Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

Abstract

SUPPLEMENTARY NOTES 12a. DISTRIBUTION /AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited 12b. DISTRIBUTION CODE Abstract (Maximum 200 Words) labstract should contain no proprietary or confidential information)We have been testing the hypothesis that chronic alcohol exposure alters expression and/or function of kainate receptors (KA-Rs) in the hippocampus. KA-Rs control hippocampal excitability and an ethanol-induced upregulation of KA-Rs could contribute to the hyperexcitability associated with alcohol withdrawal. Unexpectedly, Western immunoblotting and immunohistochemical studies have demonstrated that chronic ethanol exposure does not upregulate KA-R subunit expression. However, studies with cultured neurons suggest that alcohol withdrawal itself, but not chronic ethanol exposure, upregulates KA-R function. Therefore, we are now focusing our efforts at testing if this is also true for animals exposed to ethanol. We have switched to a different method of alcohol exposure; we are using the inhalation route, which reproducibly produces high ethanol levels. We are currently processing brain sections from control rats and rats withdrawn from a 14-day inhalational ethanol exposure paradigm. These sections will be immunostained with anti-GluR6/7 antibodies and will be used for radioligand binding experiments. We have also characterized the acute effects of ethanol on the function of interneuronal KA-Rs. Moreover, a preliminary experiment with hippocampal slices from rats withdrawn from a 6-day inhalational exposure paradigm suggests that the function of these receptors is upregulated. During the last year of support, we will concentrate on characterizing the function of KA-Rs in the CA1 and CAS regions in alcohol withdrawn rats. Alcohol-related medical disorders affect many organs and systems of the body, including the central nervous system (CNS). As with other drugs of abuse, long-term alcohol ingestion results in the development of tolerance, addiction, and dependence. Alcohol produces these effects by altering the actions of neurotransmitters and their receptors in the brain. Chronic ethanol exposure has complex and long-lasting effects on the function and/or expression of a myriad of neurotransmitter receptors and their modulators. A group of proteins affected by chronic ethanol exposure are hgand-gated ion channels such as the glutamatergic ionotropic receptors. Glutamate activates three major classes of ionotropic receptors. These three major types of channels are the NMD A, AMPA and kainate receptors (KA-Rs). The purpose of this proposal is to test whether or not chronic ethanol exposure results in alterations in subunit expression and/or function of KA-Rs in the hippocampus. Maladaptive changes in hippocampal KA-R expression could contribute to the pathophysiology of alcohol withdrawal syndrome. The alcohol withdrawal syndrome is associated with neuronal hyperexcitabiUty and seizures. Since kainate receptors are important regulators of excitability in the hippocampus, upregulation o...