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1.
Corticotropin‐releasing factor (CRF) in the amygdala is involved in stress responses. Moreover, dopaminergic neurotransmission in the brain reward system including the amygdala plays a significant role in the pathology of cocaine addiction. The present study analysed CRF‐induced synaptic plasticity, its pharmacological sensitivity and interactions with the dopamine (DA) system in the basolateral to lateral capsula central amygdala (lcCeA) pathway after a 2‐week withdrawal from repeated cocaine administration. A physiologically relevant CRF concentration (25 nm ) induced long‐term potentiation (LTP) that was enhanced after cocaine withdrawal. In saline‐treated rats, CRF‐induced LTP was mediated through N‐methyl‐d ‐aspartate (NMDA) receptors, L‐type voltage‐gated calcium channels (L‐VGCCs) and CRF1 receptors. However, in cocaine‐withdrawn animals, activation of CRF1 and CRF2 receptors was found to enhance LTP. This enhanced CRF‐induced LTP after cocaine withdrawal was mediated through endogenous activation of both D1‐ and D2‐like receptors. Furthermore, expression of the D1 receptor (D1R) but not the D2R, D3R, D4R or D5R was significantly increased after cocaine withdrawal. CRF1 but not CRF2 protein expression was increased, suggesting that elevated levels of these proteins contributed to the enhancement of CRF‐induced LTP during cocaine withdrawal. CRF interactions with the DA system in the amygdala may represent a fundamental neurochemical and cellular mechanism linking stress to cocaine‐induced neuronal plasticity.  相似文献   

2.
The corticotropin‐releasing factor (CRF) family of peptides includes CRF and three urocortins, which signal through two distinct G‐protein coupled receptors, CRF1 and CRF2. Although the cellular distribution of CRF receptor expression has been well characterized at the mRNA level, the localization of receptor protein, and, by inference, of functional receptors, has been limited by a lack of reliable immunohistochemical evidence. Recently, a CRF‐related peptide, termed PD‐sauvagine, was isolated from the skin of the frog, Pachymedusa dacnicolor, and validated as a high‐affinity ligand for CRF receptor studies. A radiolabeled analog, [125I]‐PD‐sauvagine, with high signal‐to‐noise ratio, was used in autoradiographic studies to map the distribution of CRF receptor binding sites in the mouse brain. Through the use of receptor‐deficient mice and subtype‐specific antagonists, CRF1 and CRF2 binding sites were isolated, and found to be readily reconcilable with regional patterns of mRNA expression. Binding site distributions within a given structure sometimes differed from mRNA patterns, however, particularly in laminated structures of the isocortex, hippocampus, and cerebellum, presumably reflecting the trafficking of receptors to their operational homes on neuronal (mostly dendritic) processes. Binding patterns of [125I]‐PD‐sauvagine provided independent assessments of controversial receptor localizations, failing to provide support for CRF1 expression in central autonomic components of the limbic forebrain, the locus coeruleus and cerebellar Purkinje cells, or for CRF2 in any aspect of the cerebellar cortex. Though lacking in ideal resolution, in vitro binding of the PD‐sauvagine radioligand currently provides the most sensitive and accurate available tool for localizing CRF receptors in rodent brain.  相似文献   

3.
Background Peripheral corticotrophin‐releasing factor (CRF) plays an important role in stress‐induced alterations of gastrointestinal motility. CRF injected peripherally inhibits gastric emptying, but its effect on gastric contractions has not been clarified in freely moving conscious rats. Methods Intraluminal gastric pressure waves were measured in freely moving conscious non‐fasted rats using the perfused manometric method. We assessed the area under the manometric trace as the motor index (MI), and compared this result with those obtained 1 h before and after drug administration. Key Results Subcutaneous injection (sc) of CRF (15 μg kg?1) increased the MI significantly. Pretreatment with intravenous astressin (100 μg kg?1), a non‐selective CRF antagonist, blocked the sc CRF (15 μg kg?1)‐induced response, but astressin2‐B (200 μg kg?1, sc), a selective CRF receptor type 2 (CRF2) antagonist, enhanced the CRF‐induced increase in MI significantly. Meanwhile urocortin 2 (15 μg kg?1, sc), a selective CRF2 agonist, did not alter the basal MI, but it inhibited the sc CRF (15 μg kg?1)‐induced stimulation of gastric contractions. The intraperitoneal injection of cortagine (30 μg kg?1), a selective CRF receptor type 1 (CRF1) agonist, mimicked the response induced by sc CRF. Conclusions & Inferences Peripheral CRF stimulates gastric contractions through CRF1. CRF2 activation inhibits the response induced by CRF, suggesting that CRF2 may have a modulatory action to CRF1 signaling in gastric motor activity.  相似文献   

4.
The baroreflex is an important blood pressure regulating mechanism. The bed nucleus of stria terminalis (BNST) modulates the baroreflex function. However, the local BNST neurochemical mechanisms involved in control of baroreflex responses are not completely understood. Therefore, in this study, we investigated the involvement of corticotropin‐releasing factor (CRF) receptors within the BNST in baroreflex control of heart rate in unanesthetized rats. For this, we evaluated effects of bilateral microinjection into the BNST of either the selective CRF1 receptor antagonist CP376395 (5 nmol/100 nL) or the selective CRF2 receptor antagonist antisauvagine‐30 (5 nmol/100 nL) in bradycardiac response evoked by blood pressure increases caused by intravenous infusion of phenylephrine as well as tachycardiac response to blood pressure decrease caused by intravenous infusion of sodium nitroprusside. Bilateral microinjection of CP376395 into the BNST decreased the baroreflex bradycardiac response without affecting the reflex tachycardia. Conversely, BNST treatment with antisauvagine‐30 decreased heart rate response during blood pressure drop without affecting the reflex bradycardia. Overall, these findings provide evidence of an involvement of CRF neurotransmission within the BNST in baroreflex activity. Nevertheless, data indicate that local CRF1 and CRF2 receptors differently modulate the baroreflex control of heart rate.  相似文献   

5.
Naked mole‐rats (Heterocephalus glaber) live in groups that are notable for their large size and caste structure, with breeding monopolized by a single female and a small number of males. Recent studies have demonstrated substantial differences between the brains of breeders and subordinates induced by changes in social standing. Corticotropin‐releasing factor (CRF) receptors—which bind the hormone CRF as well as related peptides—are important regulators of stress and anxiety, and are emerging as factors affecting social behavior. We conducted autoradiographic analyses of CRF1 and CRF2 receptor binding densities in female and male naked mole‐rats varying in breeding status. Both globally and in specific brain regions, CRF1 receptor densities varied with breeding status. CRF1 receptor densities were higher in subordinates across brain regions, and particularly in the piriform cortex and cortical amygdala. Sex differences were present in CRF2 receptor binding densities, as is the case in multiple vole species. CRF2 receptor densities were higher in females, both globally and in the cortical amygdala and lateral amygdalar nucleus. These results provide novel insights into the neurobiology of social hierarchy in naked mole‐rats, and add to a growing body of work that links changes in the CRF system with social behavior. J. Comp. Neurol. 524:228–243, 2016. © 2015 Wiley Periodicals, Inc.  相似文献   

6.
Corticotropin-releasing factor (CRF), a 41 amino acid peptide exhibits its actions through two pharmacologically distinct CRF receptor subtypes CRF1 and CRF2. Regulation of the relative contribution of the two CRF receptors to central CRF activity may be essential in coordinating physiological responses to stress. To facilitate the analysis of their differential involvement, we recently developed a CRF1-selective agonist cortagine by synthesis of chimeric peptides derived from human/rat CRF, ovine CRF, and sauvagine. Cortagine was analyzed in behavioral experiments using male wild type and CRF2-deficient C57BL/6J mice for its action on anxiety- and depression-like behaviors. In contrast to the current hypothesis that increased CRF1 activity facilitates the expression of anxiety- and depression-like behavior, cortagine combines anxiogenic properties with antidepressant effects. In this article, we show that antidepressant effects are partially mediated by CRF1 of the dorsal hippocampus. Possible pathways responsible for the paradoxical antidepressant effects observed after CRF1 activation are discussed.  相似文献   

7.
Corticotropin‐releasing factor (CRF)‐CRF1 receptor in the brain plays a key role in stress‐related alterations of behavior including anxiety/depression, and autonomic and visceral functions. In particular, CRF1 signaling mediates hypersensitivity to colorectal distension (CRD) in various models (early life adverse events, repeated psychological stress, chronic high anxiety, postcolonic inflammation, or repeated nociceptive CRD). So far, knowledge of brain sites involved is limited. A recent article demonstrates in rats that CRF microinjected into the central amygdala (CeA) induces a hyperalgesic response to CRD and enhances the noradrenaline and dopamine levels at this site. The visceral and noradrenaline, unlike dopamine, responses were blocked by a CRF1 antagonist injected into the CeA. Here, we review the emerging role that CRF‐CRF1 signaling plays in the CeA to induce visceral hypersensitivity. In the somatic pain field, CRF in the CeA was shown to induce pain sensitization. This is mediated by the activation of postsynaptic CRF1 receptors and protein kinase A signaling that increases N‐methyl‐d ‐aspartate receptor neurotransmission. In addition, the activation of tetraethylamonium‐sensitive ion channels such as Kv3 accelerates repolarization and firing rate. Whether facilitation of pain transmission underlies CRF action in the CeA‐induced visceral hypersensitivity will need to be delineated. CRF1 signaling in the CeA is also an important component of the neuronal circuitry inducing anxiety‐like behavior and positioned at the interphase of the reciprocal relationship between pain and affective state. The hyperactivity of this system may represent the neuroanatomical and biochemical substrate contributing to the coexpression of hypersensitivity to CRD and mood disorders in subsets of irritable bowel syndrome patients.  相似文献   

8.
Dysfunctional social behavior is a major clinical feature of mood, anxiety, autism spectrum, and substance-related disorders, and may dramatically contribute to the poor outcome of these diseases. Nevertheless, the mechanisms underlying social behavior deficits are still largely unknown. The corticotropin-releasing factor (CRF) system, a major coordinator of the stress response, has been hypothesized to modulate social behavior. CRF signaling is mediated by two receptor types, termed CRF1 and CRF2. Using the three-chamber task for sociability (i.e., preference for an unfamiliar conspecific vs. an object), this study demonstrates that CRF2 receptor null mutation (CRF2−/−) reduces sociability in female mice but increases it in male mice. Both female and male CRF2−/− mice display a preference for social odor cues over neutral cues, indicating that sex- and CRF2 receptor-dependent sociability is not due to altered olfaction or impaired social cues discrimination. Moreover, treatment with the CRF1 receptor-preferring antagonist, antalarmin, consistently induces sociability in non-social mice but disrupts it in social mice, independently of CRF2 receptor deficiency. Sex, CRF2 receptor deficiency, or antalarmin affect locomotor activity during the three-chamber test. However, throughout the study CRF1 and CRF2 receptor-linked sociability is independent of locomotor activity. The present findings highlight major functions for the CRF system in the regulation of social behavior. Moreover, they provide initial evidence of sex-linked roles for the CRF1 and the CRF2 receptor, emphasizing the importance of sex as a major biological variable to be taken into consideration in preclinical and clinical studies.  相似文献   

9.
Interactions between corticotropin‐releasing factor (CRF) and monoaminergic systems originating from the dorsal raphe nucleus (DR) and ventral tegmental area (VTA) have been implicated in the etiology and pathophysiology of several stress‐related neuropsychiatric disorders such as depression and substance abuse. Sub‐regions within the DR and VTA give rise to specific projections that have unique roles in limbic‐ and reward‐related behaviors. Given that these disorders typically emerge during adolescence, it is surprising that few studies have examined the age‐, sex‐, and region‐dependent expression of CRF receptors throughout multiple stages of adolescence in these stress‐relevant circuits. To determine the ontogeny of CRF receptors during adolescent development, three regions of the DR (dorsal, caudal, and ventrolateral parts) and the posterior VTA were microdissected from Sprague‐Dawley male and female rats on postnatal day (P) 25, P35, P42, P56, and P90. Tissue was processed and analyzed with qRT‐PCR to measure CRF1 and CRF2 receptors. The serotonin and catecholamine enzymes in the DR and VTA, tryptophan hydroxylase 2 (TPH2) and tyrosine hydroxylase, respectively, were also analyzed for maturational differences. This study identified that CRF1 receptors are lower in males than females within the dorsal, ventrolateral region of the DR (DRVL), which is involved in anxiety‐, stress‐, and panic‐related responses. Females had higher CRF2 receptors compared to males in the DRVL only. Levels of TPH2 mRNA in the DRVL were overproduced transiently in females before declining into adulthood. These fundamental studies suggest that sex differences in CRF receptors should be considered when examining stress‐related neuropsychiatric disorders and their treatment. Synapse 70:125–132, 2016. © 2016 Wiley Periodicals, Inc.  相似文献   

10.
Pituitary adrenocorticotropin hormone (ACTH) secretion following stress is mediated primarily by the release of corticotropin-releasing factor (CRF) from the brain. We have hypothesized that stress-induced alterations of autonomic nervous system activity also may be dependent on CRF release within the brain because administration of CRF into the brain produces changes in autonomic nervous system function that are similar to those observed following exposure to various types of stress. We now report confirmation of this hypothesis with studies using a CRF receptor antagonist. The CRF receptor antagonist, α-helical CRF9–41, placed into the brains of rats suppressed stress-induced elevations of plasma epinephrine levels. Thus, CRF appears to be physiologically involved in coordinating the pituitary and autonomic nervous system responses to stress.  相似文献   

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