Antisense‐induced knockdown of cAMP response element‐binding protein downregulates Per1 gene expression in the shell region of nucleus accumbens resulting in reduced alcohol consumption in mice. (23rd August 2021)

• Record Type: Journal Article
• Authors: Sharma, Rishi; Mishra, Vaibhav; Parikh, Meet; Soni, Anshul; Sahota, Pradeep; Thakkar, Mahesh
• Is Part Of: Alcoholism. Volume 45:Number 10(2021)
• Page Start: 1940
• Page End: 1949
• Publication Date: 2021-08-23
• Subjects: alcohol -- binge drinking -- CREB‐binding protein -- nucleus accumbens -- Per1; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.14687
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract: Introduction: We recently showed that circadian genes expressed in the shell region of nucleus accumbens (NAcSh) play a key role in alcohol consumption, though, the molecular mechanism of those effects is unclear. Because CREB‐binding protein (CBP) promotes Per1 gene expression, we hypothesized that alcohol consumption would increase CBP expression in the NAcSh and antisense‐induced knockdown of CBP would reduce Per1 expression and result in a reduction in alcohol consumption. Methods: To test our hypothesis, we performed two experiments. The Drinking‐in‐the‐dark (DID) paradigm was used to evaluate alcohol consumption in male C57BL/6J mice. In Experiment 1 we examined the effects of alcohol consumption on CBP gene expression in the NAcSh. Control animals were exposed to, sucrose [10% (w/v) taste and calorie] and water (consummatory behavior). In Experiment 2 examined the effects of CBP gene silencing on the expression of the Per1 gene in the NAcSh and alcohol consumption in mice exposed to alcohol using the DID paradigm. CBP gene silencing was achieved by local infusion of two doses of either CBP antisense oligodeoxynucleotides (AS‐ODNs; Antisense group) or nonsense ODNs (NS‐ODNs; Nonsense group) bilaterally microinjected into the NAcSh within 24 h before alcohol consumption on Day 4 of the DID paradigm. The microinfusion sites were verified by cresyl violet staining. Results: Compared to sucrose, alcohol consumption, under the DID paradigm, significantly increased the expression of CBP in the NAcSh. Compared to Controls, bilateral infusion of CBP AS‐ODNs significantly reduced the expression of Per1 in the NAcSh and alcohol consumption without affecting the amount of sucrose consumed. Conclusions: Our results suggest that CBP is an upstream regulator of Per1 expression in the NAcSh and may act via Per1 to modulate alcohol consumption. Abstract : The CREB‐binding protein (CBP), a transcriptional co‐activator with histone acetyltransferase activity, is associated with alcohol consumption; however, the exact neuroanatomical substrate is not known. In this study, we have shown that mice exposed to binge alcohol consumption display a significant increase in CBP expression in the nucleus accumbens shell region. Antisense‐induced knockdown of CBP in this region significantly reduced alcohol consumption and Per1 gene expression suggesting that CBP acts via accumbal shell region to increase alcohol consumption and Per1 expression.