RESUMEN
Corticotropin-releasing factor (CRF, corticoliberin) is a neuromodulatory peptide activating the hypothalamic-pituitary-adrenal (HPA) axis, widely distributed in the central nervous system (CNS) in mammals. In addition to its neuroendocrine effects, CRF is essential in regulating many functions under physiological and pathophysiological conditions through CRF1 and CRF2 receptors (CRF1R, CRF2R). This review aims to present selected examples of the diverse and sometimes opposite effects of CRF and its receptor ligands in various pathophysiological states, including stress/anxiety, depression, and processes associated with brain injury. It seems interesting to draw particular attention to the fact that CRF and its receptor ligands exert different effects depending on the brain structures or subregions, likely stemming from the varied distribution of CRFRs in these regions and interactions with other neurotransmitters. CRFR-mediated region-specific effects might also be related to brain site-specific ligand binding and the associated activated signaling pathways. Intriguingly, different types of CRF molecules can also influence the diverse actions of CRF in the CNS.
Asunto(s)
Ansiedad , Hormona Liberadora de Corticotropina , Receptores de Hormona Liberadora de Corticotropina , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Humanos , Animales , Hormona Liberadora de Corticotropina/metabolismo , Ansiedad/metabolismo , Ansiedad/fisiopatología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/fisiopatología , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Depresión/metabolismo , Depresión/fisiopatología , Encéfalo/metabolismo , Encéfalo/fisiopatologíaRESUMEN
Background: Disruption in androgen profiles and testicular adrenal rest tumors in males with congenital adrenal hyperplasia (CAH) can negatively affect sexual activity and fertility. Adrenal hyperandrogenism suppresses gonadotropin secretion and testicular adrenal rest tumors (TARTS), despite being noncancerous lesions, cause obstructive azoospermia and impaired testosterone (T) production. Circulating T in men with uncontrolled CAH is often predominantly adrenal in origin, which is reflected in high androstenedione/testosterone ratios (A4/T). Therefore, decreased luteinizing hormone (LH) levels and an increased A4/T are markers of impaired fertility in these individuals. Methods: Oral tildacerfont 200 to 1000 mg once daily (QD) (n=10) or 100 to 200 mg twice daily (n=9 and 7) for 2 weeks (Study 201), and 400 mg QD (n=11) for 12 weeks (Study 202). Outcomes measured changes from baseline in A4, T, A4/T, and LH. Results: Mean T levels increased in Study 201 from 375.5 ng/dL to 390.5 ng/dL at week 2 (n=9), 485.4 ng/dL at week 4 (n=4) and 420.7 ng/dL at week 6 (n=4). In Study 202, T levels fluctuated in the normal range from 448.4 ng/dL at baseline to 412.0 ng/dL at week 12. Mean LH levels increased in Study 201 from 0.68 IU/L to 1.59 IU/L at week 2 (n=10), 1.62 IU/L at week 4 (n=5) and 0.85 IU/L at week 6 (n=4). In Study 202, mean LH levels increased from 0.44 IU/L at baseline to 0.87 IU/L at week 12. Mean A4/T decreased across both studies. In Study 201, the mean A4/T changed from a baseline of 1.28 to 0.59 at week 2 (n=9), 0.87 at week 4 (n=4), and 1.03 at week 6 (n=4). In Study 202, the A4/T decreased from baseline of 2.44 to 0.68 at week 12. Four men were hypogonadal at baseline; all experienced improved A4/T and 3/4 (75%) reached levels <1. Conclusion: Tildacerfont treatment demonstrated clinically meaningful reductions in A4 levels, and A4/T with concomitant increased LH levels indicating increased testicular T production. The data suggests improvement in hypothalamic-pituitary-gonadal axis function, but more data is required to confirm favorable male reproductive health outcomes.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Tumor de Resto Suprarrenal , Neoplasias Testiculares , Humanos , Masculino , Hormona Liberadora de Corticotropina , Receptores de Corticotropina , Receptores de Hormona Liberadora de Corticotropina , Salud Reproductiva , Testosterona , Hiperplasia Suprarrenal Congénita/complicaciones , Neoplasias Testiculares/complicacionesRESUMEN
G protein-coupled-receptors (GPCRs) are the largest family of cell surface receptors with tremendous therapeutic potential. They mediate signal transduction activities via G protein-dependent signaling pathways, G protein-independent signaling pathways, and other complicated regulatory processes. The corticotropin-releasing factor receptor type 1 (CRF1R) is a member of class B GPCRs that is predominantly found in the central nervous system, where it plays a key role in stress-related neuro-disorders. To date, no drug targeting this receptor has been approved, partly due to inadequate understanding of the activation mechanism of class B GPCRs. Previously, using MD simulation, we demonstrated that the CRF1R complexed with a small-molecule antagonist CP-376395 maintains a conformation of its transmembrane domain (TMD). Here, using the most abundant structures derived from those simulations, we carried out a structure-based virtual screening of ZINC15 "Druglike" library containing approximately 17 million compounds. The docking complexes of the CRF1R with the top 30 hits were submitted to MD simulation to examine the stability of ligand binding mode. Furthermore, MM-GBSA binding energy calculations were performed on all the complexes to rank them with improving accuracy. Hit 1 (ZINC000046079839) and hit 20 (ZINC000032907937) span the allosteric site of the CRF1R, persistently forming interactions with transmembrane helices 3 and 6. These interactions are likely to keep the receptor in an inactive state since both transmembrane helices play a critical role in the activation of the receptor.
Asunto(s)
Proteínas de Unión al GTP , Simulación de Dinámica Molecular , Ansiedad , Sitios de Unión , Proteínas de Unión al GTP/metabolismo , Ligandos , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Secundaria de ProteínaRESUMEN
The sexually dimorphic bed nucleus of the stria terminalis (BNST) is comprised of several distinct regions, some of which act as a hub for stress-induced changes in neural circuitry and behavior. In rodents, the anterodorsal BNST is especially affected by chronic exposure to stress, which results in alterations to the corticotropin-releasing factor (CRF)-signaling pathway, including CRF receptors and upstream regulators. Stress increases cellular excitability in BNST CRF+ neurons by potentiating miniature excitatory postsynaptic current (mEPSC) amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K+ current that stabilizes membrane potential). Rodent anterodorsal and anterolateral BNST neurons are also critical regulators of behavior, including avoidance of aversive contexts and fear learning (especially that of sustained threats). These rodent behaviors are historically associated with anxiety. Furthermore, BNST is implicated in stress-related mood disorders, including anxiety and Post-Traumatic Stress Disorders in humans, and may be linked to sex differences found in mood disorders.
RESUMEN
Corticotropin releasing factor (CRF) signaling via limbic CRF1 and 2 receptors (CRF1R and CRF2R, respectively) is known to modulate binge-like ethanol consumption in rodents. Though CRF signaling in the medial prefrontal cortex (mPFC) has been shown to modulate anxiety-like behavior and ethanol seeking, its role in binge ethanol intake is unknown. Here, we used "drinking-in-the-dark" (DID) procedures in male and female C57BL/6J mice to address this gap in the literature. First, the role of CRF1R and CRF2R signaling in the mPFC on ethanol consumption was evaluated through site-directed pharmacology. Next, we evaluated if CRF1R antagonist reduction of binge-intake was modulated in part through CRF2R activation by co-administration of a CRF1R and CRF2R antagonist. Intra-mPFC inhibition of CRF1R and activation of CRF2R resulted in decreased binge-like ethanol intake. Further, the inhibitory effect of the CRF1R antagonist was attenuated by co-administration of a CRF2R antagonist. We provide novel evidence that (1) inhibition of CRF1R or activation of CRF2R in the mPFC reduces binge-like ethanol intake; and (2) the effect of CRF1R antagonism may be mediated via enhanced CRF2R activation. These observations provide the first direct behavioral pharmacological evidence that CRF receptor activity in the mPFC modulates binge-like ethanol consumption.
RESUMEN
Perfluorooctane sulfonate (PFOS) is an endocrine disruptor highly persistent, bioaccumulative and neurotoxic, whose presence has been detected in different compartments of the environment. The aim of this study was to investigate whether PFOS could alter the HPA axis activity by modifying the gene and protein expression of corticotropin-releasing factor 1 receptor (CRF1r) and glucocorticoid receptor (Gr). For that purpose, Sprague-Dawley adult male rats were orally treated by gavage with 0.5; 1.0; 3.0 and 6.0â¯mg of PFOS/kg/day for 28 consecutive days. After PFOS administration, gene and protein expression of CRF1r were analysed in the hypothalamus, hippocampus, pituitary and adrenal glands. Moreover, Gr gene and protein expression were measured in hypothalamus, pituitary gland, prefrontal cortex, amygdala and hippocampus. The reported results indicate that (1) PFOS could inhibit HPA axis activity by diminishing gene and protein expression of CRF1r in the pituitary gland; (2) PFOS inhibits Gr protein expression in both prefrontal cortex and amygdala, which could be related to the toxic effects of this contaminant in this neuroendocrine axis and finally, (3) PFOS-treated rats would try to maintain the physiological levels of corticosterone by reducing the protein expression of Gr in the pituitary gland.
Asunto(s)
Ácidos Alcanesulfónicos/toxicidad , Disruptores Endocrinos/toxicidad , Fluorocarburos/toxicidad , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Receptores de Glucocorticoides/efectos de los fármacos , Hormona Adrenocorticotrópica/sangre , Animales , Corticosterona/sangre , Hormona Liberadora de Corticotropina/sangre , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/genética , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse to drug-seeking/taking behavior triggered by opiate withdrawal-associated aversive memories.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Complejo Nuclear Basolateral/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Giro Dentado/metabolismo , Dependencia de Morfina/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Animales , Reacción de Prevención/fisiología , Complejo Nuclear Basolateral/metabolismo , Condicionamiento Psicológico/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Distribución Aleatoria , Conducta Espacial/efectos de los fármacos , Conducta Espacial/fisiologíaRESUMEN
BACKGROUND: The corticotropin releasing factor (CRF) family of neuropeptides, CRF and the Urocortins, and their receptors are present not only within the central nervous system but also in the periphery at various locations and at the sites of inflammation where they influence its progress in a complex local / paracrine manner. OBJECTIVE AND METHODS: This review summarizes current knowledge regarding the regulation of inflammatory process by CRF family of neuropeptides and receptors with a special sight into their role in inflammatory pain and in chronic low grade inflammation that occurs in obesity. For this purpose, we searched for relevant peer-reviewed research articles using bibliographic databases. RESULTS: The CRF neuropeptides are either produced locally, by components of the inflammatory response or they may reach the inflammation sites via postganglionic sympathetic and sensory afferent nerve transport. It now appears that most immune cells taking part in the inflammatory process express CRF receptor type 1 (CRF1R) and type 2 (CRF2R) and thus represent targets of CRF neuropeptides. Indeed, mast cells, monocytes / macrophages, neutrophils and other types of immune cells express both types of the CRF receptors. In addition to their role in the pathophysiology of inflammation, CRF and its receptors also exert modulatory effects on inflammatory pain. Finally, it now appears that the CRF system is also present in adipose tissue and may play a crucial role in the development of the chronic low grade inflammation, which is characteristic of obesity. CONCLUSION: The local effects of the CRF family of neuropeptides can be either pro- or antiinflammatory depending on concentration of each type of neuropeptide present and the ratio of the local expression of their receptors CRF1R and CRF2R.
Asunto(s)
Hormona Liberadora de Corticotropina/metabolismo , Inflamación/patología , Comunicación Paracrina , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Animales , Humanos , Macrófagos/metabolismo , Mastocitos/metabolismoRESUMEN
The structural analysis of class B G protein-coupled receptors (GPCR), cell surface proteins responding to peptide hormones, has until recently been restricted to the extracellular domain (ECD). Corticotropin-releasing factor receptor type 1 (CRF1R) is a class B receptor mediating stress response and also considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of human CRF1R in complex with the small-molecule antagonist CP-376395 in a hexagonal setting with translational non-crystallographic symmetry. Molecular dynamics and metadynamics simulations on this novel structure and the existing TMD structure for CRF1R provides insight as to how the small molecule ligand gains access to the induced-fit allosteric binding site with implications for the observed selectivity against CRF2R. Furthermore, molecular dynamics simulations performed using a full-length receptor model point to key interactions between the ECD and extracellular loop 3 of the TMD providing insight into the full inactive state of multidomain class B GPCRs.
Asunto(s)
Receptores de Hormona Liberadora de Corticotropina/química , Sitio Alostérico , Aminopiridinas/farmacología , Sitios de Unión , Cristalografía por Rayos X/métodos , Humanos , Simulación de Dinámica Molecular , Conformación Proteica , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismoRESUMEN
BACKGROUND: Animal models proposed to reproduce some of the human irritable bowel syndrome (IBS) symptoms are based on the hypothesis that psychosocial stressors play a pivotal role in the IBS etio-pathology. We investigated the wrap restraint stress (WRS) model with the aim to analyze the morphological changes of the entire colonic wall of these animals that showed some of the human IBS symptoms such as visceral hypersensitivity. METHODS: Male Wistar rats were used and WRS was maintained for 2 h. Abdominal contractions (AC) were recorded in the colon-rectum by balloon distension. Fecal pellets were quantitated. Colonic specimens were examined by routine histology, immunohistochemistry and western blot. KEY RESULTS: WRS animals were characterized by: (i) increase in AC number and fecal pellets mean weight; (ii) clusters of mononucleated cells, increase in eosinophilic granulocytes and mast cells in the mucosa; (iii) increase in CGRP-immunoreactive (IR) nerve fibers in the lamina propria; (iv) decrease in myenteric NK1r-IR and nNOS-IR neurons and in submucous nNOS-IR neurons; (v) decrease in SP-IR nerve fibers in the muscle wall; (vi) reduction in S100ß-IR glia in the entire colonic wall; (vii) increase in CRF1r-IR myenteric neurons; (viii) no change in ChAT-IR neurons, smooth muscle cells and interstitial cells of Cajal. CONCLUSIONS AND INFERENCES: The present results support the consistency of the WRS as a potential model where part of the human IBS signs and symptoms are reproduced. The changes in glial cells and in excitatory and inhibitory neurotransmitters might represent the substrate for the dysmotility and hypersensitivity.
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Colon/metabolismo , Síndrome del Colon Irritable/metabolismo , Neuronas/metabolismo , Neurotransmisores/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Estrés Psicológico/metabolismo , Animales , Modelos Animales de Enfermedad , Síndrome del Colon Irritable/patología , Masculino , Neuronas/patología , Ratas , Ratas Wistar , Restricción Física , Estrés Psicológico/patologíaRESUMEN
Different neurotransmitter systems are involved in behavioural and molecular responses to morphine. The brain stress system is activated by acute administration of drugs of abuse, being CRF the main neuropeptide of this circuitry. In this study we have studied the role of CRF1R in the rewarding effects of morphine using the CPP paradigm. For that, animals were treated with a CRF1R antagonist (CP-154,526) or vehicle during 6 days. Thirty min after receiving the antagonist, mice were injected with morphine on the same days that CP-154,526 was administered; another group received saline on the same days that vehicle was administered, and both groups were immediately conditioned. Control animals received vehicle and saline every day. On day 7, animals were tested for morphine-induced CPP. c-Fos, TH and OXA immunohistochemistry, NA turnover (HPLC), and corticosterone plasma concentration (RIA) were evaluated. Administration of a CRF1R antagonist CP-154,526 blocked the morphine-induced CPP and the increased NA turnover in the NAc in morphine-paired mice. CP-154-526 antagonised the enhancement in c-Fos expression evoked by morphine-induced CPP in the VTA and NAc, and the activation of the orexinergic neurons in the LLH. Present work demonstrates that morphine-induced CPP activates different brain areas involved in reward, and points out a critical role of CRF1R in molecular changes involved in morphine-conducted behaviours. Thus, our study supports a therapeutic potential of CRF1R antagonists in addictive disorders.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Morfina/farmacología , Narcóticos/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Recompensa , Conducta Espacial/efectos de los fármacos , Animales , Condicionamiento Operante/fisiología , Antagonistas de Hormonas/farmacología , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiología , Masculino , Ratones , Dependencia de Morfina/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Pirimidinas/farmacología , Pirroles/farmacología , Distribución Aleatoria , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Conducta Espacial/fisiología , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiologíaRESUMEN
There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated by naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction.
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Hipotálamo/metabolismo , Dependencia de Morfina/metabolismo , Miocardio/metabolismo , Receptores de Hormona Liberadora de Corticotropina/deficiencia , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Peso Corporal , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Corazón/anatomía & histología , Masculino , Ratones Noqueados , Naloxona , Antagonistas de Narcóticos , Neuronas/metabolismo , Norepinefrina/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de Hormona Liberadora de Corticotropina/genética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The corticotropin-releasing factor (CRF) type 1 receptor (CRF1R) for the 41-amino acid peptide CRF is a class B G protein-coupled receptor, which plays a key role in the response of our body to stressful stimuli and the maintenance of homeostasis by regulating neural and endocrine functions. CRF and related peptides, such as sauvagine, bind to the extracellular regions of CRF1R and activate the receptor. In contrast, small nonpeptide antagonists, which are effective against stress-related disorders, such as depression and anxiety, have been proposed to interact with the helical transmembrane domains (TMs) of CRF1R and allosterically antagonize peptide binding and receptor activation. Here, we aimed to elucidate the role of the third TM (TM3) in the molecular mechanisms underlying activation of CRF1R. TM3 was selected because its tilted orientation, relative to the membrane, allows its residues to establish key interactions with ligands, other TM helices, and the G protein. Using a combination of pharmacological, biochemical, and computational approaches, we found that Phe-203(3.40) and Gly-210(3.47) in TM3 play an important role in receptor activation. Our experimental findings also suggest that Phe-203(3.40) interacts with nonpeptide antagonists.
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Membrana Celular/metabolismo , Receptores de Hormona Liberadora de Corticotropina/química , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Regulación Alostérica/efectos de los fármacos , Secuencia de Aminoácidos , Secuencia Conservada , Células HEK293 , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Estructura Terciaria de Proteína , Pirimidinas/farmacología , Pirroles/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/genética , Alineación de Secuencia , Relación Estructura-ActividadRESUMEN
Humans with stress-related anxiety disorders exhibit increases in arousal and alcohol drinking, as well as altered pain processing. Our lab has developed a predator odor stress model that produces reliable and lasting increases in alcohol drinking. Here, we utilize this predator odor stress model to examine stress-induced increases in arousal, nociceptive processing, and alcohol self-administration by rats, and also to determine the effects of corticotropin-releasing factor-1 receptors (CRF1Rs) in mediating these behavioral changes. In a series of separate experiments, rats were exposed to predator odor stress, then tested over subsequent days for thermal nociception in the Hargreaves test, acoustic startle reactivity, or operant alcohol self-administration. In each experiment, rats were systemically injected with R121919, a CRF1R antagonist, and/or vehicle. Predator odor stress increased thermal nociception (i.e., hyperalgesia) and acoustic startle reactivity. Systemic administration of R121919 reduced thermal nociception and hyperarousal in stressed rats but not unstressed controls, and reduced operant alcohol responding over days. Stressed rats exhibited increased sensitivity to the behavioral effects of R121919 in all three tests, suggesting up-regulation of brain CRF1Rs number and/or function in stressed rats. These results suggest that post-stress alcohol drinking may be driven by a high-nociception high-arousal state, and that brain CRF1R signaling mediates these stress effects.