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A critical role of striatal A2A R-mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine.

Wright, SR, Zanos, P, Georgiou, P, Yoo, JH, Ledent, C, Hourani, SM, Kitchen, I, Winsky-Sommerer, R and Bailey, A (2015) A critical role of striatal A2A R-mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine. ADDICT BIOL.

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Abstract

Addiction to psychostimulants is a major public health problem with no available treatment. Adenosine A2A receptors (A2A R) co-localize with metabotropic glutamate 5 receptors (mGlu5 R) in the striatum and functionally interact to modulate behaviours induced by addictive substances, such as alcohol. Using genetic and pharmacological antagonism of A2A R in mice, we investigated whether A2A R-mGlu5 R interaction can regulate the locomotor, stereotypic and drug-seeking effect of methamphetamine and cocaine, two drugs that exhibit distinct mechanism of action. Genetic deletion of A2A R, as well as combined administration of sub-threshold doses of the selective A2A R antagonist (SCH 58261, 0.01 mg/kg, i.p.) with the mGlu5 R antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (0.01 mg/kg, i.p.), prevented methamphetamine- but not cocaine-induced hyperactivity and stereotypic rearing behaviour. This drug combination also prevented methamphetamine-rewarding effects in a conditioned-place preference paradigm. Moreover, mGlu5 R binding was reduced in the nucleus accumbens core of A2A R knockout (KO) mice supporting an interaction between these receptors in a brain region crucial in mediating addiction processes. Chronic methamphetamine, but not cocaine administration, resulted in a significant increase in striatal mGlu5 R binding in wild-type mice, which was absent in the A2A R KO mice. These data are in support of a critical role of striatal A2A R-mGlu5 R functional interaction in mediating the ambulatory, stereotypic and reinforcing effects of methamphetamine but not cocaine-induced hyperlocomotion or stereotypy. The present study highlights a distinct and selective mechanistic role for this receptor interaction in regulating methamphetamine-induced behaviours and suggests that combined antagonism of A2A R and mGlu5 R may represent a novel therapy for methamphetamine addiction.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Biochemical Sciences
Authors :
AuthorsEmailORCID
Wright, SRUNSPECIFIEDUNSPECIFIED
Zanos, PUNSPECIFIEDUNSPECIFIED
Georgiou, PUNSPECIFIEDUNSPECIFIED
Yoo, JHUNSPECIFIEDUNSPECIFIED
Ledent, CUNSPECIFIEDUNSPECIFIED
Hourani, SMUNSPECIFIEDUNSPECIFIED
Kitchen, IUNSPECIFIEDUNSPECIFIED
Winsky-Sommerer, RUNSPECIFIEDUNSPECIFIED
Bailey, AUNSPECIFIEDUNSPECIFIED
Date : 15 May 2015
Identification Number : 10.1111/adb.12259
Uncontrolled Keywords : A2A receptor, cocaine, conditioned-place preference, mGlu5 receptor, methamphetamine, stereotypy
Related URLs :
Additional Information : This is the peer reviewed version of the following article: Wright, SR, Zanos, P, Georgiou, P, Yoo, JH, Ledent, C, Hourani, SM, Kitchen, I, Winsky-Sommerer, R and Bailey, A (2015) A critical role of striatal A2A R-mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine. ADDICT BIOL. ISSN 1355-6215, which has been published in final form at http://dx.doi.org/10.1111/adb.12259. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Depositing User : Symplectic Elements
Date Deposited : 07 Oct 2015 13:40
Last Modified : 15 May 2016 01:08
URI: http://epubs.surrey.ac.uk/id/eprint/808744

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