Neuropsychiatry Disorders

Affective Disorders - Many patients with major depression are hypercortisolemic and exhibit an abnormal dexamethasone suppression test (23,24). Given the primary role of CRF in stimulating pituitary-adrenocortical secretion, the hypothesis has been put forth that hypersecretion/hyperactivity of CRF in brain might underlie the hypercortisolemia and symptomatology seen in major depression. The concentration of CRF is significantly increased in the cerebrospinal fluid (CSF) of drug-free depressed individuals (25-27), and a significant positive correlation is observed between CRF concentrations in the CSF and the degree of post-dexamethasone suppression of plasma Cortisol (28). Furthermore, the observation of a decrease in CRF binding sites in the frontal cerebral cortex of suicide victims compared to controls is consistent with the hypothesis that CRF is hypersecreted in major depression (29). The increased CSF concentrations of CRF seen in depressed individuals are decreased following treatment with electroconvulsive therapy (30). In addition, a blunted ACTH response to intravenously administered ovine or human CRF is observed in depressed patients when compared to normal controls (31-33). The blunted ACTH response to exogenous CRF seen in depressed patients may be due to the intact negative feedback of Cortisol on the corticotrophs, due to a compensatory decrease in CRF receptors subsequent to chronic hypersecretion of the peptide and/or desensitization of the pituitary corticotrophs to respond to CRF.

Preclinical studies provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression. In the rat, intracerebroventricular administration of low doses of CRF produces several behavioral effects including changes in activity (increased locomotion, sniffing, grooming and rearing in a familiar surrounding), increased "emotionality" and assumption of a freeze posture in a foreign environment, decreased feeding and sexual behavior and increased conflict behavior (14-16,22). CRF administered intrathecal^ in unrestrained monkeys induces a hunched-over posture similar to that observed in primates undergoing separation reactions and their associated "behavioral despair" phase (15,34). The CRF induced behavioral effects in rodents and nonhuman primates described above bear a striking resemblance to the symptoms of human depression and suggest that CRF hypersecretion may be responsible for some of the symptomatology seen in the disorder.

In view of the preclinical and clinical data suggesting a role for CRF in depression, the hypothesis has been put forth that antidepressants may produce their "therapeutic" effects, in part, by decreasing CRF secretion. An increase in CRF binding sites (presumably to compensate for chronic suppression of CRF secretion) is observed In some brain regions such as the brain stem in rats treated chronically with tricyclic antidepressants such as imipramine (35). Although the relevance of the up-regulation in CRF receptors in the brain stem following antidepressant treatment is presently unknown, an important role for this peptide has been postulated in the locus ceruleus of the brain stem. The locus ceruleus receives a rich CRF innervation (6), contains a moderate density of CRF receptors (17), and is markedly activated following iontophoretic or intracerebroventricular administration of CRF (11,21). Furthermore, the concentrations of CRF are selectively increased in the locus ceruleus following application of acute or chronic stress (36). A link between CRF and the locus ceruleus in major depression is further suggested by clinical data that CSF levels of CRF correlate positively with indices of locus ceruleus-noradrenergic activation, such as CSF concentrations of norepinephrine and its metabolite MHPG (37). Given the major involvement of the brain noradrenergic system, in particular in the locus ceruleus in depression (38-

40), and the effects of CRF to activate noradrenergic neurons in this brain region (11,21), it is tempting to speculate that antidepressants may function by suppressing CRF secretion in the locus cemleus, resulting in the observed increase in brain stem CRF binding sites.

Anxiety-Related Disorders - A number of studies suggest that anxiety-related disorders (such as panic disorder and generalized anxiety disorder) and depression are independent syndromes which share both clinical and biological characteristics. The role that has been proposed for CRF in major depressive disorders along with preclinical data in rats demonstrating effects of CRF administration to produce several behavioral changes characteristic of anxiogenic compounds (14) have led to the suggestion that CRF may also be involved in anxiety-related disorders. A role for CRF in panic disorder has been suggested by observations of blunted ACTH responses to intravenously administered CRF in panic disorder patients when compared to control subjects (41). The blunted ACTH response to CRF in panic disorder patients most likely reflects a process occurring at or above the hypothalamus, resulting in excess secretion of endogenous CRF (41).

Preclinical studies demonstrating interactions between benzodiazepine anxiolytics and CRF provide further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test (42,43) and in the acoustic startle test (44) in rats. The effects of chlordiazepoxide on these behavioral effects of CRF suggest that these substances may interact in brain. More recent data using the operant conflict test in rats have demonstrated that the benzodiazepine receptor antagonist (Ro15-1788) which was without behavioral activity when given alone, reversed the effects of CRF in a dose-dependent manner whereas the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF (43). Preliminary studies examining the effects of a CRF receptor antagonist (a-helical ovine CRFg^ji) in a variety of behavioral paradigms suggest that the CRF antagonist produces "anxiolytic-like" effects, qualitatively similar to benzodiazepines (14).

Neurochemical, endocrine and receptor binding data also demonstrate interactions between CRF and benzodiazepines. Acute administration of the triazolobenzodiazepines, alprazolam and adinazolam results in increased hypothalamic concentrations of CRF while decreasing the concentrations of CRF in other brain regions, including locus ceruleus, amygdala, pyriform cortex and clngulate cortex (45). Of particular interest is the finding that the two triazolobenzodiazepines exert effects on CRF concentrations in the locus ceruleus and hypothalamus that are opposite to CRF changes seen after stress (45). Chronic administration of diazepam, alprazolam, or adinazolam in rats results in significant decreases in CRF receptors in the frontal cerebral cortex and hippocampus and there is a trend for CRF receptors to be decreased in other brain areas and increased in the anterior pituitary (35). The latter data demonstrating increases in CRF receptor concentrations support the hypothesis for effects of the benzodiazepines to inhibit CRF release which in turn modulate the receptors. Further support for this hypothesis is provided by potent in vitro effects of benzodiazepines (46) and especially the triazolobenzodiazepines (47) to inhibit hypothalamic CRF release. Conversely, the reduced concentrations of CRF in the other brain regions described above following in vivo administration of the benzodiazepines (45) may relate to increased release of CRF, which would be expected to decrease receptors in regions like the frontal cortex and hippocampus (35). Although the mechanisms and sites of action through which the benzodiazepines produce their therapeutic effects in the treatment of panic/anxiety disorders remains to be elucidated, it seems reasonable to speculate that their actions may involve suppression of CRF hypersecretion that may occur in these disorders.

Feeding Disorders - Anorexia nervosa is an eating disorder characterized by tremendous weight loss in the pursuit of thinness. There is similar pathophysiology in anorexia nervosa and in depression including the manifestation of hypercortisolism, hypothalamic hypogonadism and anorexia (48,49). Furthermore, the incidence of depression in anorexia nervosa patients is high (50). Like depressed patients, anorexics show a markedly attenuated ACTH response to intravenously administered CRF (48,49) and significantly higher basal CSF levels of CRF than controls (49). When the underweight anorexic subjects are studied after their body weight had been restored to normal, their basal hypercortisolism, increased levels of CRF in the CSF, and diminished ACTH responses to exogenous CRF all return to normal at varying periods during the recovery phase (48,49). CRF can potently inhibit food consumption in rats which further suggests that the hypersecretion of CRF may be responsible for the weight loss observed in anorexics (16). In addition, the observation that central administration of CRF diminishes a variety of reproductive functions (22,51) lends relevance to the clinical observations of hypogonadism in anorexics.

Obesity is associated with hyperphagia, decreased sympathetic and increased parasympathetic activities (effects that are opposite to those seen following central administration of CRF) (52). Furthermore, the development of obesity in a variety of rodent models is prevented by adrenalectomy (an experimental manipulation associated with increased synthesis and release of hypothalamic CRF) (52). These observations have led to the hypothesis that CRF may be involved in the development of obesity syndromes. Central administration of CRF at a dose that was without affect in lean rats stopped the excessive weight gain of obese animals (53). These effects of CRF appeared unrelated to changes in food intake, since both CRF- and saline-injected rats were pair-fed (53). Rather, they appeared to be due to stimulation of the sympathetic nervous system resulting in increased thermogenesis (53-55) and inhibition of the parasympathetic nervous system (53). In addition, recent data suggest that antiobesity drugs such as fenfluramine are potent stimulators of hypothalamic CRF release (56) which is consistent with the hypothesis that these drugs may produce their weight-reducing effects through increased CRF release. The relevance of these preclinical studies to the involvement of CRF in the development of obesity in humans remains to be demonstrated.

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