However, recent data from various neuroscience disciplines have questioned the major role of amines in the pathogenesis of depression. A considerable amount of evidence has accumulated that suggests that normalization of the hypothalamo-pituitary-adrenal (HPA) system might be the GW786034 clinical trial final step necessary for a remission of depression. In addition, an increasing body of clinical and postmortem evidence is pointing to a role played by gamma-aminobutyric acid (GABA) and glutamate in the etiology of depression. This review examines the evidence, mainly obtained from clinical studies or from postmortem brain material, for a major role of the HPA
axis, glutamatergic, and GABAergic systems in the pathogenesis of major and bipolar depression. The authors hope that these insights will stimulate further studies with the final aim of developing new types of antidepressants that combine increased efficacy with a shorter delay of the onset of action and reduced side-effect profiles.”
“Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors
(nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the alpha 3, alpha 5, and beta selleck chemical 4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the alpha 3, and beta 4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at alpha 3 beta 4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at a3b4 nAChRs correlate with their unbound
rat brain concentrations, suggesting that the effects ARN-509 mw on ethanol self-administration are mediated via interaction with alpha 3 beta 4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with alpha 3 beta 4 nAChRs. Furthermore, the selective alpha 4 beta 2* nAChR antagonist, DH beta E, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs. Neuropsychopharmacology (2011) 36, 603-615; doi:10.1038/npp.2010.