title: Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice.
abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the brain and implicated in alcohol abuse in humans and behavioral responses to ethanol in mice. Previous studies have shown an association of human ALK with acute responses to alcohol and alcohol dependence. In addition, Alk knockout (Alk -/-) mice consume more ethanol in a binge-drinking test and show increased sensitivity to ethanol sedation. However, the function of ALK in excessive drinking following the establishment of ethanol dependence has not been examined. In this study, we tested Alk -/- mice for dependence-induced drinking using the chronic intermittent ethanol-two bottle choice drinking (CIE-2BC) protocol. We found that Alk -/- mice initially consume more ethanol prior to CIE exposure, but do not escalate ethanol consumption after exposure, suggesting that ALK may promote the escalation of drinking after ethanol dependence. To determine the mechanism(s) responsible for this behavioral phenotype we used an electrophysiological approach to examine GABA neurotransmission in the central nucleus of the amygdala (CeA), a brain region that regulates alcohol consumption and shows increased GABA signaling after chronic ethanol exposure. GABA transmission in ethanol-naïve Alk -/- mice was enhanced at baseline and potentiated in response to acute ethanol application when compared to wild-type (Alk +/+) mice. Moreover, basal GABA transmission was not elevated by CIE exposure in Alk -/- mice as it was in Alk +/+ mice. These data suggest that ALK plays a role in dependence-induced drinking and the regulation of presynaptic GABA release in the CeA.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, SP30-2400, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Schweitzer
authors.affiliation: Department of Molecular and Cellular Neuroscience, MB-18, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Cates-Gatto
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, SP30-2400, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Florence P
authors.initials: FP
authors.lastname: Varodayan
authors.affiliation: Department of Molecular and Cellular Neuroscience, MB-18, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Tali
authors.initials: T
authors.lastname: Nadav
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, SP30-2400, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, M/C 912, Chicago, IL 60612, USA. Electronic address: alasek@psych.uic.edu.
authors.forename: Amy W
authors.initials: AW
authors.lastname: Lasek
authors.affiliation: Department of Molecular and Cellular Neuroscience, MB-18, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Roberts
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism; D000437:Alcoholism / Q000201:enzymology*; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D066274:Central Amygdaloid Nucleus / Q000187:drug effects / Q000201:enzymology; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D015331:Cohort Studies; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology*; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; Addiction; Amygdala; Chronic intermittent ethanol; GABA; Synaptic