Pharmacological Studies

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: CI (NBI-27914)

Anxiety and Depression - Central administration of CRF produces anxiety-like behavior in animals and antagonists of the CRF receptors have reversed these effects (6,7). Astressin reversed the CRF induced anxiety-like behavioral effects as measured in the plus maze paradigm and reversed the anxiogenic effects of social stress (53 , 54). Strangely, astressin had no effect in reducing the CRF induced increases in locomotor activity analogous to the small molecule CRF! selective antagonist 19 (54) unlike the effects observed with CRF(9-41) and [D-Phe12]CRF(12-41). Peptide antagonists have also been utilized to reduce the abnormally fearful behavior of the offspring of pregnant rats that were exposed to the stress of daily handling and saline injections and the anxiogenic effects of the C-type natriuretic peptide, an important neuromodulatory peptide within the CNS (55, 56).

Selective small molecule CRFi antagonists have also reversed the anxiogenic effects of CRF, implicating CRFi as the key receptor mediating these effects. Analogous to the peptide antagonists, 19 blocked ultrasonic vocalizations of rats exposed to stress and neonatal separation and blocked interferon-a (IFN-a) depression-like behavior as measured by the tail suspension test in mice (57 - 59). Depression is a common side effect observed in IFN-a treated hepatitis C patients which is reversed with antidepressent therapy. Chronic administration of 19 (3.2 mg / kg / day) for 10 days in rodents resulted in a decrease of anxiety-associated behavior in the defensive withdrawal model whereas acute treatment had no effect. Increased expression of CRF (mRNA) in the hypothalamic paraventricular nucleus was observed in the high (32 mg / kg) chronic dose, which is opposite to the postmortem analysis of depressed humans where CRF is increased (60). Oral administration of 19 also inhibited anxiety-associated behaviors in the intruder paradigm in primates providing evidence that CRFi antagonists may be useful in treating anxiety and depression (61).

Since earlier work had shown that CRFi null mice displayed anxiolytic-like effects, CRF2_/' mice were also studied in anxiety paradigms such as the elevated plus maze (62). The mutant mice were hypersensitive to stress, displayed increased anxiety-like behavior and had decreased food intake upon food deprivation, the later possibly a marker of an increased anxiety state following deprivation (63). Whilst iv infusion of urocortin into wild type mice produced a depressor response, CRF2-'" animals showed no measurable change. In other experiments, male, but not female, mutant mice exhibited enhanced anxious behavior which correlated with a reduction in Creb phosphorylation leading to the proposal that CRF2 mediates a central anxiolytic response to oppose the anxiogenic effect of CRFi (64).

Stress-Induced Gastrointestinal Dysfunction - Adverse events in life such as family death, marital stress and physical or sexual abuse have been reported more frequently in irritable bowel syndrome (IBS) patients than the general population. Similar to various stressors, CRF inhibits gastric emptying while accelerating colonic motility (8). Stress and central or peripherally administered CRF stimulated defecation (65, 66) can be blocked with astressin, icv 20 or ip 19. Intracisternal (ic) administration of astressin blocked ic CRF delay of gastric emptying while ic 20 had no effect. Intravenous 1 also did not attenuate CRF induced gastric emptying (67). It appears that CRFi mediates the stress associated increase in colonic motility of and CRF2 mediates the associated delay of gastric emptying suggesting that CRFi and CRF2 antagonists may prove to be novel treatments of IBS.

Drug Addiction - There is evidence that CRF may play a role in the stress-induced relapse of drug abuse as well as the anxiety-like behaviors observed during acute drug withdrawal (9). Chronic cocaine administration in rats is anxiogenic and icv [D-Phe12]CRF(12-41) attenuates the behavior, as characterized by the defensive burying paradigm (68). The compound 19 alleviated the symptoms associated with opiate withdrawal after chronic morphine, and blocked drug seeking behavior as measured through cocaine self administration (69, 70). Stress-induced relapse of alcohol seeking and opiate relapse was diminished by 19 but not antisauvigine-30 suggesting a CRFi role (71, 72).

Eating Disorders - Stress decreases food intake and weight gain and these effects are reproduced with centrally administered CRF (11). These effects are inhibited by antisauvigine-30 and CRF(9-41), which also alleviates the stress-like effects are also seen with the brain anorectic agent, CART (68, 73 - 74). In contrast, the small molecule CRFi antagonist 20 had no effect CRF induced decreases in body weight suggesting a role for CRF2 (73). Urocortin is a 30-fold selective CRF2 agonist whose effects on food intake can also be blocked by antisauvigine-30. Antisauvagine-30 had no effect on the associated changes in tissue weights and serum chemistry seen with central CRF administration implying that CRF2 mediates only the anorexic, not the metabolic effects, of CRF (71). Central administration of urocortin-ll has supported earlier observations in CRF1 knock out mice that intimated CRF2 activation may be only responsible for later stage (beyond 6 hours) suppression of food intake and not the early stage anorexic effects or the effects on metabolism that CRF1 activation provides (52, 75).

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