Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · Jun 2004
Comparative StudyCorticotropin-releasing hormone antagonists, astressin B and antalarmin: differing profiles of activity in rhesus monkeys.
The present study compares the activity of two chemically distinct corticotropin-releasing hormone (CRH) antagonists at the level of the pituitary gland in rhesus monkeys, using exogenous CRH-stimulated increases in adrenocorticotropin (ACTH) and cortisol. Of chief interest was whether the CRH-R1-selective pyrrolopyrimidine, antalarmin, shown previously to have activity in the central nervous system (CNS), would differ in its antagonist profile from the CRH-R1- & 2-selective peptide, astressin B, which is unlikely to have access to the CNS following systemic administration. Nine rhesus monkeys (eight male), each with an indwelling venous catheter, were subjects in this study. ⋯ At a larger dose, antalarmin stimulated ACTH and cortisol release and produced behavioral sedation. These latter effects diminished with repeated administration of antalarmin. The differences between astressin B and antalarmin may be due either to non-CRH receptor-mediated effects of antalarmin or to a complex interaction of antalarmin's effects at both central and peripheral CRH receptors.
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Neuropsychopharmacology · Jun 2004
Comparative StudyGenetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior.
Although there is much evidence for a role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the pathophysiology of anxiety and depression, the role of GABA(B) receptors in behavioral processes related to these disorders has not yet been fully established. GABA(B) receptors are G-protein-coupled receptors, which act as functional heterodimers made up of GABA(B(1)) and GABA(B(2)) subunits. Using recently generated GABA(B(1)) -/- mice, which lack functional GABA(B) receptors, and pharmacological tools we assessed the role of GABA(B) receptors in anxiety- and antidepressant-related behaviors. ⋯ These behavioral effects are unrelated to alterations in locomotor activity. In confirmation of the genetic data, acute and chronic treatment with CGP56433A, a selective GABA(B) receptor antagonist, also decreased immobility in the FST, whereas GS39783 did not alter this behavior. Taken together, these data suggest that positive modulation of the GABA(B) receptor may serve as a novel therapeutic strategy for the development of anxiolytics, whereas GABA(B) receptor antagonism may serve as a basis for the generation of novel antidepressants.