Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: a therapeutic window

Mihov, Yoan; Hasler, Gregor (2016). Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: a therapeutic window. International journal of neuropsychopharmacology, 19(7), pp. 1-11. Cambridge University Press 10.1093/ijnp/pyw002

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Background: Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to nd out if mGluR5 NAMs have a therapeutic potential that can be translated to the clinic. Methods: Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) and 2-Methyl-6-(phenylethynyl)pyridine (MPEP) on paradigms with cocaine, ethanol, nicotine, and food in rats. Results: MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine at doses ≥1 mg/kg and 2.5mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical signi cance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine, but not food, was reduced by MTEP and MPEP in the dose range of 1 to 2mg/kg and 2.5 to 3.2mg/kg, respectively. This dose range corresponds to approximately 50% to 80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window. Conclusion: Altogether, this review suggests a therapeutic window for mGluR5 NAMs that can be translated to the treatment of substance-related and addictive disorders.

Item Type:

Journal Article (Review Article)

Division/Institute:

04 Faculty of Medicine > University Psychiatric Services > University Hospital of Psychiatry and Psychotherapy > Translational Research Center
04 Faculty of Medicine > University Psychiatric Services > University Hospital of Psychiatry and Psychotherapy
04 Faculty of Medicine > University Psychiatric Services > University Hospital of Psychiatry and Psychotherapy > Healthcare Research

UniBE Contributor:

Mihov, Yoan and Hasler, Gregor

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1461-1457

Publisher:

Cambridge University Press

Funders:

[UNSPECIFIED] University of Bern

Language:

English

Submitter:

Yoan Venceslavov Mihov

Date Deposited:

08 Mar 2017 14:22

Last Modified:

08 Mar 2017 14:22

Publisher DOI:

10.1093/ijnp/pyw002

PubMed ID:

26802568

Additional Information:

Supplementary Information (Text & Abbildungen) sind auf der Seite des Verlegers verfügbar.

Uncontrolled Keywords:

glutamate; mGluR5; addiction; MPEP; MTEP

BORIS DOI:

10.7892/boris.92319

URI:

https://boris.unibe.ch/id/eprint/92319

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