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Kenner C Rice - One of the best experts on this subject based on the ideXlab platform.

  • Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats.
    Psychoneuroendocrinology, 2018
    Co-Authors: Hongxin Dong, Kenner C Rice, Jack Keegan, Ellie Hong, Christopher Gallardo, Janitza L. Montalvo-ortiz, Becky Wang, John G. Csernansky
    Abstract:

    Abstract Mounting evidence suggests that chronic stress can alter brain structure and function and promote the development of neuropsychiatric disorders, such as depression and Alzheimer’s disease. Although the results of several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown whether antagonists of a key stress regulator, the corticotrophin releasing factor receptor 1 (CRF1), can prevent stress-induced anxiety and memory deficits in animal models. In this study, we evaluated the potential benefits of two CRF1 antagonists, R121919 and Antalarmin, for preventing stress-induced anxiety-related behavioral and memory deficits and neurodegeneration in aged rats. We stressed rats using isolation-restraint for 3 months starting from the 18 months of age. Subsets of animals were administrated either R121919 or Antalarmin through food chow for 3 months, followed by a series of behavioral, biochemical and morphological analyses. We found that stressed aged rats displayed body weight losses and increased corticosterone levels, as well as anxiety-related behaviors and memory deficits. Additionally, chronic stress induced a loss of cortical dendritic spines and synapses. However, R121919 and Antalarmin both prevented stress-induced behavioral changes including anxiety-related behaviors and memory deficits and prevented synapse loss, perhaps through reversing HPA axis dysfunction. These results suggest that CRF1 antagonists may hold promise as a potential therapy for preventing stress-induced anxiety and memory deficits in aged individuals.

  • Psychopharmacology (2002) 164:268–276 DOI 10.1007/s00213-002-1187-y
    2016
    Co-Authors: Jillian H Broadbear, Kenner C Rice, Gail Winger, James H. Woods
    Abstract:

    Abstract Rationale: During the course of our investiga-tion of Antalarmin, a corticotropin-releasing hormone (CRH) antagonist, in rhesus monkeys, we noticed that large, intravenous doses of Antalarmin resulted in behav-ioral changes that resembled intoxication. Objectives: An-talarmin was evaluated in rhesus monkeys for its reinforcing effectiveness as well as for its effects on hypothalamic-pituitary-adrenal (HPA) axis activity. Methods: Twelve monkeys, each with a surgically implanted indwelling venous catheter, were trained to respond for and receive the short-acting barbiturate, methohexital. Monkeys responded on one of two sched

  • Stress-Induced Potentiation of Cocaine Reward: A Role for CRF R1 and CREB
    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2009
    Co-Authors: Arati S. Kreibich, Kenner C Rice, Lisa A. Briand, Jessica N. Cleck, Laurel E. Ecke, Julie A. Blendy
    Abstract:

    Both clinical and preclinical research have shown that stress can potentiate drug use; however, the underlying mechanisms of this interaction are unknown. Previously, we have shown that a single exposure to forced swim (FS) reinstates extinguished conditioned place preference (CPP) to cocaine and that cAMP response element binding protein (CREB) is necessary for this response. CREB can be activated by corticotropin releasing factor (CRF) receptor type 1 (CRF(R1)) binding, which mediates neuroendocrine and behavioral responses to stress as well as to drugs of abuse. The present experiments investigate whether changes in cocaine reward elicited by previous exposure to stress are mediated by CREB and/or CRF(R1). Chronic exposure to FS in advance of conditioning enhances cocaine CPP in wild-type mice, but this is blocked in CREB-deficient mice. In addition, pretreatment with the CRF(R1) antagonist, Antalarmin, before FS exposure blocks this stress-induced enhancement of cocaine CPP. Furthermore, FS-induced increase in phosphorylated CREB (pCREB), specifically in the lateral septum (LS) and nucleus accumbens (NAc) is also blocked by Antalarmin. Taken together, these studies suggest that both CREB and CRF(R1) activation are necessary for stress-induced potentiation of drug reward.

  • Integration of in vivo and in vitro approaches to characterize the toxicity of Antalarmin, a corticotropin-releasing hormone receptor antagonist.
    Toxicology, 2008
    Co-Authors: Thomas L. Horn, J. Brooks Harder, William D. Johnson, Patrick T. Curry, Ralph E. Parchment, Robert L. Morrissey, Paul W. Mellick, Karim A. Calis, Philip W. Gold, Kenner C Rice
    Abstract:

    Non-clinical studies were conducted to evaluate the toxicity of Antalarmin, a corticotropin-releasing hormone type 1 receptor antagonist being developed for therapy of stress-related pathologies. Antalarmin was not genotoxic in bacterial mutagenesis assays, mammalian cell mutagenesis assays, or in vivo DNA damage assays. In a 14-day range-finding study in rats, Antalarmin doses >or=500 mg/kg/day (3,000 mg/m(2)/day) induced mortality. In a 90-day toxicity study in rats, no gross toxicity was seen at doses of 30, 100, or 300 mg/kg/day (180, 600, or 1,800 mg/m(2)/day, respectively). Antalarmin (300 mg/kg/day) induced mild anemia, increases in serum gamma-glutamyl transferase activity, and microscopic hepatic pathology (bile duct hyperplasia and epithelial necrosis, periportal inflammation). Microscopic renal changes (cortical necrosis, inflammation, hypertrophy, nephropathy) were observed in rats at all Antalarmin doses. In a 14-day range-finding study in dogs, Antalarmin doses >or=50mg/kg/day (1,000 mg/m(2)/day) induced repeated emesis and bone marrow suppression. In a 90-day toxicity study in dogs, Antalarmin (4, 8, or 16 mg/kg/day (80, 160, or 320 mg/m(2)/day, respectively)) induced bone marrow and lymphoid depletion, but no gross toxicity. Comparative in vitro studies using rat, dog, and human neutrophil progenitors demonstrated that canine bone marrow cells are highly sensitive to Antalarmin cytotoxicity, while rat and human bone marrow cells are relatively insensitive. As such, the bone marrow toxicity observed in dogs is considered likely to over-predict Antalarmin toxicity in humans. The hepatic and renal toxicities seen in rats exposed to Antalarmin identify those tissues as the most likely targets for Antalarmin toxicity in humans.

  • The CRF_1 receptor antagonist Antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats
    Psychopharmacology, 2007
    Co-Authors: Peter W Marinelli, Douglas Funk, W Juzytsch, Kenner C Rice, Stephen Harding, Yavin Shaham
    Abstract:

    Rationale and objectives Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF_1) receptor antagonist Antalarmin. Materials and methods In Exp. 1, we trained rats to lever press for alcohol solutions (12% w / v , 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of Antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg)-induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of Antalarmin on yohimbine-induced increases in plasma corticosterone levels in the previously self-administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested Antalarmin’s effect on yohimbine-induced reinstatement of alcohol seeking. Results Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by Antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol-experienced rats. Conclusions These results suggest that extrahypothalamic CRF_1 receptors are involved in the effect of yohimbine on operant alcohol self-administration and on relapse to alcohol seeking and support the notion that CRF_1 receptor antagonists should be considered in alcohol addiction treatment.

George P Chrousos - One of the best experts on this subject based on the ideXlab platform.

  • Printed in U.S.A. Copyright © 1999 by The Endocrine Society The Impact of the Nonpeptide Corticotropin-Releasing Hormone Antagonist Antalarmin on Behavioral and Endocrine Responses to Stress*
    2013
    Co-Authors: Terrence Deak, Kien T Nguyen, Andrea L Ehrlich, Linda R Watkins, Robert L Spencer, Steven F Maier, Julio Licinio, Mali Wong, George P Chrousos
    Abstract:

    The nonpeptide CRH antagonist Antalarmin has been shown to block both behavioral and endocrine responses to CRH. However, it’s potential activity in blunting behavioral and endocrine sequelae of stressor exposure has not been assessed. Because antagonism of central CRH by �-helical CRH attenuates conditioned fear responses, we sought to test Antalarmin in this regard. In addition, it remains unclear as to whether this is a result of receptor blockade during conditioning or during testing. Thus, we explored whether CRH mediates the induction or expression of conditioned fear (freezing in a context previously associated with 2 footshocks; 1.0 mA, 5 sec each)

  • The effect of CRH and its inhibitor, Antalarmin, on in vitro growth of preantral mouse follicles, early embryo development, and steroidogenesis.
    Endocrinology, 2012
    Co-Authors: Vasiliki Dinopoulou, George P Chrousos, Antonis Makrigiannakis, G. A. Partsinevelos, Despina Mavrogianni, Elli Anagnostou, P. Drakakis, Dimitrios Loutradis
    Abstract:

    In vitro growth systems of preantral follicles allow studying the effect of various endocrine, paracrine, and autocrine factors on follicular growth and oocyte maturation. CRH is a 41-amino-acid neuropeptide responsible for endocrine, autonomic, immunological, and behavioral responses of mammals to stress and has two receptors, CRH receptor type 1 (CRH-R1) and CRH-R2. Antalarmin, a CRH-R1 antagonist, has been used to elucidate the role of CRH in stress, inflammation, and reproduction. The present study describes in vitro growth of mouse preantral follicles, early embryo development, and steroidogenesis in the presence of CRH and its antagonist Antalarmin. We cultured 732 follicles in control media, 1306 in CRH 10(-7) mol/liter, and 1202 in CRH 10(-7) plus Antalarmin 10(-6) mol/liter. The culture medium was assayed on alternate days for 17β-estradiol, progesterone, and β-human chorionic gonadotropin. Total RNA was extracted from preantral follicles as well as early preimplantation embryos and was assessed by real-time RT-PCR for the expression of CRH-R1 and CRH-R2 mRNAs. Hormone analysis showed that the CRH group had lower levels of 17β-estradiol, progesterone, and β-human chorionic gonadotropin as the culture progressed, in comparison with the other two groups. RT-PCR demonstrated the presence of CRH-R1 and CRH-R2 in all stages of preantral follicle culture. Morula/blastocyst-stage embryos expressed only CRH-R1. In conclusion, CRH has an inhibitory effect on in vitro fertilized oocytes, resulting from cultured preantral follicles at all stages of preimplantation embryo development. Furthermore, the presence of CRH in the culture medium inhibits steroidogenesis by preantral mouse follicles cultured in vitro.

  • The role of corticotropin -releasing hormone in blastocyst implantation and early fetal immunotolerance
    Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2007
    Co-Authors: Sophia N Kalantaridou, E Zoumakis, Antonis Makrigiannakis, H. Godoy, George P Chrousos
    Abstract:

    During blastocyst implantation, the maternal endometrial response to the invading semi-allograft has characteristics of an acute, aseptic inflammatory response. However, once implanted, the embryo suppresses this response and prevents rejection. Simultaneously, the mother's immune system prevents a graft VS. host reaction deriving from the fetal immune system. We have shown that embryonic trophoblast and maternal decidua cells, i.e., cells located in the interface between the fetal placenta and the maternal endometrium, produce corticotropin-releasing hormone (CRH) and express Fas ligand. CRH may play a crucial role in the implantation and the anti-rejection process that protects the fetus from the maternal immune system, primarily by killing activated T cells through the Fas-FasL interaction. In experimental animals, type 1 CRH receptor (CRH-R1) blockade by Antalarmin, a specific type 1 CRH receptor antagonist, decreased implantation sites by approximately 70%. CRH is also involved in controlled trophoblast invasion, by downregulating the synthesis of the carcinoembryonic antigen-related cell adhesion molecule 1 by extravillous trophoblast cells. IN VITRO findings showed that CRH-R1 blockade by Antalarmin increased trophoblast invasion by approximately 60%. Defective uterine CRH/CRH-R1 system during early pregnancy may be implicated in the pathophysiology of recurrent miscarriage, placenta accreta, and preeclampsia.

  • Involvement of the neuropeptide corticotropin-releasing hormone in an animal model of Shigella-related seizures
    Journal of Neuroimmunology, 2004
    Co-Authors: Yael Yuhas, George P Chrousos, Abraham Weizman, Hilla Ovadia, Shai Ashkenazi
    Abstract:

    Convulsions are common complications of shigellosis in children. Corticotropin-releasing hormone (CRH), a stress neurohormone, has been implicated in the susceptibility of young children to seizures. We investigated the role of CRH in Shigella-related seizures. Pretreatment with Shigella dysenteriae sonicate enhanced mice response to pentylenetetrazole (PTZ)-induced seizures. Preinjection of Antalarmin, a CRH-receptor 1 antagonist, decreased both the mean convulsion score (MCS: 1.6 vs. 1.1, p

  • Uterine and embryonic trophoblast CRH promotes implantation and maintenance of early pregnancy.
    Annals of the New York Academy of Sciences, 2003
    Co-Authors: Antonis Makrigiannakis, George P Chrousos, Sophia N Kalantaridou, Emmanouil Zoumakis, A Gravanis
    Abstract:

    : Epithelial cells of human endometrium and differentiated endometrial stromal cells express the corticotropin-releasing hormone (CRH) gene. CRH is also produced by the human placental cytotrophoblast. Endometrial and placental CRH is under the endocrine control of gonadal steroids as well as under an autocrine/paracrine regulation by prostanoids and interleukins. Human endometrium, myometrium and placenta also express the relevant receptors. Invasive trophoblasts promote apoptosis of activated Fas-expressing human T lymphocytes, an effect potentiated by CRH and inhibited by the CRH type 1 antagonist, Antalarmin. Female rats treated with Antalarmin during the first 6 days of gestation had a dose-dependent decrease of implantation sites and live embryos, and significantly decreased endometrial FasL expression. Our data suggest important physiological roles of endometrial and placental CRH in the regulation of decidualization, blastocyst implantation, and early maternal tolerance.

Jay Schulkin - One of the best experts on this subject based on the ideXlab platform.

  • Corticotropin releasing factor type-1 receptor antagonism in the dorsolateral bed nucleus of the stria terminalis disrupts contextually conditioned fear, but not unconditioned fear to a predator odor
    Psychoneuroendocrinology, 2016
    Co-Authors: Arun Asok, Jay Schulkin, Jeffrey B Rosen
    Abstract:

    The bed nucleus of the stria terminalis (BNST) plays a critical role in fear and anxiety. The BNST is important for contextual fear learning, but the mechanisms regulating this function remain unclear. One candidate mechanism is corticotropin-releasing-factor (CRF) acting at CRF type 1 receptors (CRFr1s). Yet, there has been little progress in elucidating if CRFr1s in the BNST are involved in different types of fear (conditioned and/or unconditioned). Therefore, the present study investigated the effect of Antalarmin, a potent CRFr1 receptor antagonist, injected intracerebroventricularly (ICV) and into the dorsolateral BNST (LBNST) during single trial contextual fear conditioning or exposure to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). Neither ICV nor LBNST Antalarmin disrupted unconditioned freezing to TMT. In contrast, ICV and LBNST Antalarmin disrupted the retention of contextual fear when tested 24h later. Neither ICV nor LBNST Antalarmin affected baseline or post-shock freezing-indicating Antalarmin does not interfere with the early phases of contextual fear acquisition. Antalarmin did not (1) permanently affect the ability to learn and express contextual fear, (2) change responsivity to footshocks, or (3) affect the ability to freeze. Our findings highlight an important role for CRFr1s within the LBNST during contextually conditioned fear, but not unconditioned predator odor fear.

  • Corticosterone implants to the amygdala and type 1 CRH receptor regulation: effects on behavior and colonic sensitivity.
    Behavioural brain research, 2005
    Co-Authors: Dean A. Myers, Jay Schulkin, Matthew S. Gibson, Beverley Greenwood Van-meerveld
    Abstract:

    Corticosterone (CORT) micropellets were stereotaxically placed bilaterally at the dorsal margin of the central nucleus of the amygala (CeA). Both behavioral and physiological responses were recorded (plus maze and colonic discomfort) at 7 days post-implantation. Corticosterone reduced the exploration of the plus maze and increased colonic distress. The ability of a CRH type 1 receptor antagonist, Antalarmin, to block behavioral and colonic effects of central placement of CORT was also examined. The diminished exploration in the plus maze and colon distress observed in response to CORT placement at the CeA were averted by the administration of Antalarmin. These results provide further evidence for the role of the CRH type 1 receptor to ameliorate both behavioral and physiological functions.

  • Corticotropin-releasing factor 1 receptor-mediated mechanisms inhibit colonic hypersensitivity in rats.
    Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 2005
    Co-Authors: B. Greenwood-van Meerveld, Jay Schulkin, Anthony C. Johnson, S. Cochrane, Dean A. Myers
    Abstract:

    The potential relationship between stress and irritable bowel syndrome (IBS) symptomatology suggests a possible role for stress-mediating hor- mones, such as corticotropin-releasing factor (CRF), in the altered perception of stimuli in IBS patients. In previous studies, Wistar-Kyoto (WKY) rats with gen- etic indices of high anxiety demonstrated colonic hypersensitivity coupled with a high basal level of CRF within the central nervous system. In the cur- rent study we tested the hypothesis that a selective, non-peptide CRF1 receptor antagonist, Antalarmin, would inhibit hypersensitivity in the WKY rat colon. Colonic sensitivity was determined by monitoring a visceromotor behavioural response during innocuous levels of colorectal distention (30 mmHg). In high anxiety WKY rats we found that Antalarmin (20 mg kg )1 , i.p.) significantly decreased the viscero- motor response induced by colorectal distention. In a second study central administration (i.c.v.) of CRF was used to induce colonic hypersensitivity in lower anxiety Fischer 344 (F-344) rats, and in this model, Antalarmin significantly inhibited the CRF-induced colonic hypersensitivity. In summary, a selective CRF1 receptor antagonist, Antalarmin, inhibits colonic hypersensitivity apparent in WKY rats or in F-344 rats given a central administration of CRF. Our findings suggest that CRF1 receptor antagonism may represent a novel therapeutic approach for the treat- ment of IBS.

  • oral administration of a corticotropin releasing hormone receptor antagonist significantly attenuates behavioral neuroendocrine and autonomic responses to stress in primates
    Proceedings of the National Academy of Sciences of the United States of America, 2000
    Co-Authors: Kamal E Habib, Kenner C Rice, Elizabeth L Webster, Jay Schulkin, Katherine P Weld, Judy Pushkas, Maribeth Champoux, Samuel J Listwak, Arthur J Atkinson, Carlo Contoreggi
    Abstract:

    We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist Antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant Antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, Antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, Antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.

John R. Mantsch - One of the best experts on this subject based on the ideXlab platform.

  • Augmented Cocaine Seeking in Response to Stress or CRF Delivered into the Ventral Tegmental Area Following Long- Access Self-Administration is Mediated by CRF-R1 but not CRF-
    2015
    Co-Authors: R Receptors, Jordan Blacktop Chad M. Seubert, John R. Mantsch
    Abstract:

    Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF-dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 hrs daily) conditions for 14 days when compared to rats provided shorter daily cocaine access (ShA rats; 2 hrs daily). Further, we have demonstrated that reinstatement in response to icv CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-R1 receptor antagonists Antalarmin (500 ng/side) or CP-376395 (500 ng/side) but not the CRF-R2 receptor antagonists astressin-2B (500 ng or 1 μg/side) or ASV-30 (500 ng/side) into the VTA. Likewise, intra-VTA Antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA Antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1 receptor-selective agonist, cortagine (100 ng/side) but not the CRF-R2 receptor-selective agonist rat urocortin II (250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1 receptor dependent regulation of addiction-related neurocircuitry in the VTA

  • Beta-2 adrenergic receptors mediate stress-evoked reinstatement of cocaine-induced conditioned place preference and increases in CRF mRNA in the bed nucleus of the stria terminalis in mice
    Psychopharmacology, 2014
    Co-Authors: Jayme R. Mcreynolds, Oliver Vranjkovic, Malia Thao, David A. Baker, Khadijah Makky, Yiwei Lim, John R. Mantsch
    Abstract:

    Rationale Understanding the mechanisms responsible for stress-induced relapse is important for guiding treatment strategies aimed at minimizing the contribution of stress to addiction. Evidence suggests that these mechanisms involve interactions between noradrenergic systems and the neuropeptide corticotropin-releasing factor (CRF). Objectives The interaction between β-adrenergic receptors (ARs) and CRF as it relates to the reinstatement of cocaine-conditioned reward in response to a stressor was examined in mice. We hypothesized that β_2-ARs are required for stress-induced activation of CRF pathways responsible for reinstatement. Methods Stress-induced relapse was examined based on the re-establishment of cocaine-induced conditioned place preference (CPP; 4 × 15 mg/kg cocaine, i.p.) after extinction using forced swim (6 min at 22 °C) or an injection of the β_2-AR agonist, clenbuterol (4 mg/kg, i.p.). The CRF-R1 antagonist Antalarmin (10 mg/kg, i.p.) or the β_2-AR antagonist ICI-118,551 (1 mg/kg, i.p.) were given 30 min prior to reinstating stimuli. Quantitative PCR was conducted in dissected bed nucleus of the stria terminalis (BNST) and amygdala, putative sources of CRF that contribute to reinstatement, to examine the effects of ICI-118,551 on swim-induced increases in CRF messenger RNA (mRNA) in mice with a cocaine history. Results Pretreatment with ICI-118,551 or Antalarmin blocked swim-induced reinstatement of CPP. Reinstatement by clenbuterol was also blocked by Antalarmin. ICI-118,551 pretreatment prevented swim-induced increases in CRF mRNA in the BNST. Effects in the amygdala were not observed. Conclusions These findings indicate that, during stress, norepinephrine, via β_2-ARs, either directly or indirectly activates CRF-releasing neurons in the BNST that interface with motivational neurocircuitry to induce reinstatement of cocaine-conditioned reward.

  • Beta-2 adrenergic receptors mediate stress-evoked reinstatement of cocaine-induced conditioned place preference and increases in CRF mRNA in the bed nucleus of the stria terminalis in mice.
    Psychopharmacology, 2014
    Co-Authors: Jayme R. Mcreynolds, Oliver Vranjkovic, Malia Thao, David A. Baker, Khadijah Makky, Yiwei Lim, John R. Mantsch
    Abstract:

    Understanding the mechanisms responsible for stress-induced relapse is important for guiding treatment strategies aimed at minimizing the contribution of stress to addiction. Evidence suggests that these mechanisms involve interactions between noradrenergic systems and the neuropeptide corticotropin-releasing factor (CRF). The interaction between β-adrenergic receptors (ARs) and CRF as it relates to the reinstatement of cocaine-conditioned reward in response to a stressor was examined in mice. We hypothesized that β2-ARs are required for stress-induced activation of CRF pathways responsible for reinstatement. Stress-induced relapse was examined based on the re-establishment of cocaine-induced conditioned place preference (CPP; 4 × 15 mg/kg cocaine, i.p.) after extinction using forced swim (6 min at 22 °C) or an injection of the β2-AR agonist, clenbuterol (4 mg/kg, i.p.). The CRF-R1 antagonist Antalarmin (10 mg/kg, i.p.) or the β2-AR antagonist ICI-118,551 (1 mg/kg, i.p.) were given 30 min prior to reinstating stimuli. Quantitative PCR was conducted in dissected bed nucleus of the stria terminalis (BNST) and amygdala, putative sources of CRF that contribute to reinstatement, to examine the effects of ICI-118,551 on swim-induced increases in CRF messenger RNA (mRNA) in mice with a cocaine history. Pretreatment with ICI-118,551 or Antalarmin blocked swim-induced reinstatement of CPP. Reinstatement by clenbuterol was also blocked by Antalarmin. ICI-118,551 pretreatment prevented swim-induced increases in CRF mRNA in the BNST. Effects in the amygdala were not observed. These findings indicate that, during stress, norepinephrine, via β2-ARs, either directly or indirectly activates CRF-releasing neurons in the BNST that interface with motivational neurocircuitry to induce reinstatement of cocaine-conditioned reward.

  • Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2.
    The Journal of Neuroscience, 2011
    Co-Authors: Jordan M. Blacktop, Chad Seubert, Nathan Ferda, Evan N. Graf, David Baker, John R. Mantsch
    Abstract:

    Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist Antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30 (ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA Antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA Antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA.

Jeffrey B Rosen - One of the best experts on this subject based on the ideXlab platform.

  • Corticotropin releasing factor type-1 receptor antagonism in the dorsolateral bed nucleus of the stria terminalis disrupts contextually conditioned fear, but not unconditioned fear to a predator odor
    Psychoneuroendocrinology, 2016
    Co-Authors: Arun Asok, Jay Schulkin, Jeffrey B Rosen
    Abstract:

    The bed nucleus of the stria terminalis (BNST) plays a critical role in fear and anxiety. The BNST is important for contextual fear learning, but the mechanisms regulating this function remain unclear. One candidate mechanism is corticotropin-releasing-factor (CRF) acting at CRF type 1 receptors (CRFr1s). Yet, there has been little progress in elucidating if CRFr1s in the BNST are involved in different types of fear (conditioned and/or unconditioned). Therefore, the present study investigated the effect of Antalarmin, a potent CRFr1 receptor antagonist, injected intracerebroventricularly (ICV) and into the dorsolateral BNST (LBNST) during single trial contextual fear conditioning or exposure to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). Neither ICV nor LBNST Antalarmin disrupted unconditioned freezing to TMT. In contrast, ICV and LBNST Antalarmin disrupted the retention of contextual fear when tested 24h later. Neither ICV nor LBNST Antalarmin affected baseline or post-shock freezing-indicating Antalarmin does not interfere with the early phases of contextual fear acquisition. Antalarmin did not (1) permanently affect the ability to learn and express contextual fear, (2) change responsivity to footshocks, or (3) affect the ability to freeze. Our findings highlight an important role for CRFr1s within the LBNST during contextually conditioned fear, but not unconditioned predator odor fear.