title: A critical role of striatal A2A R-mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine.
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.
authors.affiliation: Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
authors.forename: Sherie R
authors.initials: SR
authors.lastname: Wright
authors.affiliation: Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
authors.forename: Panos
authors.initials: P
authors.lastname: Zanos
authors.affiliation: Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
authors.forename: Polymnia
authors.initials: P
authors.lastname: Georgiou
authors.affiliation: Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Yoo
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.affiliation: Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Hourani
authors.affiliation: Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Kitchen
authors.affiliation: Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Winsky-Sommerer
authors.affiliation: Sleep, Chronobiology and Addiction Group, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK.
authors.forename: Alexis
authors.initials: A
authors.lastname: Bailey
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects*; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000493:pharmacokinetics*; D051379:Mice; D018345:Mice, Knockout; D011597:Psychomotor Performance / Q000187:drug effects*; D043705:Receptor, Adenosine A2A / Q000187:drug effects*; D064529:Receptor, Metabotropic Glutamate 5 / Q000187:drug effects*
chemical_list: D000697:Central Nervous System Stimulants; D043705:Receptor, Adenosine A2A; D064529:Receptor, Metabotropic Glutamate 5; D008694:Methamphetamine
keywords: A2A receptor; cocaine; conditioned-place preference; mGlu5 receptor; methamphetamine; stereotypy