[Show abstract][Hide abstract] ABSTRACT: Exposure to stressors promotes ethanol (EtOH) consumption and enhances drug craving during abstinence. Corticotropin-releasing factor (CRF), and in particular, CRF actions via type 1 CRF receptors (CRF(1)) are critical in behavioral responses to stressors. CRF(1) play a role in EtOH-induced behavioral neuroadaptation, in binge-like EtOH consumption, and in heightened EtOH consumption in dependent animals.
We investigated the involvement of CRF(1) in swim-stress-induced changes in EtOH consumption and in baseline consumption as a function of EtOH concentration. The role of CRF(2) in adapting to effects of the stressor was also examined.
Wild-type mice and knockout mice lacking CRF(1) were tested for two-bottle choice EtOH consumption at concentrations of 3-20%. Also, intake of 10% EtOH was examined in wild-type mice and knockout mice lacking CRF(1), or lacking both CRF(1) and CRF(2), before and after acute or repeated swim stress exposures.
EtOH intake was reduced in CRF(1) compared with wild-type mice when presented at a concentration of 20% but not when presented at lower concentrations. No genotype-dependent effects were found for saccharin or quinine drinking. Acute swim stress had no effect, but repeated swim stress resulted in higher levels of EtOH consumption in wild-type mice, compared with both types of knockout mice. Stress effects on EtOH drinking were longer lasting in double knockout mice.
These data suggest a prominent role of CRF(1) in stressor-induced changes in EtOH consumption, with involvement of CRF(2) in recovery from stressor effects.
[Show abstract][Hide abstract] ABSTRACT: Developmental stressors are consistently reported to increase risk for certain neuropsychiatric disorders including schizophrenia, depression, and post-traumatic stress disorder. Recent clinical evidence supports a "double-hit" hypothesis of genetic vulnerability interacting with developmental challenges to modulate this risk. Early life stressor effects on behavior may be modulated in part by alterations in corticotropin releasing factor (CRF) signaling via two known receptors, CRF(1) and CRF(2). One extant hypothesis is that CRF(2) activation may modulate long-term adaptive responses after homeostatic challenge. As such, loss of CRF(2) activity via genetic variance may increase sensitivity to the long-term effects of developmental stress.
We tested the hypothesis that CRF(2) function may mitigate the behavioral effects of isolation rearing, predicting that loss of CRF(2) function increases sensitivity to this developmental challenge. Using the behavioral pattern monitor (BPM), we examined exploratory behavior and locomotor patterns in adult CRF(2) wild-type (WT) and gene knockout (KO) mice reared socially or in isolation.
Isolation housing produced robust increases in the amount of locomotor activity and investigatory holepoking, and altered the temporal distribution of activity in CRF(2) KO but not CRF(2) WT mice. Isolation housing significantly increased rearing behavior and altered spatial patterns of locomotor activity regardless of genotype.
Loss of CRF(2) function increased sensitivity to the effects of chronic social isolation on exploratory locomotor behavior. Thus, CRF(2) activation appears to mitigate isolation rearing effects on exploratory behavior. Further research assessing the interaction between CRF(2) function and developmental challenges is warranted.
[Show abstract][Hide abstract] ABSTRACT: Post-weaning social isolation of rodents is used to model developmental stressors linked to neuropsychiatric disorders including schizophrenia as well as anxiety and mood disorders. Isolation rearing produces alterations in emotional memory and hippocampal neuropathology. Corticotropin releasing factor (CRF) signaling has recently been shown to be involved in behavioral effects of isolation rearing. Activation of the CRF(2) receptor is linked to stress-induced alterations in fear learning and may also be involved in long-term adaptation to stress. Here we tested the hypothesis that CRF(2) contributes to isolation rearing effects on emotional memory. At weaning, mice were housed either in groups of three or individually in standard mouse cages. In adulthood, isolation-reared mice exhibited significant reductions in context-specific, but not cue-specific, freezing. Isolation-reared mice exhibited no significant changes in locomotor exploration during brief exposure to a novel environment, suggesting that the reduced freezing in response to context cues was not due to activity confounds. Isolation rearing also disrupted context fear memory in mice with a CRF(2) gene null mutation, indicating that the CRF(2) receptor is not required for isolation effects on fear memory. Thus, isolation rearing disrupts hippocampal-dependent fear learning as indicated by consistent reductions in context-conditioned freezing in two separate cohorts of mice, and these effects are via a CRF(2)-independent mechanism. These findings may be clinically relevant because they suggest that isolation rearing in mice may be a useful model of developmental perturbations linked to disruptions in emotional memory in a variety of neuropsychiatric disorders.
Behavioural brain research 05/2010; 209(1):80-4. · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Corticotropin-releasing factor (CRF) peptides and their receptors have crucial roles in behavioral and endocrine responses to stress. Dysregulation of CRF signaling has been linked to post-traumatic stress disorder, which is associated with increased startle reactivity in response to threat. Thus, understanding the mechanisms underlying CRF regulation of startle may identify pathways involved in this disorder. Here, we tested the hypothesis that both CRF1 and CRF2 receptors contribute to fear-induced increases in startle. Startle responses of wild type (WT) and mice with null mutations (knockout, KO) for CRF1 or CRF2 receptor genes were measured immediately after footshock (shock sensitization) or in the presence of cues previously associated with footshock (ie fear-potentiated startle, FPS). WT mice exhibited robust increases in startle immediately after footshock, which was dependent upon contextual cues. This effect was completely absent in CRF1 KO mice, and significantly attenuated in CRF2 KO mice. In contrast, CRF1 and CRF2 KO mice exhibited normal potentiation of startle by discrete conditioned cues. Blockade of both receptors via CRF1 receptor antagonist treatment in CRF2 KO mice also had no effect on FPS. These results support an additive model of CRF1 and CRF2 receptor activation effects on potentiated startle. These data also indicate that both CRF receptor subtypes contribute to contextual fear but are not required for discrete cued fear effects on startle reactivity. Thus, we suggest that either CRF1 or CRF2 could contribute to the increased startle observed in anxiety disorders with CRF system abnormalities.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2008; 34(6):1494-503. · 8.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A common expression of neuroadaptations induced by repeated exposure to addictive drugs is a persistent sensitized behavioral response to their stimulant properties. Neuroplasticity underlying drug-induced sensitization has been proposed to explain compulsive drug pursuit and consumption characteristic of addiction. The hypothalamic-pituitary-adrenal (HPA) axis-activating neuropeptide, corticotropin-releasing factor (CRF), may be the keystone in drug-induced neuroadaptation. Corticosterone-activated glucocorticoid receptors (GRs) mediate the development of sensitization to ethanol (EtOH), implicating the HPA axis in this process. EtOH-induced increases in corticosterone require CRF activation of CRF1 receptors. We posited that CRF1 signaling pathways are crucial for EtOH-induced sensitization. We demonstrate that mice lacking CRF1 receptors do not show psychomotor sensitization to EtOH, a phenomenon that was also absent in CRF1 + 2 receptor double-knockout mice. Deletion of CRF2 receptors alone did not prevent sensitization. A blunted endocrine response to EtOH was found only in the genotypes showing no sensitization. The CRF1 receptor antagonist CP-154,526 attenuated the acquisition and prevented the expression of EtOH-induced psychomotor sensitization. Because CRF1 receptors are also activated by urocortin-1 (Ucn1), we tested Ucn1 knockout mice for EtOH sensitization and found normal sensitization in this genotype. Finally, we show that the GR antagonist mifepristone does not block the expression of EtOH sensitization. CRF and CRF1 receptors, therefore, are involved in the neurobiological adaptations that underlie the development and expression of psychomotor sensitization to EtOH. A CRF/CRF1-mediated mechanism involving the HPA axis is proposed for acquisition, whereas an extrahypothalamic CRF/CRF1 participation is suggested for expression of sensitization to EtOH.
Proceedings of the National Academy of Sciences 08/2008; 105(26):9070-5. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-alpha (TNFalpha) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFalpha in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFalpha are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFalpha before middle cerebral artery occlusion in mice and show that TNFalpha is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFalpha are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFalpha (approximately threefold) and the proximal TNFalpha signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (approximately 2.5-fold), which may neutralize the effect of TNFalpha and reduce TNFalpha-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFalpha after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFalpha in the setting of ischemia. Our studies suggest that TNFalpha is a twin-edged sword in the setting of stroke: TNFalpha upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFalpha signaling during ischemia confers neuroprotection after LPS preconditioning.
[Show abstract][Hide abstract] ABSTRACT: Acute stress affects gut functions through the activation of corticotropin-releasing factor (CRF) receptors. The impact of acute stress on pelvic viscera in the context of chronic stress is not well characterized. We investigated the colonic, urinary, and locomotor responses monitored as fecal pellet output (FPO), urine voiding, and ambulatory activity, respectively, in female and male CRF-overexpressing (CRF-OE) mice, a chronic stress model, and their wild-type littermates (WTL). Female CRF-OE mice, compared with WTL, had enhanced FPO to 2-min handling (150%) and 60-min novel environment (155%) but displayed a similar response to a 60-min partial restraint stress. Female CRF-OE mice, compared with WTL, also had a significantly increased number of urine spots (7.3 +/- 1.4 vs. 1.3 +/- 0.8 spots/h) and lower locomotor activity (246.8 +/- 47.8 vs. 388.2 +/- 31.9 entries/h) to a novel environment. Male CRF-OE mice and WTL both responded to a novel environment but failed to show differences between them in colonic and locomotor responses. Male WTL, compared with female WTL, had higher FPO (113%). In female CRF-OE mice, the CRF(1)/CRF(2) receptor antagonist astressin B and the selective CRF(2) receptor agonist mouse urocortin 2 (injected peripherally) prevented the enhanced defecation without affecting urine or locomotor responses to novel environment. RT-PCR showed that CRF(1) and CRF(2) receptors are expressed in the mouse colonic tissues. The data show that chronic stress, due to continuous central CRF overdrive, renders female CRF-OE mice to have enhanced pelvic and altered behavioral responses to superimposed mild stressors and that CRF(1)-initiated colonic response is counteracted by selective activation of CRF(2) receptor.
[Show abstract][Hide abstract] ABSTRACT: Two cognate receptors (CRF(1) and CRF(2)) mediate the actions of the stress-regulatory corticotropin-releasing factor (CRF) family of peptides. Defining the respective roles of these receptors in the central nervous system is critical in understanding stress neural circuitry and the development of psychiatric disorders. Here, we examined the role of CRF(2) in several paradigms that assess coping responses to stress. We report that CRF(2) knockout mice responded to a novel setting with increased aggressive behavior toward a bulbectomized conspecific male and show increased immobility during acute swim stress compared with wild-type mice. In addition, CRF(2)-deficient mice exhibited impaired adaptation to isolation stress as evinced by prolonged hypophagia and associated weight loss. Collectively, these results point toward a role for CRF(2) pathways in neural circuits that subserve stress-coping behaviors.
Genes Brain and Behavior 04/2006; 5(2):131-8. · 3.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite important health benefits, the presence of depressive symptoms may decrease the prevalence of breastfeeding. The current study assessed the relationship between depressive symptoms and breastfeeding at 6 and 12 weeks postpartum. Participants were recruited from a cohort completing a clinical trial of calcium for prevention of preeclampsia. At 6 weeks postpartum, the Edinburgh Postnatal Depression Scale (EPDS) was completed by mail. At 12 weeks postpartum, the EPDS was completed at an outpatient visit. There was an inverse relationship between depressive symptoms and breastfeeding at 6 weeks postpartum (P<.001) but not at 12 weeks. This relationship persisted even after controlling for prior history of depression, increased life stress, and current psychoactive medication. The results suggest that depressive symptoms early in the postpartum period may lower the prevalence of breastfeeding.
Journal of Human Lactation 12/2005; 21(4):444-9; quiz 450-4. · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stress is believed to influence alcohol use and relapse in alcoholics. Animal studies suggest an interaction between corticotropin-releasing factor (CRF) and its receptors and the behavioral effects and consumption of alcohol. The objective of these studies was to examine the effect of corticotropin-releasing factor receptor type 2 (CRF2) on ethanol consumption, conditioned taste aversion, sedation, and hypothermia.
CRF2-null mutant or knock-out (KO), and wild-type (WT) mice were used to assess consumption of increasing concentrations of ethanol in a two-bottle, 24-hr test and during daily limited-access sessions. Ethanol-induced conditioned taste aversion (CTA), loss of righting reflex (LORR), hypothermia, and ethanol metabolism kinetics were also examined in the CRF2 KO and WT mice.
CRF2 KO mice did not differ from WT mice in sensitivity to ethanol-induced CTA, LORR, hypothermia, or ethanol metabolism kinetics. There was no genotypic difference in ethanol intake or preference in the 24-hr, two-bottle choice procedure, and only modestly increased [corrected] consumption of the 7.5 and 10% ethanol solutions in KO versus WT mice in the limited-access procedure.
CRF2 deficiency had little effect on several ethanol-associated behaviors in CRF2-null mutant compared with WT mice, suggesting that this receptor does not have a primary role in modulating these behaviors. Evidence of a role for this receptor in neural circuits subserving stress-coping behaviors suggest that future studies should focus on the role of endogenous CRF2 in ethanol-associated behaviors in mice that are stressed or withdrawing from dependence on ethanol.
Alcoholism Clinical and Experimental Research 10/2005; 29(9):1601-9. · 3.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The corticotropin-releasing factor (CRF) family constitutes a primary system that mediates adaptive neuroendocrine, autonomic, and behavioral responses to stress, a process known as allostasis. Genetically engineered mice provide a powerful tool for dissection of corticotropin pathways. A collection of models have been generated that harbor specific alterations in ligands, receptors, and the binding protein. In this review, we describe prominent neuroendocrine and behavioral features of these genetic mouse models that have led to new insights of allostatic regulation and associated pathology.
Techniques in the Behavioral and Neural Sciences 01/2005; 15:51-74.
[Show abstract][Hide abstract] ABSTRACT: Corticotropin-releasing factor (CRF) may play a significant role in drug and alcohol abuse.
To evaluate the role of CRF in these processes, we examined several ethanol (EtOH) related behaviors in mice that carry a transgene that causes overexpression of CRF.
We examined voluntary EtOH drinking, loss of the righting reflex (LORR), EtOH-induced conditioned taste aversion (CTA), and EtOH clearance in littermate transgenic (TG) and non-transgenic (non-TG) mice. In addition, because preliminary results indicated that age exacerbated differences in EtOH consumption between the two genotypes, we performed a cross-sectional and longitudinal evaluation of this trait at two ages ( approximately 100 and 200 days old).
We found that TG mice consumed significantly less EtOH and had a lower preference for EtOH-containing solutions compared with their non-TG littermates. We also found that the older drug-naive TG mice drank less EtOH as compared with the younger mice of the same genotype; however, the same relationship did not exist for drug-naive non-TG mice. Prior experience in drinking EtOH when 100 days old led to decreased EtOH drinking when 200 days old in both genotypes. Duration of LORR was longer in the TG mice, EtOH-induced CTA was marginally greater in non-TG mice at the highest dose tested, and there were significant but small differences in EtOH clearance parameters.
These data show that CRF overexpressing mice voluntarily consume less EtOH. This difference is associated with greater sensitivity to the sedative-hypnotic effects of EtOH, but not with increased sensitivity to the aversive effects of EtOH.
[Show abstract][Hide abstract] ABSTRACT: Two receptors activated by the corticotropin-releasing factor (CRF) family of peptides have been identified, the CRF 1 receptor (CRF1R) and the CRF 2 receptor (CRF2R). Of these, the CRF2R is expressed in skeletal muscle. To understand the role of the CRF2R in skeletal muscle, we utilized CRFR knockout mice and CRF2R-selective agonists to modulate nerve damage and corticosteroid- and disuse-induced skeletal muscle atrophy in mice. These analyses demonstrated that activation of the CRF2R decreased nerve damage and corticosteroid- and disuse-induced skeletal muscle mass and function loss. In addition, selective activation of the CRF2R increased nonatrophy skeletal muscle mass. Thus we describe for the first time a novel activity of the CRF2R, modulation of skeletal muscle mass.
AJP Endocrinology and Metabolism 11/2003; 285(4):E889-98. · 4.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current study examined the relationship between calcium supplementation during pregnancy and blood pressure (BP) in the mother and offspring at 3 months and at 2 years postpartum.
Nulliparous pregnant women were assigned to either receive 2 g of calcium or placebo daily beginning between weeks 13 to 21 of gestation and continuing until delivery. Blood pressure was measured in children and their mothers at 3 months (n = 260) and (n = 57) at 2 years postpartum. Systolic BP was measured in the infants using a sphygmomanometer with ultrasonic amplification. For the toddlers, three supine BP measurements were taken from the right arm using a Critikon automated sphygmomanometer just after measurement of left ventricular wall thickness.
Systolic BP in the calcium-supplemented infants was 2.2 mm Hg lower than in the placebo group (P >.05). At 2 years of age, systolic BP was 4.8 mm Hg lower in the calcium supplemented group (P <.05), whereas diastolic BP was 3 mm Hg lower (P >.05). There was no difference in left ventricular mass index between groups, although there was a significant correlation between systolic BP and wall thickness (P <.05). Maternal BP was positively correlated with circulating 1,25(OH)(2)D3 (P <.001) but did not differ between calcium groups at 3 months postpartum.
The data on BP in the children are in agreement with previous studies and argue strongly for additional research into the effects of prenatal calcium supplementation on BP regulation in the offspring.
American Journal of Hypertension 10/2003; 16(10):801-5. · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since its discovery 2 decades ago, potent effects of corticotropin-releasing hormone (CRH) on the heart and vasculature have been consistently observed. The recent discoveries of novel CRH-related peptides residing in the heart and a distinct cardiac CRH receptor (CRH-R2), have renewed interest in the role of the CRH family on cardiovascular function. This review highlights the emerging view of a peripheral, cardiac CRH system and its potential relevance in mediating the adaptive response of the heart to stress.
Trends in Cardiovascular Medicine 06/2002; 12(4):176-82. · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the influence of dietary calcium on spaceflight-induced alterations in calcium metabolism and blood pressure (BP), 9-wk-old spontaneously hypertensive rats, fed either high- (2%) or low-calcium (0.02%) diets, were flown on an 18-day shuttle flight. On landing, flight animals had increased ionized calcium (P < 0.001), elevated parathyroid hormone levels (P < 0.001), reduced calcitonin levels (P < 0.05), unchanged 1,25(OH)(2)D(3) levels, and elevated skull (P < 0.01) and reduced femur bone mineral density. Basal and thrombin-stimulated platelet free calcium (intracellular calcium concentration) were also reduced (P < 0.05). There was a tendency for indirect systolic BP to be reduced in conscious flight animals (P = 0.057). However, mean arterial pressure was elevated (P < 0.001) after anesthesia. Dietary calcium altered all aspects of calcium metabolism (P < 0.001), as well as BP (P < 0.001), but the only interaction with flight was a relatively greater increase in ionized calcium in flight animals fed low- compared with high-calcium diets (P < 0.05). The results indicate that 1) flight-induced disruptions of calcium metabolism are relatively impervious to dietary calcium in the short term, 2) increased ionized calcium did not normalize low-calcium-induced elevations of BP, and 3) parathyroid hormone was paradoxically increased in the high-calcium-fed flight animals after landing.
Journal of Applied Physiology 02/2002; 92(1):3-12. · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ground studies indicate that spaceflight may diminish vascular contraction. To examine that possibility, vascular function was measured in spontaneously hypertensive rats immediately after an 18-day shuttle flight. Isolated mesenteric resistance arterial responses to cumulative additions of norepinephrine, acetylcholine, and sodium nitroprusside were measured using wire myography within 17 h of landing. After flight, maximal contraction to norepinephrine was attenuated (P < 0.001) as was relaxation to acetylcholine (P < 0.001) and sodium nitroprusside (P < 0.05). At high concentrations, acetylcholine caused vascular contraction in vessels from flight animals but not in vessels from vivarium control animals (P < 0.05). The results are consistent with data from ground studies and indicate that spaceflight causes both endothelial-dependent and endothelial-independent alterations in vascular function. The resulting decrement in vascular function may contribute to orthostatic intolerance after spaceflight.
Journal of Applied Physiology 02/2002; 92(1):13-7. · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since its discovery 2 decades ago, potent effects of corticotropin-releasing hormone (CRH) on the heart and vasculature have been consistently observed. The recent discoveries of novel CRH-related peptides residing in the heart and a distinct cardiac CRH receptor (CRH-R2), have renewed interest in the role of the CRH family on cardiovascular function. This review highlights the emerging view of a peripheral, cardiac CRH system and its potential relevance in mediating the adaptive response of the heart to stress. (Trends Cardiovascular Med 2002;12:176–182).
Trends in Cardiovascular Medicine - TREND CARDIOVASC MED. 01/2002; 12(4):176-182.
[Show abstract][Hide abstract] ABSTRACT: Two receptors (CRH receptor type 1 and CRH receptor type 2) have been identified for the stress-induced neuropeptide, CRH and related peptides, urocortin, and urocortin II. We previously found marked down-regulation of cardiac CRH receptor type 2 expression following administration of bacterial endotoxin, lipopolysaccharide, a model of systemic immune activation, and inflammation. We postulated that inflammatory cytokines may regulate CRH receptor type 2. We show that systemic IL-1alpha administration significantly down-regulates CRH receptor type 2 mRNA in mouse heart. In addition, TNFalpha treatment also reduces CRH receptor type 2 mRNA expression, although the effect was not as marked as with IL-1alpha. However, CRH receptor type 2 mRNA expression is not altered in adult mouse ventricular cardiomyocytes stimulated in vitro with TNFalpha or IL-1alpha. Thus, cytokine regulation may be indirect. Exogenous administration of corticosterone in vivo or acute restraint stress also reduces cardiac CRH receptor type 2 mRNA expression, but like cytokines, in vitro corticosterone treatment does not modulate expression in cardiomyocytes. Interestingly, treatment with urocortin significantly decreases CRH receptor type 2 mRNA in cultured cardiomyocytes. We speculate that in vivo, inflammatory mediators such as lipopolysaccharide and/or cytokines may increase urocortin, which in turn down-regulates CRH receptor type 2 expression in the heart. Because CRH and urocortin increase cardiac contractility and coronary blood flow, impaired CRH receptor type 2 function during systemic inflammation may ultimately diminish the adaptive cardiac response to adverse conditions.
[Show abstract][Hide abstract] ABSTRACT: Two receptors (CRH receptor type 1 and CRH receptor type 2) have been identified for the stress-induced neuropeptide, CRH and related peptides, urocortin, and urocortin II. We previously found marked down-regulation of cardiac CRH receptor type 2 expression following administration of bacterial endotoxin, li- popolysaccharide, a model of systemic immune activation, and inflammation. We postulated that inflammatory cytokines may regulate CRH receptor type 2. We show that systemic IL-1a ad- ministration significantly down-regulates CRH receptor type 2 mRNA in mouse heart. In addition, TNFa treatment also reduces CRH receptor type 2 mRNA expression, although the effect was not as marked as with IL-1a. However, CRH receptor type 2 mRNA expression is not altered in adult mouse ventricular car- diomyocytes stimulated in vitro with TNFa or IL-1a. Thus, cy- tokine regulation may be indirect. Exogenous administration of corticosterone in vivo or acute restraint stress also reduces car- diac CRH receptor type 2 mRNA expression, but like cytokines, in vitro corticosterone treatment does not modulate expression in cardiomyocytes. Interestingly, treatment with urocortin sig- nificantly decreases CRH receptor type 2 mRNA in cultured cardiomyocytes. We speculate that in vivo, inflammatory medi- ators such as lipopolysaccharide and/or cytokines may increase urocortin, which in turn down-regulates CRH receptor type 2 expression in the heart. Because CRH and urocortin increase cardiac contractility and coronary blood flow, impaired CRH receptor type 2 function during systemic inflammation may ul- timately diminish the adaptive cardiac response to adverse conditions. (Endocrinology 142: 3537-3545, 2001)