@article {46610, title = {An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011 Jul 22}, pages = {e22636}, abstract = {

Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention.

}, keywords = {Alcohol Drinking, Alcoholics, Animals, Behavior, Animal, Conscious Sedation, Drosophila melanogaster, Drosophila Proteins, Ethanol, Evolution, Molecular, Female, Gene Expression Regulation, Enzymologic, Homeodomain Proteins, Humans, Male, Mice, Polymorphism, Genetic, Receptor Protein-Tyrosine Kinases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0022636}, author = {Lasek, Amy W and Lim, Jana and Kliethermes, Christopher L and Berger, Karen H and Joslyn, Geoff and Brush, Gerry and Xue, Liquan and Robertson, Margaret and Moore, Monica S and Vranizan, Karen and Morris, Stephan W and Schuckit, Marc A and White, Raymond L and Heberlein, Ulrike} } @article {46608, title = {Insulin attenuates the acquisition and expression of ethanol-induced locomotor sensitization in DBA/2J mice.}, journal = {Life Sciences}, volume = {89}, year = {2011}, month = {2011 Dec 19}, pages = {968-74}, abstract = {

AIM: Ethanol-induced locomotor sensitization is a behavioral manifestation of physiological responses to repeated ethanol exposures. While ethanol exerts direct effects on multiple neurotransmitter systems in the brain, ethanol-induced changes in metabolic state, including acute hyperglycemia and inhibition of insulin signaling, also have plausible roles in the expression of ethanol-related behaviors through direct and indirect effects on brain function. The current experiments examined whether insulin administration or the resultant hypoglycemia might attenuate the development of sensitization to the locomotor stimulant effect of ethanol.

MAIN METHODS: Male and female DBA/2J mice received daily injections of 5 or 10 IU/kg insulin before or after a stimulating dose of ethanol and subsequent testing in an automated activity monitor. Blood glucose levels were determined upon the completion of the experiments.

KEY FINDINGS: Insulin injected prior to ethanol blunted the acute stimulant response as well as the acquisition and expression of locomotor sensitization, while insulin given after ethanol did not affect the development of the sensitized response. In a separate experiment, mice given glucose concurrently with insulin developed ethanol-induced locomotor sensitization normally.

SIGNIFICANCE: These experiments suggest that insulin attenuates the development of ethanol-induced locomotor sensitization, and that blood glucose levels can largely account for this effect. Further studies of the role of ethanol-induced metabolic states should provide novel information on the expression of ethanol-related behaviors.

}, keywords = {Animals, Behavior, Animal, Blood Glucose, Central Nervous System Depressants, Dose-Response Relationship, Drug, Ethanol, Female, Glucose, Hypoglycemia, Hypoglycemic Agents, Insulin, Male, Mice, Mice, Inbred DBA, Motor Activity}, issn = {1879-0631}, doi = {10.1016/j.lfs.2011.10.011}, author = {Kliethermes, Christopher L and Heberlein, Ulrike} }