This is a renewal of ongoing R01 funding to define molecular sites of alcohol action in brain and to link alcohol effects on these receptors with specific behaviors such as consumption, reward/aversion, intoxication and physical dependence. During the current period of funding we were successful in providing molecular and even atomic level of analysis of alcohol sites on pentameric ligand-gated (pLGIC) ion channels, including the first crystallographic structure of alcohols bound within a channel protein. We also succeeded in constructing mutant mice with GABAa receptor subunits which are resistant to alcohol modulation allowing us to link specific GABAa receptors with discrete behavioral actions of alcohol. We are in the middle of the fourth year of this project period and to date have 30 publications with 7 more submitted or in preparation. Although we and others have made considerable progress, the molecular sites of alcohol action in the brain are not completely defined. Emerging evidence from human and rodent genetics, as well as recombinant receptors, indicates that several targets which have received only limited attention may be important sites of alcohol action in brain. We propose to define the role of two groups of ligand-gated ion channels, the glycine-activated chloride channels (GlyR) and GABAaRs formed from ? subunits (? GABAaRs) in actions of alcohol at the molecular, electrophysiological and behavioral levels. A strength of this proposal is the combined use of knock-out (KO) and knock-in (KI) mice allowing us to define the importance of the presence of a subunit (KO) and the importance of direct alcohol action on the protein (KI) for behavioral actions of alcohol. An innovative aspect is use of a new technology (transcription activator- like effector nuclease;TALEN) to be employed by our collaborator, Dr. Gregg Homanics, that markedly reduces the time and cost required for construction of mutant mice. In addition to our behavioral studies, mutant mice will be used by our collaborator, Dr. Neil Harrison for electrophysiological studies of glycinergic function in accumbal regions. Several GlyRs and ? GABAaRs are genetically linked with human alcohol dependence and understanding their role in alcohol actions may provide new targets for pharmacotherapies of alcohol abuse and alcoholism.
Even though alcohol (ethanol) has been consumed for thousands of years, we know remarkably little about the way it produces its effects on the brain. An important advance was the identification of specific proteins (neurotransmitter receptors and ion channels) involved in communication between neurons as a target for ethanol. We will define how ethanol acts on these proteins using novel techniques, ranging from the molecular to the behavioral level, combining mutations in mice with electrophysiological and behavioral studies. The final objective is to define key protein sites that can serve as pharmacological or genetic targets for new therapies to alleviate alcohol addiction.
|Blednov, Yuri A; Black, Mendy; Benavidez, Jillian M et al. (2016) PPAR Agonists: II. Fenofibrate and Tesaglitazar Alter Behaviors Related to Voluntary Alcohol Consumption. Alcohol Clin Exp Res 40:563-71|
|Blednov, Yuri A; Black, Mendy; Benavidez, Jillian M et al. (2016) PPAR Agonists: I. Role of Receptor Subunits in Alcohol Consumption in Male and Female Mice. Alcohol Clin Exp Res 40:553-62|
|Mayfield, J; Arends, M A; Harris, R A et al. (2016) Genes and Alcohol Consumption: Studies with Mutant Mice. Int Rev Neurobiol 126:293-355|
|Borghese, Cecilia M; Ruiz, Carlos I; Lee, Ui S et al. (2016) Identification of an Inhibitory Alcohol Binding Site in GABAA Ï1 Receptors. ACS Chem Neurosci 7:100-8|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2015) Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines. Neuropharmacology 95:309-20|
|Bajo, M; Herman, M A; Varodayan, F P et al. (2015) Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun 45:189-97|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2015) Glycine receptors containing Î±2 or Î±3 subunits regulate specific ethanol-mediated behaviors. J Pharmacol Exp Ther 353:181-91|
|Mayfield, Jody; Blednov, Yuri A; Harris, R Adron (2015) Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction. Int Rev Neurobiol 123:279-313|
|Borghese, Cecilia M (2015) The molecular pharmacology of volatile anesthetics. Int Anesthesiol Clin 53:28-39|
|Horani, Suzzane; Stater, Evan P; Corringer, Pierre-Jean et al. (2015) Ethanol Modulation is Quantitatively Determined by the Transmembrane Domain of Human Î±1 Glycine Receptors. Alcohol Clin Exp Res 39:962-8|
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