title: Pharmacologically Counteracting a Phenotypic Difference in Cerebellar GABAA Receptor Response to Alcohol Prevents Excessive Alcohol Consumption in a High Alcohol-Consuming Rodent Genotype.
abstract: Cerebellar granule cell GABAA receptor responses to alcohol vary as a function of alcohol consumption phenotype, representing a potential neural mechanism for genetic predilection for alcohol abuse (Kaplan et al., 2013; Mohr et al., 2013). However, there are numerous molecular targets of alcohol in the cerebellum, and it is not known how they interact to affect cerebellar processing during consumption of socially relevant amounts of alcohol. Importantly, direct evidence for a causative role of the cerebellum in alcohol consumption phenotype is lacking. Here we determined that concentrations of alcohol that would be achieved in the blood after consumption of 1-2 standard units (9 mm) suppresses transmission through the cerebellar cortex in low, but not high, alcohol consuming rodent genotypes (DBA/2J and C57BL/6J mice, respectively). This genotype-selective suppression is mediated exclusively by enhancement of granule cell GABAA receptor currents, which only occurs in DBA/2J mice. Simulating the DBA/2J cellular phenotype in C57BL/6J mice by infusing the GABAA receptor agonist, 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol hydrochloride, into cerebellar lobules IV-VI, in vivo, significantly reduced their alcohol consumption and blood alcohol concentrations achieved. 4,5,6,7-Tetrahydroisoxazolo-[5,4-c]pyridine-3-ol hydrochloride infusions also significantly decreased sucrose consumption, but they did not affect consumption of water or general locomotion. Thus, genetic differences in cerebellar response to alcohol contributes to alcohol consumption phenotype, and targeting the cerebellar GABAA receptor system may be a clinically viable therapeutic strategy for reducing excessive alcohol consumption.
  
  
  
  Alcohol abuse is a leading cause of preventable death and illness; and although alcohol use disorders are 50%-60% genetically determined, the cellular and molecular mechanisms of such genetic influences are largely unknown. Here we demonstrate that genetic differences in cerebellar granule cell GABAA receptor responses to recreational concentrations of alcohol are the primary determinant of alcohol's impact on cerebellar processing and that pharmacologically modifying such responses alters alcohol consumption. These data highlight the cerebellum as an important neuroanatomical region in alcohol consumption phenotype and as a target for pharmacological treatment of alcohol use disorders. The results also add to the growing list of cognitive/emotional roles of the cerebellum in psychiatric disease and drug abuse.
authors: Oregon Health & Science University, Department of Behavioral Neuroscience, Portland, Oregon 97239, Veterans Administration Portland Health Care System, Portland, Oregon 97239, and.
authors: Josh Steven
authors: JS
authors: Kaplan
authors: Oregon Health & Science University, Department of Behavioral Neuroscience, Portland, Oregon 97239, Veterans Administration Portland Health Care System, Portland, Oregon 97239, and.
authors: Michelle A
authors: MA
authors: Nipper
authors: Washington State University, Integrative Physiology and Neuroscience, Pullman, Washington 99164.
authors: Ben D
authors: BD
authors: Richardson
authors: Oregon Health & Science University, Department of Behavioral Neuroscience, Portland, Oregon 97239.
authors: Jeremiah
authors: J
authors: Jensen
authors: Oregon Health & Science University, Department of Behavioral Neuroscience, Portland, Oregon 97239, Veterans Administration Portland Health Care System, Portland, Oregon 97239, and.
authors: Melinda
authors: M
authors: Helms
authors: Oregon Health & Science University, Department of Behavioral Neuroscience, Portland, Oregon 97239, Veterans Administration Portland Health Care System, Portland, Oregon 97239, and.
authors: Deborah Ann
authors: DA
authors: Finn
authors: Oregon Health & Science University, Department of Behavioral Neuroscience, Portland, Oregon 97239, Washington State University, Integrative Physiology and Neuroscience, Pullman, Washington 99164 rossid@vetmed.wsu.edu.
authors: David James
authors: DJ
authors: Rossi
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000097:blood / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018755:GABA Agonists / Q000008:administration & dosage*; D018756:GABA Antagonists / Q000494:pharmacology; D005838:Genotype; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000008:administration & dosage*; D007736:Kynurenic Acid / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018408:Patch-Clamp Techniques; D011724:Pyridazines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D013045:Species Specificity; D013395:Sucrose / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018756:GABA Antagonists; D007555:Isoxazoles; D011724:Pyridazines; D011963:Receptors, GABA-A; D000431:Ethanol; D013395:Sucrose; C049853:gabazine; D007736:Kynurenic Acid; C015542:gaboxadol
keywords: GABA; THIP; addiction; alcohol; cerebellum