title: Adenosine 2A receptors modulate reward behaviours for methamphetamine.
abstract: Addiction to methamphetamine (METH) is a global health problem for which there are no approved pharmacotherapies. The adenosine 2A (A2 A ) receptor presents a potential therapeutic target for METH abuse due to its modulatory effects on striatal dopamine and glutamate transmission. Notably, A2 A receptor signalling has been implicated in the rewarding effects of alcohol, cocaine and opiates; yet, the role of this receptor in METH consumption and seeking is essentially unknown. Therefore, the current study used A2 A knockout (KO) mice to assess the role of A2 A in behaviours relevant to METH addiction. METH conditioned place preference was absent in A2 A KO mice compared with wild-type (WT) littermates. Repeated METH treatment produced locomotor sensitization in both genotypes; however, sensitization was attenuated in A2 A KO mice in a dose-related manner. METH intravenous self-administration was intact in A2 A KO mice over a range of doses and schedules of reinforcement. However, the motivation to self-administer was reduced in A2 A KO mice. Regression analysis further supported the observation that the motivation to self-administer METH was reduced in A2 A KO mice even when self-administration was similar to WT mice. Sucrose self-administration was also reduced in A2 A KO mice but only at higher schedules of reinforcement. Collectively, these data suggest that A2 A signalling is critically required to integrate rewarding and motivational properties of both METH and natural rewards.
authors.affiliation: Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Australia.|Florey Department of Neuroscience and Mental Health, University of Melbourne, Australia.
authors.forename: Rose
authors.initials: R
authors.lastname: Chesworth
authors.affiliation: Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Australia.|Florey Department of Neuroscience and Mental Health, University of Melbourne, Australia.|Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Brown
authors.affiliation: Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Australia.|Florey Department of Neuroscience and Mental Health, University of Melbourne, Australia.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Institut de Recherche Interdisciplinaire, Faculté de Médecine, Université de Bruxelles, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.affiliation: Behavioural Neuroscience Division, Florey Institute of Neuroscience and Mental Health, Australia.|Florey Department of Neuroscience and Mental Health, University of Melbourne, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003216:Conditioning, Operant; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D043683:Receptors, Adenosine A2 / Q000502:physiology*; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration; D013395:Sucrose / Q000494:pharmacology; D013549:Sweetening Agents / Q000494:pharmacology
chemical_list: D000697:Central Nervous System Stimulants; D043683:Receptors, Adenosine A2; D013549:Sweetening Agents; D008694:Methamphetamine; D013395:Sucrose
keywords: Conditioned place preference; intravenous self-administration; mice; psychostimulant