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


CONCLUSIONS
(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.
Department of Pharmacology, S.T.E.S.s Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune, MS, 411048, India, Ajay.Kumar.N.Sharma@uth.tmc.edu.
Ajaykumar N
AN
Sharma
Ashish
A
Pise
Jay N
JN
Sharma
Praveen
P
Shukla
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D001007:Anxiety / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D000431:Ethanol / Q000008:administration & dosage*; D000069450:Liraglutide / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000523:psychology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
D014151:Anti-Anxiety Agents; D000431:Ethanol; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists