Corticotropin-releasing hormone (Crh) is a critical coordinator of the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, Crh released from the paraventricular nucleus (PVN) of the hypothalamus activates Crh receptors on anterior pituitary corticotropes, resulting in release of adrenocorticotropic hormone (Acth) into the bloodstream. Acth in turn activates Acth receptors in the adrenal cortex to increase synthesis and release of glucocorticoids. The receptors for Crh, Crhr1 and Crhr2, are found throughout the central nervous system and periphery. Crh has a higher affinity for Crhr1 than for Crhr2, and urocortin (Ucn), a Crh-related peptide, is thought to be the endogenous ligand for Crhr2 because it binds with almost 40-fold higher affinity than does Crh. Crhr1 and Crhr2 share approximately 71% amino acid sequence similarity and are distinct in their localization within the brain and peripheral tissues. We generated mice deficient for Crhr2 to determine the physiological role of this receptor. Crhr2-mutant mice are hypersensitive to stress and display increased anxiety-like behaviour. Mutant mice have normal basal feeding and weight gain, but decreased food intake following food deprivation. Intravenous Ucn produces no effect on mean arterial pressure in the mutant mice.

Corticotropin releasing factor (CRF) is a major integrator of adaptive responses to stress. Two biochemically and pharmacologically distinct CRF receptor subtypes (CRFR1 and CRFR2) have been described. We have generated mice null for the CRFR1 gene to elucidate the specific developmental and physiological roles of CRF receptor mediated pathways. Behavioral analyses revealed that mice lacking CRFR1 displayed markedly reduced anxiety. Mutant mice also failed to exhibit the characteristic hormonal response to stress due to a disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Homozygous mutant mice derived from crossing heterozygotes displayed low plasma corticosterone concentrations resulting from a marked agenesis of the zona fasciculata region of the adrenal gland. The offspring from homozygote crosses died within 48 hr after birth due to a pronounced lung dysplasia. The adrenal agenesis in mutant animals was attributed to insufficient adrenocorticotropic hormone (ACTH) production during the neonatal period and was rescued by ACTH replacement. These results suggest that CRFR1 plays an important role both in the development of a functional HPA axis and in mediating behavioral changes associated with anxiety.

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Corticotropin-releasing factor (CRF) and its family of peptides are critical coordinators of homeostasis whose actions are mediated through their receptors, CRF receptor 1 (CRFR1) and CRFR2, found throughout the CNS and periphery. The phenotypes of mice deficient in either CRFR1 or CRFR2 demonstrate the critical role these receptors play. CRFR1-mutant mice have an impaired stress response and display decreased anxiety-like behavior, whereas CRFR2-mutant mice are hypersensitive to stress and display increased anxiety-like behavior. To further elucidate the roles of both CRF receptors and determine their interaction in behaviors, we have generated mice deficient in both CRFR1 and CRFR2. The behavioral phenotype of these mice demonstrates a novel role of the mother's genotype on development of pup anxiety. We have found that although the female double-mutant mice display anxiolytic-like behavior, the male double-mutant mice show significantly more anxiety-like behavior compared with the females. We have also determined that the dam's CRFR2 genotype affects the anxiety-like behavior of the male mice, such that a pup born to a heterozygous or mutant dam displays significantly more anxiety-like behavior regardless of that pup's genotype. Double-mutant mice also display an even greater impairment of their hypothalamic-pituitary-adrenal axis response to stress than that of the CRFR1-mutant mice. CRF mRNA levels are elevated in CRFR1-and double-mutant mice, and urocortin III and vasopressin mRNA levels are increased in CRFR2-and double-mutant mice. These results indicate that both CRFR1 and CRFR2 have critical roles in gene regulation and the maintenance of homeostasis in response to stress.

Urocortin is a member of the corticotropin-releasing hormone peptide family and is found in many discrete brain regions. The distinct expression pattern of urocortin suggests that it influences such behaviors as feeding, anxiety and auditory processing. To better define the physiological roles of urocortin, we have generated mice carrying a null mutation of the urocortin gene. Urocortin-deficient mice have normal basal feeding behavior and stress responses, but show heightened anxiety-like behaviors in the elevated plus maze and open-field tests. In addition, hearing is impaired in the mutant mice at the level of the inner ear, suggesting that urocortin is involved in the normal development of cochlear sensory-cell function. These results provide the first example of a function for any peptidergic system in hearing.

The negative affective symptoms of opiate withdrawal powerfully motivate drug-seeking behavior and may trigger relapse to heroin abuse. To date, no medications exist that effectively relieve the negative affective symptoms of opiate withdrawal. The corticotropin-releasing factor (CRF) system has been hypothesized to mediate the motivational effects of drug dependence. The CRF signal is transmitted by two distinct receptors named CRF receptor-1 (CRF 1) and CRF2. eroin addiction is one of the most common and serious substance-related disorders (1). In addicted individuals, heroin ''highs'' are inexorably followed by a severe opiate withdrawal syndrome composed of somatic signs and negative affective states, such as dysphoria and depressed mood (2). The negative affective states of opiate withdrawal dramatically motivate compulsive heroin-seeking behavior and opiate abuse (3, 4). However, available treatments do not effectively relieve the negative affective symptoms of opiate withdrawal, thus leaving opiate addicts vulnerable to relapse to heroin.The corticotropin-releasing factor (CRF) system might mediate the motivational effects of drug dependence. Functional antagonism of CRF neurotransmission reduces stress-induced reinstatement of drug-seeking behavior and may attenuate anxiety-like and affective states associated with drug withdrawal (5). The latter findings point to the CRF system as a potential therapeutic target for treating the negative affective consequences of drug addiction. However, recent studies showing opposite functions for the two known CRF receptor pathways, CRF receptor-1 (CRF 1 ) and CRF 2 , in anxiety-like and depression-like behaviors indicate a complex role for the CRF system in affect regulation (6-11). Elements in the CRF circuitry might also differentially contribute to the negative affective states of drug withdrawal. However, the specific role for the different components of the CRF system in drug withdrawal-induced negative affect is still unknown.Mutant mice bearing targeted mutations of the CRF system are unique tools to elucidate the role of CRF in drug dependence and withdrawal. Here we used genetically engineered mice lacking functional CRF 1 receptor levels to study the role for CRF͞CRF 1 receptor pathways in the negative affective states of opiate withdrawal (6). Moreover, in keeping with the clinical setting where signs and symptoms of opiate withdrawal ''spontaneously'' and gradually rise along with the drug removal from the body, behavioral and molecular studies reported here were conducted in mice undergoing spontaneous opiate withdrawal. In contrast, previous studies that have examined the role of CRF in the somatic and aversive effects of opiate withdrawal have all used opioid receptor antagonist-precipitated opiate withdrawal procedures (12-16). However, high-affinity competitive opioid receptor antagonists ''precipitate'' behavioral, endocrine, and molecular patterns that greatly differ from those observed upon spontaneous opiate withdrawal (17-20), thus making questi...

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