F

6.03.7.1.2.2 Corticotropin-releasing factor (CRF)

The 41 amino acid neuropeptide CRF initiates the HPA axis response to stress, and may have utility in the treatment of depression and anxiety.58 In a small, open-label clinical trial, symptoms of anxiety and depression in patients with major depression were reduced during treatment with the CRF1 receptor antagonist R-12919 (80).

6.03.7.1.2.3 Melanin concentrating hormone (MCH)

MCH is an orexigenic hypothalamic neuropeptide that plays an important role in the complex regulation of energy balance and body weight. SNAP-7941 (81) is a selective, high-affinity MCH1 receptor (MCH1-R) antagonist that has been shown to inhibit food intake stimulated by central administration of MCH and reduce consumption of palatable food; chronic administration of SNAP-7941 to rats with diet-induced obesity resulted in a marked, sustained decrease in body weight.59 In addition to the orexigenic effects, SNAP-7941 produced effects similar to clinically used antidepressants and anxiolytics in animal models of depression/anxiety: the rat FST, rat social interaction, and guinea pig maternal separation vocalization tests. Given these observations, it has been suggested that MCH1-R antagonists may be useful not only in the management of obesity but also as a treatment for depression and/or anxiety.

6.03.7.1.2.4 Galanin

Galanin is a biologically active neuropeptide that is widely distributed in the central and peripheral nervous systems and the endocrine system. The amino acid sequence of galanin is very conserved (almost 90% among species), indicating the importance of the molecule. Galanin has multiple biological effects.60 In the CNS, galanin alters the release of several neurotransmitters. In particular, the ability of galanin to inhibit acetylcholine release together with the observation of hyperinervation of galanin fibers in the human basal forebrain of Alzheimer's disease patients suggests a possible role for galanin in this neurodegenerative disease. Galanin may also be involved in other neuronal functions, such as learning and memory, epileptic activity, nociception, spinal reflexes, and feeding. Three human and rodent galanin receptor subtypes have been cloned. The GAL3 receptor antagonist SNAP-37889 (82) may have utility as a novel antidepressant.61'62

6.03.7.1.2.5 Neuropeptide Y

Neuropeptide Y (NPY) is abundantly expressed in numerous brain areas, including the locus coeruleus, hypothalamus, amygdala, hippocampus, nucleus accumbens, and neocortex.59 Central NPY colocalizes with NE, GABA, somatostatin, and agouti-related protein. Actions of NPY are mediated through the Y1, Y2, and Y5 receptor. In rodent models, NPY is expressed and released following stress, and attenuates the behavioral consequences of stress. Rodent studies have demonstrated antidepressant-like effects of centrally administered Y1 receptor agonists.59

6.03.7.1.2.6 Vasopressin VP1b receptor antagonists

The nonpeptide vasopressin, which is synthesized in the PVN and supraoptic nucleus, acts via vasopressin receptors (Via and V1b) expressed mainly in limbic areas and in the hypothalamus.57 Abnormalities in vasopressin expression or receptor activity occur in both clinical depression and rodent genetic models of depression, whereas vasopressin release predicts anxiety reactions to stress provocation in healthy volunteers. The nonpeptide V1b receptor antagonist SSR-149415 (83) exerts marked anxiolytic- and antidepressant-like effects in rodents.57

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