The CRF1 receptor antagonist, R121919, attenuates the severity of precipitated morphine withdrawal.

Corticotropin-releasing factor (CRF) regulates the hypothalamic-pituitary-adrenal axis, coordinates the mammalian stress response, and acting primarily via the CRF(1) receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, the behavioral and autonomic activation that occurs following withdrawal in drug dependent animals resembles the mammalian stress response. Concordant with this view is evidence of enhanced CRF transcription, release and activity following withdrawal from several drugs of abuse. Conversely, CRF receptor antagonists have been demonstrated to reduce the severity of many drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed during withdrawal. To extend these findings, we investigated whether pretreatment with a selective CRF(1) receptor antagonist, R121919, is capable of similarly decreasing the autonomic, behavioral and neuroendocrine activation observed following precipitation of morphine withdrawal in dependent rats. The results indicate that pretreatment with R121919 attenuates the global severity of the precipitated morphine withdrawal syndrome as measured by the Gellert-Holtzman scale. In addition, rats pretreated with R121919 prior to precipitation of morphine withdrawal demonstrated decreased hypothalamic-pituitary-adrenal axis activation, as measured by plasma ACTH concentrations, and decreased early expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA. These findings suggest that activation of CRF neuronal systems via the CRF(1) receptor may be one element of the neurobiological mechanisms activated during drug withdrawal and that CRF(1) receptor antagonists may have a potential therapeutic role in the treatment of human drug withdrawal syndromes.

The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal.

RATIONALE: Corticotropin-releasing factor (CRF) is the primary physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to globally coordinate the mammalian stress response. Hyperactivity of central nervous system CRF neurotransmission, acting primarily via the CRF(1) receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, there is evidence of enhanced CRF transcription, release, and neuronal activity after the administration of and withdrawal from several drugs of abuse, including cannabis, cocaine, ethanol, and morphine. Treatment with CRF antagonists has been demonstrated to reduce the severity of certain drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed after abrupt drug discontinuation. OBJECTIVES/METHODS: To extend these findings, we investigated whether pretreatment with the selective CRF(1) receptor antagonist R121919 decreases the behavioral and neuroendocrine activation observed after the precipitation of benzodiazepine (BZ) withdrawal in BZ-dependent rats. RESULTS: Pretreatment with R121919 attenuated the subsequent HPA axis activation, behavioral measures of anxiety, and expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA, which occurs after flumazenil-precipitation of withdrawal from the BZ, lorazepam. CONCLUSIONS: These results indicate that the activation of CRF neuronal systems may be a common neurobiological mechanism in withdrawal from drugs of abuse and moreover, that the CRF(1) receptor subtype plays a major role in mediating the effects of CRF on neuroendocrine and behavioral responses during BZ withdrawal. Therefore, CRF(1) receptor antagonists may be of therapeutic utility in the treatment of drug withdrawal syndromes.

Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression.

Corticotropin-releasing factor (CRF) is the major physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and plays a key role in coordinating the mammalian stress response. Substantial data implicates hyperactivity of CRF neuronal systems in the pathophysiology of depression and anxiety disorders. Enhanced CRF expression, release, and function have also been demonstrated during acute withdrawal from several drugs of abuse. Previous studies revealed that chronic administration of the anxiolytic alprazolam reduced indices of CRF and CRF1 receptor function. Conversely, measures of urocortin I and CRF2 receptor function were increased. To further scrutinize these findings, we sought to determine whether CRF neuronal systems are activated during spontaneous withdrawal from the triazolobenzodiazepine alprazolam in dependent rats and to characterize the time course, extent, and regional specificity of the patterns of activation. After 14 d of alprazolam administration (90 mg x kg(-1) x d(-1)), spontaneous withdrawal produced activation of the HPA axis, as well as suppression of food intake and weight loss that peaked 24-48 hr after withdrawal. Remarkably, CRF mRNA expression in the cerebral cortex was markedly (>300%) increased over the same time period. Other indices of CRF-CRF1 and urocortin I-CRF2A function, altered by chronic alprazolam treatment as previously described, returned to pretreatment levels over 96 hr. The physiologic significance of this dramatic induction of cortical CRF mRNA expression, as well as whether this occurs during withdrawal from other drugs of abuse is yet to be determined. The marked increase in CRFergic neurotransmission is hypothesized to play a major role in benzodiazepine withdrawal.

The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems.

Corticotropin-releasing factor (CRF) plays a preeminent role in coordinating the endocrine, autonomic, and behavioral responses to stress. Dysregulation of both hypothalamic and extrahypothalamic CRF systems have been reported in patients with major depression and post-traumatic stress disorder. Moreover, effective treatment of these conditions leads to normalization of these CRF systems. Although there is virtually no data concerning alterations of CRF systems in bipolar disorder (manic depressive illness), previous work indicates that valproic acid, an anticonvulsant also effective in the treatment of acute mania, alters central CRF neuronal systems. In the current studies, we chronically administered valproic acid and lithium, two clinically effective mood stabilizers, in nonstressed rats to extend our previous findings. Chronic valproic acid administration decreased CRF mRNA expression in the paraventricular nucleus of the hypothalamus; lithium administration increased CRF mRNA expression in the central nucleus of the amygdala. Although valproic acid increased CRF(1) receptor mRNA expression in the cortex, CRF(1) receptor binding was decreased in both the basolateral amygdala and cortex, suggesting that chronic valproate treatment may in fact dampen the overall tone in this central stress pathway. Valproate treatment decreased CRF(2A) mRNA expression in both the lateral septum and hypothalamus, although CRF(2A) receptor binding was unchanged. Lithium administration decreased CRF(1) mRNA expression in both the amygdala and frontal cortex, but CRF(1) receptor binding also remained unchanged. These results suggest that the therapeutic actions of these mood stabilizers may, in part, result from their actions on central CRF neuronal systems. The distinct actions of each drug on CRF systems may underlie their synergistic clinical effects.

The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress.

Corticotropin-releasing factor (CRF) is the major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to coordinate the mammalian endocrine, autonomic, and behavioral responses to stress. Considerable literature from clinical and preclinical data suggests that hypersecretion of hypothalamic and/or extrahypothalamic CRF systems is a major factor in the pathogenesis of affective and anxiety disorders. Based on this premise, a CRF(1) receptor antagonist has been hypothesized to possess anxiolytic and/or antidepressant properties. In this study, an acute dose of the lipophilic CRF(1) receptor antagonist 3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine (R121919), administered i.v. to rats with surgically implanted jugular cannula 60 min before a 5-min restraint stress, dose dependently attenuated peak plasma adrenocorticopin hormone (ACTH) and corticosterone concentrations by 91 and 75%, respectively. In a second study, acute administration of R121919 reduced measures of anxiety in a rodent defensive withdrawal paradigm. R121919 dose dependently decreased latency to exit the tube, and total time spent in the tube 60 min after a single subcutaneous administration. In addition, the ACTH and corticosterone response to novelty was decreased by 82 and 97%, respectively, at the 10-mg/kg dose of R121919. In another study, this dose was associated with approximately an 85% occupancy of the CRF(1) receptor in the cortex measured 75-min postsubcutaneous injection. These data confirm that R121919 acts as a CRF(1) receptor antagonist in vivo, attenuates HPA axis responsivity, and possesses anxiolytic properties.

Are CRF receptor antagonists potential antidepressants?

Corticotropin-releasing factor (CRF) is the major regulator of the hypothalamic-pituitary-adrenal (HPA) axis, and plays a key role in coordinating the endocrine, as well as autonomic and behavioral responses of an organism to stress. Direct CNS administration of CRF to laboratory animals produces an aggregate of effects that mimic the mammalian stress response. Impeding CRF function with CNS administration of a peptidergic CRF antagonist can block these manifestations of the stress response whether produced by exogenous CRF or occurring naturally in response to a stressor. A role for hypersecretion of CRF in the pathophysiology of depression is suggested by the finding that CNS administration of CRF mirrors many of the signs and symptoms utilized as diagnostic criteria for major depression. In addition, a large body of clinical evidence points to excess hypothalamic secretion of CRF and an accompanying HPA axis hyperactivity in patients with major depression. The recent development of selective, small molecule CRF(1) receptor antagonists, which block the effects of CRF both in vitro and in vivo, suggest that these compounds may be effective in the treatment of affective and anxiety disorders. Early evidence indicates that these agents possess anxiolytic and antidepressant activity in animal behavioral models. Copyright 2001 John Wiley & Sons, Ltd.