Intracerebroventricular corticotropin-releasing factor increases limbic glucose metabolism and has social context-dependent behavioral effects in nonhuman primates

Abstract

Corticotropin-releasing factor (CRF) is a neuropeptide involved in integrating the behavioral, autonomic, and hormonal responses to stress within the central nervous system. Patients suffering from depression have abnormal activity in stress responsive brain regions and elevated cerebrospinal fluid CRF. The DSM-IV criteria for major depressive disorder include behavioral changes such as depressed mood, anhedonia, and psychomotor agitation͞retarda-tion. We studied the effects of 434 g of CRF given intracerebroventricularly over 40 min in group and individually housed monkeys to examine the role of elevated levels of central CRF on behavior. CRF elicited a wide range of behaviors, which fell into three broad categories: anxiety-like, depressive-like, and externally oriented. Externally oriented behaviors decreased, and anxiety-like behaviors increased regardless of how the animals were housed. Interestingly, increased depressive-like behaviors were only observed when the animals were socially housed. In a separate experiment, we examined the effects of the same dose of CRF on the regional cerebral glucose metabolism of lightly anesthetized monkeys by using positron emission tomography and [ 18 F]fluorodeoxyglucose. CRF infusion increased glucose metabolism in the pituitary͞infundibulum, the amygdala, and hippocampus. These results indicate that increased central CRF tone affects primate behavior in a context-dependent manner, and that it activates limbic and stress-responsive regions. The fact that intracerebroventricular CRF increases depressive-like behavior in socially housed animals and increases activity in limbic brain regions may help explain the behavioral and metabolic alterations in humans with affective disorders, and this model could therefore have significant value in the development of novel antidepressant treatments. C orticotropin releasing factor (CRF) is a 41-aa peptide (1) that plays an important role in the mammalian stress response by integrating the behavioral, autonomic, and hormonal responses. CRF and its receptors are widely distributed throughout the brain, but are especially dense in the hypothalamus, where CRF plays a neuroendocrine role, and in extrahypothalamic regions such as the amygdala, the cerebral cortex, and brainstem autonomic nuclei (2, 3), regions implicated in mood and anxiety disorders.In rodents, intracerebroventricular (ICV) CRF causes physiological and behavioral changes similar to those observed in humans undergoing stress (4, 5). However, the behavior elicited by CRF in rodents is different depending on the context and the dose given. For example, Sutton et al. (5) showed that CRF has ''activating'' effects in familiar environments, but is anxiogenic in novel environments. In monkeys, ICV CRF also elicits distinct behavioral changes if the animals are tested when restrained compared with when freely moving (6).For these reasons, attention has focused on the role of CRF in psychiatric disorders related to increased stress or anxiety. Increased cerebrospinal fluid (CSF...

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Dose-dependent effects of the CRF1 receptor antagonist R317573 on regional brain activity in healthy male subjects

“…Strome et al (2002) reported increased glucose metabolism in the amygdala, pituitary, and hippocampus concurrent with increases in plasma cortisol levels, plasma ACTH levels, and anxiety and/or depressive symptoms after ICV infusion of CRF in rhesus macaque. The interaction of the amygdala with the hippocampus, dorsal and ventral striatum, orbital frontal cortex, paraventricular nucleus of the hypothalamus, and midbrain (Charney and Drevets 2002;Davis 2005) may be relevant to the additional glucose metabolic changes observed in those regions.…”

CSF Corticotropin-Releasing Factor in Personality Disorder: Relationship with Self-Reported Parental Care

“…Acute stress causes upregulation of CRF in amygdala (Stout et al, 2002). Stimulation of amygdalar CRF receptors, and consequent increase in amygdalar metabolic activity, results in increased anxiety-like and decreased pro-social behaviors (Strome et al, 2002;DeVries et al, 2002). CRF is also released in the frontal cortex, where it signals the salience of environmental cues (Merali et al, 2004).…”