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.

Modulation of ethanol reward sensitivity by nicotinic acetylcholine receptors containing the α6 subunit

“…The CPP assay used was a 6-day protocol adapted from Gibb et al (2011). The CPP apparatus (Med Associates, USA) consisted of three distinct chambers, a small, neutral, gray chamber flanked on each side by a larger conditioning chamber containing a wire-mesh floor and white walls and the other chamber containing a metal-rod floor and black walls.…”

Nicotinic Acetylcholine Receptors Containing the α4 Subunit Modulate Alcohol Reward

“…The conditioning chambers were separated by a neutral grey chamber. Experiments were conducted over 6 consecutive days as in Gibb et al 2011 [28] (also see supplemental materials). …”

MLR-1023 Is a Potent and Selective Allosteric Activator of Lyn Kinase In Vitro That Improves Glucose Tolerance In Vivo

“…Lyn kinase is a Src-related nonreceptor-linked tyrosine kinase that is found in an array of cell types and tissues including smooth muscle, liver, brain, myeloid cells, and adipose tissue (Pertel et al, 2006;Scapini et al, 2009;Yamada et al, 2010;Gibb et al, 2011). Although Lyn kinase has been studied primarily in myeloid lineage cells, there are key data that implicate Lyn kinase as a regulator of insulin signaling and glucose regulation.…”