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Dipeptidyl-peptidase IV (DPP-IV) inhibitor delays tolerance to anxiolytic effect of ethanol and withdrawal-induced anxiety in rats

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Abstract

Dipeptidyl-peptidase IV (DPP-IV) is an enzyme responsible for the metabolism of endogenous gut-derived hormone, glucagon-like peptide-1 (GLP-1). DPP-IV is known for its role in energy homeostasis and pharmacological blockade of this enzyme is a recently approved clinical strategy for the management of type II diabetes. Accumulating evidences suggest that enzyme DPP-IV can affect spectrum of central nervous system (CNS) functions. However, little is known about the role of this enzyme in ethanol-mediated neurobehavioral complications. The objective of the present study was to examine the impact of DPP-IV inhibitor, sitagliptin on the development of tolerance to anxiolytic effect of ethanol and anxiety associated with ethanol withdrawal in rats. A dose–response study revealed that sitaglitpin (20 mg/kg, p.o.) per se exhibit anxiolytic effect in the elevated plus maze (EPM) test in rats. Tolerance to anxiolytic effect of ethanol (2 g/kg, i.p.; 8 % w/v) was observed from 7th day of ethanol-diet (6 % v/v) consumption. In contrast, tolerance to anxiolytic effect of ethanol was delayed in rats that were treated daily with sitagliptin (20 mg/kg, p.o.) as tolerance was observed from 13thday since commencement of ethanol-diet consumption. Discontinuation of rats from ethanol-diet after 15-days of ethanol consumption resulted in withdrawal anxiety between 8 h and 12 h post-abstinence. However, rats on 15-day ethanol-diet with concomitant sitagliptin (20 mg/kg, p.o.) treatment exhibited delay in appearance (24 h post-withdrawal) of withdrawal anxiety. In summary, DPP-IV inhibitors may prove as an attractive research strategy against ethanol tolerance and dependence.

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Authors and Affiliations

  1. Department of Pharmacology, S.T.E.S.s Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune, MS, 411048, India

    Ajaykumar N. Sharma & Ashish Pise

  2. Center for Molecular Psychiatry and Experimental Models in Psychiatry, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston UT Center of Excellence on Mood Disorders, 1941 East Road, Houston, TX, 77054, USA

    Ajaykumar N. Sharma

  3. Department of Chemistry, University of Louisville, Louisville, KY, 40292, USA

    Jay N. Sharma

  4. Department of Medicine, Division of Cardiology, Cardiovascular Institute Stanford University School of Medicine, Stanford, CA, 94305, USA

    Praveen Shukla

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  1. Ajaykumar N. Sharma
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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. Dipeptidyl-peptidase IV (DPP-IV) inhibitor delays tolerance to anxiolytic effect of ethanol and withdrawal-induced anxiety in rats. Metab Brain Dis 30, 659–667 (2015). https://doi.org/10.1007/s11011-014-9603-7

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