Anaplastic lymphoma kinase regulates binge‐like drinking and dopamine receptor sensitivity in the ventral tegmental area. (11th January 2016)

• Record Type: Journal Article
• Authors: Dutton, John W.; Chen, Hu; You, Chang; Brodie, Mark S.; Lasek, Amy W.
• Is Part Of: Addiction biology. Volume 22:Number 3(2017)
• Page Start: 665
• Page End: 678
• Publication Date: 2016-01-11
• Subjects: Alcohol addiction -- ALK -- binge‐drinking -- dopamine receptor -- ventral tegmental area; Substance abuse -- Periodicals; Substance abuse -- Physiological aspects -- Periodicals; Substance-Related Disorders -- periodicals; 616.86
• DOI: 10.1111/adb.12358
• Languages: English
• ISSNs: 1355-6215

Abstract

Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase associated with alcohol dependence in humans and behavioral responses to ethanol in mice. To characterize the ability of ALK to control ethanol consumption, we treated mice with the ALK inhibitors TAE684 or alectinib before testing them for binge‐like drinking using the drinking in the dark protocol. Mice treated with ALK inhibitors drank less ethanol than controls. In addition, TAE684 treatment abolished ethanol conditioned place preference, indicating that ALK regulates the rewarding properties of ethanol. Because the ventral tegmental area (VTA) is a key brain region involved in the rewarding effects of ethanol, we determined if Alk expression in the VTA is important for binge‐like ethanol consumption. Mice expressing a short hairpin ribonucleic acid targeting Alk in the VTA drank less ethanol compared with controls. ALK is expressed on dopamine (DA) neurons in the VTA, suggesting that ALK might regulate their firing properties. Extracellular recordings of putative DA neurons in VTA slices demonstrated that ALK inhibition did not affect the ability of ethanol to stimulate, or DA to inhibit, the firing of DA neurons. However, inhibiting ALK attenuated the time‐dependent reversal of inhibition produced by moderate concentrations of DA, suggesting that ALK affects DA D2 autoreceptor (D2R) desensitization. Altered desensitization of the D2R changes the firing of DA neurons and is predicted to affect DA levels and alcohol drinking. These data support the possibility that ALK might be a novel target of pharmacotherapy for reducing excessive alcohol consumption. Abstract : We tested anaplastic lymphoma kinase (ALK) inhibitors in a mouse model of binge drinking and found that ALK inhibition reduced binge‐like alcohol consumption. ALK appears to act in the ventral tegmental area to regulate binge‐like drinking and may affect ethanol consumption through modulation of dopamine D2 receptor activity. Our results indicate that treatment with small molecule inhibitors of ALK might be a viable therapeutic strategy to reduce binge drinking in individuals with alcohol use disorders.