Distribution of corticotropin-releasing factor receptors in primate brain.

Abstract

The distribution and properties of receptors for corticotropin-releasing factor (CRF) were analyzed in the brain of cynomolgus monkeys. Binding of [125I]tyrosine-labeled ovine CRF to frontal cortex and amygdala membrane-rich fractions was saturable, specific, and time-and temperaturedependent, reaching equilibrium in 30 min at 23TC. Scatchard analysis of the binding data indicated one class of high-affinity sites with a Kd of 1 nM and a concentration of 125 fmol/mg (,30% of the receptor number in monkey anterior pituitary membranes). As in the rat pituitary and brain, CRF receptors in monkey cerebral cortex and amygdala were coupled to adenylate cyclase. Autoradiographic analysis of specific CRF binding in brain sections revealed that the receptors were widely distributed in the cerebral cortex and limbic system. Receptor density was highest in the pars tuberalis of the pituitary and throughout the cerebral cortex, specifically in the prefrontal, frontal, orbital, cingulate, insular, and temporal areas, and in the cerebellar cortex. A very high binding density was also present in the hippocampus, mainly in the dentate gyrus, and in the arcuate nucleus and nucleus tuberis lateralis. A high binding density was present in the amygdaloid complex and mammary bodies, olfactory tubercle, and medial portion of the dorsomedial nucleus of the thalamus. A moderate binding density was found in the nucleus accumbens, claustrum, caudate-putamen, paraventricular and posterior lateral nuclei of the thalamus, inferior colliculus, and dorsal parabrachial nucleus. A low binding density was present in the superior colliculus, locus coeruleus, substantia gelatinosa, preoptic area, septal area, and bed nucleus of the stria terminalis. These data demonstrate that receptors for CRF are present within the primate brain at areas related to the central control of visceral function and behavior, suggesting that brain CRF may serve as a neurotransmitter in the coordination of endocrine and neural mechanisms involved in the response to stress.In addition to its role as a major regulator of corticotropin (ACTH) release from the anterior pituitary (1), corticotropinreleasing factor (CRF) also exerts direct actions within the central nervous system in several animal species. Intracerebroventricular administration of CRF in experimental animals results in altered behavior and activates the hypothalamic-pituitary adrenal axis and the sympathetic nervous system, similar to the changes observed during stress (1-4). Immunoreactive CRF has been found in several extrahypothalamic sites in the brain, including many parts of the limbic system and centers known to control the autonomic nervous system (1, 5-7). These findings suggest that the peptide acts as a neurotransmitter in the brain to modulate the integrated responses to stress. This view is supported by the demonstration that CRF receptors are present in the rat brain, with a distribution corresponding to the components of the limbic system and cerebral cortex (8). There is evidence indic...

The human lateral tuberal nucleus: Immunohistochemical characterization and analogy to the rodent PV1-nucleus

“…The rodent PV1-nucleus did not stain for these markers. Similarly discrepant findings in phylogeny have been reported for the corticotropin-releasing factors, the muscarinic cholinergic receptor and GABA, each of which are expressed in regions of the human brain but not in the rodent (Pelletier et al, 1983;Millan et al, 1986;De Souza et al, 1985;Cortes et al, 1986;Trottier et al, 2002;Sakaue et al, 1988;Tappaz et al, 1977). Neither the human LTN nor the rodent PV1-nucleus manifested immunoreactivity for either calbindin or calretinin.…”

PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

“…Nonspecific binding was determined in the presence of 1 µM of unlabeled oCRF. They reported concentrations of CRF binding sites from cingulate cortex, amygdala, and hippocampus of 138 ±9, 150±7, and 47±11 fmol/mg, respectively [46]. Because oCRF is reported to bind both CRF1 and CRF2, the reported specific binding concentrations by Millan et al may reflect binding to CRF1 and CRF2.…”

“…No brain region had detectable specific binding, with nearly identical time-activity curves for regions known to have higher (cerebellum, occipital cortex) and lower (putamen) CRF1 receptor density reported for primates in the literature [9,46,47]. Likewise, no brain region demonstrated evidence for detectable specific binding of any radiolabeled metabolite of these radiotracers.…”

“…However, similar to our prior report of the CRF1 radioligand [ 11 C]SN003 [33], in vivo testing of these ligands failed to demonstrate detectable specific binding in baboon brain using PET. The imaging analyses included several brain regions known to contain significant levels of the CRF1 receptor in primate such as cerebellum and multiple cortical regions [9,46,47]. The distribution pattern of radioactivity throughout brain demonstrated by the time-activity curves indicated these radioligands penetrate the BBB and accumulate in brain tissue.…”

Corticotropin-Releasing Hormone Directly Activates Noradrenergic Neurons of the Locus Ceruleus RecordedIn Vitro

“…CRH receptors have been demonstrated in the LC (Millan et al, 1986;Primus et al, 1997;Sanchez et al, 1999). CRH receptors are divided in two main classes (Hauger et al, 2003b;Bale and Vale, 2004), and at least some receptors in the LC are of the CRH 1 receptor subtype (Sauvage and Steckler, 2001).…”