title: Lyn kinase regulates mesolimbic dopamine release: implication for alcohol reward.
abstract: We report here that the Src family tyrosine kinase Lyn negatively regulates the release of dopamine (DA) in the mesolimbic system, as well as the rewarding properties of alcohol. Specifically, we show that RNA interference-mediated knockdown of Lyn expression results in an increase in KCl-induced DA release in DAergic-like SH-SY5Y cells, whereas overexpression of a constitutively active form of Lyn (CA-Lyn) leads to a decrease of DA release. Activation of ventral tegmental area (VTA) DAergic neurons results in DA overflow in the nucleus accumbens (NAc), and we found that the evoked release of DA was higher in the NAc of Lyn knock-out (Lyn KO) mice compared with wild-type littermate (Lyn WT) controls. Acute exposure of rodents to alcohol causes a rapid increase in DA release in the NAc, and we show that overexpression of CA-Lyn in the VTA of mice blocked alcohol-induced (2 g/kg) DA release in the NAc. Increase in DA levels in the NAc is closely associated with reward-related behaviors, and overexpression of CA-Lyn in the VTA of mice led to an attenuation of alcohol reward, measured in a conditioned place preference paradigm. Conversely, alcohol place preference was increased in Lyn KO mice compared with Lyn WT controls. Together, our results suggest a novel role for Lyn kinase in the regulation of DA release in the mesolimbic system, which leads to the control of alcohol reward.
authors.affiliation: Ernest Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, USA.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Gibb
authors.forename: Jerome
authors.initials: J
authors.lastname: Jeanblanc
authors.forename: Segev
authors.initials: S
authors.lastname: Barak
authors.forename: Quinn V
authors.initials: QV
authors.lastname: Yowell
authors.forename: Rami
authors.initials: R
authors.lastname: Yaka
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D004563:Electrochemistry / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D018709:Statistics, Nonparametric; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C412373:AG 1879; D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014316:Tritium; D049452:Green Fluorescent Proteins; D000431:Ethanol; D011189:Potassium Chloride; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D004298:Dopamine