Selective attenuation of psychostimulant-induced behavioral responses in mice lacking A(2A) adenosine receptors.
A(2A) adenosine receptors are highly expressed in the striatum where they modulate dopaminergic activity. The role of A(2A) receptors in psychostimulant action is less well understood because of the lack of A(2A)-selective compounds with access to the central nervous system. To investigate the A(2A) adenosinergic regulation of psychostimulant responses, we examined the consequences of genetic deletion of A(2A) receptors on psychostimulant-induced behavioral responses. The extent of dopaminergic innervation and expression of dopamine receptors in the striatum were indistinguishable between A(2A) receptor knockout and wild-type mice. However, locomotor responses to amphetamine and cocaine were attenuated in A(2A) knockout mice. In contrast, D(1)-like receptor agonists SKF81297 and SKF38393 produced identical locomotor stimulation and grooming, respectively, in wild-type and A(2A) knockout mice. Similarly, the D(2)-like agonist quinpirole produced motor-depression and stereotypy that were indistinguishable between A(2A) knockout and wild-type mice. Furthermore, attenuated amphetamine- (but not SKF81297-) induced locomotion was observed in pure 129-Steel as well as hybrid 129-SteelxC57BL/6 mice, confirming A(2A) receptor deficiency (and not genetic background) as the cause of the blunted psychostimulant responses in A(2A) knockout mice. These results demonstrate that A(2A) receptor deficiency selectively attenuates psychostimulant-induced behavioral responses and support an important role for the A(2A) receptor in modulating psychostimulant effects.
Chen
J F
JF
Molecular Neurobiology Laboratory and Neurology Research Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Beilstein
M
M
Xu
Y H
YH
Turner
T J
TJ
Moratalla
R
R
Standaert
D G
DG
Aloyo
V J
VJ
Fink
J S
JS
Schwarzschild
M A
MA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005838:Genotype; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000032:analysis / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000032:analysis / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics*
D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018047:Receptors, Purinergic P1; D003042:Cocaine; D004298:Dopamine