Ethanol modulates the actions of multiple neurotransmitter systems, including GABA. However, its enhancing effects on GABA signaling typically are seen only at high concentrations. In contrast, although GABA is a prominent neurotransmitter in the circadian clock of the suprachiasmatic nucleus (SCN), we see ethanol modulation of clock phase resetting at low concentrations (<50 mM). A possible explanation is that ethanol enhances GABAergic signaling in the SCN through activating GABA A receptors that contain the δ subunit (GABA Aδ receptors), which are sensitive to low ethanol concentrations. Therefore, we investigated whether ethanol acts on GABA Aδ receptors in the SCN. Here we show that acute application of the GABA Aδ receptor antagonist, RO15-4513, to mouse hypothalamic slices containing the SCN prevents ethanol inhibition of nighttime glutamate-induced (photic-like) phase delays of the circadian clock. Diazepam, which enhances activity of GABA Aγ receptors, does not modulate these phase shifts. Moreover, we find that RO15-4513 prevents ethanol enhancement of daytime serotonergic (non-photic) phase advances of the circadian clock. Furthermore, diazepam phase-advances the SCN circadian clock when applied alone in the daytime, while ethanol has no effect by itself at that time. These data support the hypothesis that ethanol acts on GABA Aδ receptors in the SCN to modulate photic and non-photic circadian clock phase resetting. They also reveal distinct modulatory roles of different GABA A receptor subtypes in circadian clock phase regulation.Keywords suprachiasmatic nucleus; circadian rhythms; GABA; alcohol; benzodiazepine Alcoholism and alcohol abuse pose major health concerns that are difficult to treat in part due to ethanol's diverse actions throughout the central nervous system. One of the neurotransmitter systems modulated by ethanol is GABA: Ethanol increases GABA release, and enhances the activity of both GABA A and GABA B receptors (see (Weiner and Valenzuela, 2006) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 December 1. (Mihic et al., 1997;Sigel et al., 1993;Vengeliene et al., 2008). At levels typically associated with social ethanol consumption (< 50 mM), however, the GABAergic effects of ethanol appear to be restricted primarily to a subset of GABA A receptors that contain the δ subunit (GABA Aδ receptors) (Mihic et al., 1997;Wallner et al., 2003;Glykys et al., 2007;Wei et al., 2004;Olsen et al., 2007;Santhakumar et al., 2007). These receptors are thought to...

Permanent post-operative cognitive dysfunction (POCD) is a grim outcome to an estimated 6% of elderly surgical patients. Volatile anesthetics impact neuronal tissue independent of effects attributed to the physical trauma of the surgery itself. While it is recognized that all aspects related to surgery may contribute to cognitive loss in some manner, the present paper focuses on the role of volatile anesthetics in promoting POCD. There is an increased risk of onset and progression of Alzheimer's disease (AD) from POCD, implying that the neuropathogenesis between the two is similar. Human studies, being ethically limited in scope, require animal models as a substitute. While the literature using rodent models contains valuable information, we believe that the accessible and practical zebrafish will greatly enhance our further understanding of the molecular mechanism of POCD as it relates to AD. Disease genes and fundamental neurobehaviors of these teleost fish mirror those of mammals and humans, validating their use as a core research model for AD. Since the gradual senescence seen in zebrafish also resembles that found in humans, we numerically correlated the two lifespans, offering researchers a computational tool. Zebrafish, being aquatic animals, necessitates the use of miscible compounds, such as trifluoroethanol, whose anesthetic potency we are presenting. We also review the rodent and zebrafish literature relevant to POCD. Continued research with the leading-edge zebrafish unlocks the possibility that, in the future, perioperative intervention will prevent POCD.

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