Antisense‐Induced Downregulation of Clock Genes in the Shell Region of the Nucleus Accumbens Reduces Binge Drinking in Mice. (19th February 2021)

• Record Type: Journal Article
• Authors: Sharma, Rishi; Puckett, Hunter; Kemerling, Micaela; Parikh, Meet; Sahota, Pradeep; Thakkar, Mahesh
• Is Part Of: Alcoholism. Volume 45:Number 3(2021)
• Page Start: 530
• Page End: 542
• Publication Date: 2021-02-19
• Subjects: Clock -- Per1 -- Per2 -- Nucleus accumbens -- Binge drinking; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.14549
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract : Introductions: Binge drinking is a deadly pattern of alcohol consumption. Evidence suggests that genetic variation in clock genes is strongly associated with alcohol misuse; however, the neuroanatomical basis for such a relationship is unknown. The shell region of the nucleus accumbens (NAcSh) is well known to play a role in binge drinking. Hence, we examined whether clock genes in the NAcSh regulate binge drinking. Methods: To address this question, 2 experiments were performed on male C57BL/6J mice. In the first experiment, mice exposed to alcohol or sucrose under the 4‐day drinking‐in‐the‐dark (DID) paradigm were euthanized at 2 different time points on day 4 [7 hours after light (pre–binge drinking) or dark (post–binge drinking) onset]. The brains were processed for RT–PCR to examine the expression of circadian clock genes (Clock, Per1, and Per2) in the NAcSh and suprachiasmatic nucleus (SCN). In the second experiment, mice were exposed to alcohol, sucrose, or water as described above. On day 4, 1 hour prior to the onset of alcohol exposure, mice were bilaterally infused with either a mixture of circadian clock gene antisense oligodeoxynucleotides (AS‐ODNs; antisense group) or nonsense/random ODNs (R‐ODNs; control group) through surgically implanted cannulas above the NAcSh. Alcohol/sucrose/water consumption was measured for 4 hours. Blood alcohol concentration was measured to confirm binge drinking. Microinfusion sites were histologically verified using cresyl violet staining. Results: As compared to sucrose, mice euthanized post–binge drinking (not pre–binge drinking) on day 4 displayed a greater expression of circadian genes in the NAcSh but not in the SCN. Knockdown of clock genes in the NAcSh caused a significantly lower volume of alcohol to be consumed on day 4 than in the control treatment. No differences were found in sucrose or water consumption. Conclusions: Our results suggest that clock genes in the NAcSh play a crucial role in binge drinking. Abstract : We examined a causal relationship between circadian genes (crucial for alcohol consumption) in the shell region of nucleus accumbens (NAcSh; a center for reward and pleasure) and binge drinking. Mice exposed to binge alcohol consumption displayed increased expression of circadian genes (Clock, Per1 and Per2) in the NAcSh but not in the suprachiasmatic nucleus. Antisense‐induced downregulation of circadian genes in the NAcSh significantly reduced binge drinking. Our results suggest that circadian genes in the NAcSh regulate binge drinking in mice.