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Glucagon-like peptide-1 (GLP-1) receptor agonist prevents development of tolerance to anti-anxiety effect of ethanol and withdrawal-induced anxiety in rats

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Abstract

Despite major advances in the understanding about ethanol actions, the precise underlying neurobiological mechanisms for ethanol dependence remain largely elusive. We recently reported that inhibition of dipeptidyl-peptidase IV (DPP-IV), an enzyme responsible for metabolism of endogenous glucagon-like peptide-1 (GLP-1), delays tolerance to anti-anxiety effect of ethanol and withdrawal-induced anxiety in rats. Intrigued with this report, present study examined the role of glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide in (1) acute anti-anxiety effect of ethanol; (2) tolerance to ethanol’s anti-anxiety-effect and (3) ethanol withdrawal-induced anxiety using elevated plus maze (EPM) test in rats. Ethanol (2 g/kg, i.p.; 8 % w/v) and liraglutide (50 μg/kg, i.p.) treatments exhibited anti-anxiety effect in EPM test. Doses of ethanol (1.0 or 1.5 g/kg, i.p.) that were not effective per se elicited anti-anxiety when combined with sub-effective dose of liraglutide (25 μg/kg, i.p.). Rats consuming ethanol-diet (6 % v/v) exhibited tolerance to anti-anxiety effect of ethanol from day-7 of ethanol consumption. Peak ethanol withdrawal-induced anxiety was observed at 8–10 h upon abstinence from ethanol-diet after 15-days consumption. Rats on simultaneous once-daily liraglutide treatment (50 μg/kg, i.p.) neither had any signs of tolerance to anti-anxiety effect of ethanol nor did they exhibit withdrawal-induced anxiety. In conclusion: (1) GLP-1 agonist, liraglutide exhibited anti-anxiety effect per se; (2) potentiated anti-anxiety effect of ethanol; (3) prevented development tolerance to anti-anxiety effect of ethanol and (4) prevented withdrawal-induced anxiety. Further studies examining intracellular cascade of events contributing to these effects may help to improve understanding about role of GLP-1 receptors in ethanol mediated behaviors.

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Correspondence to Ajaykumar N. Sharma or Praveen Shukla.

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Sharma, A.N., Pise, A., Sharma, J.N. et al. Glucagon-like peptide-1 (GLP-1) receptor agonist prevents development of tolerance to anti-anxiety effect of ethanol and withdrawal-induced anxiety in rats. Metab Brain Dis 30, 719–730 (2015). https://doi.org/10.1007/s11011-014-9627-z

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  • DOI: https://doi.org/10.1007/s11011-014-9627-z

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