discrete regions of the amygdala in the unconditional generation and learned maintenance of fear-related behavior. At the human level, extrahypothalamic CRH has been implicated in a number of human disorders such as major depression (Gold et al., 1996; Nemeroff, 1996), PTSD (Grillon et al., 1996), and bulimia (Krahn and Gosnell, 1989). As a result, the development of novel therapeutic agents that target specific CRH receptor subtypes has become a major thrust in recent years. However, one major problem associated with the use of anti-CRH drugs to treat human clinical populations has been that most of these agents do not pass through the blood-brain barrier efficiently and thus cannot bind to CRH receptors in the necessary neural substrates to effect therapeutic change. As a result, there has been a push in the past decade toward the development of nonpeptide CRH antagonists that cross the blood-brain barrier and can be used in treating human clinical populations. Several of these drugs are currently in clinical trials and have enjoyed moderate success in treating human clinical populations (Zobel et al., 2000).
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