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 m odulate dopaminergic activity. The role of A(2A) receptors in psychostimula nt action is less well understood because of the lack of A(2A)-selective co mpounds with access to the central nervous system. To investigate the A(2A) adenosinergic regulation of psychostimulant responses, we examined the con sequences of genetic deletion of A(2A) receptors on psychostimulant-induced behavioral responses. The extent of dopaminergic innervation and expressio n of dopamine receptors in the striatum were indistinguishable between A(2A ) receptor knockout and wild-type mice. However, locomotor responses to amp hetamine and cocaine were attenuated in A(2A), knockout mice. In contrast, D-1-like receptor agonists SKF81297 and SKF38393 produced identical locomot or stimulation and grooming, respectively, in wildtype and A(2A) knockout m ice. Similarly, the D-2-like agonist quinpirole produced motor-depression a nd stereotypy that were indistinguishable between A(2A) knockout and wild-t ype mice. Furthermore, attenuated amphetamine- (but not SKF81297-) induced locomotion was observed in pure 129-Steel as well as hybrid 129-Steel x C57 BL/6 mice, confirming A(2A) receptor deficiency land not genetic background ) as the cause of the blunted psychostimulant responses in A(2A) knockout m ice. These results demonstrate that A(2A) receptor deficiency selectively attenu ates psychostimulant-induced behavioral responses and support an important role for the A(2A) receptor in modulating psychostimulant effects. (C) 2000 IBRO. Published by Elsevier Science Ltd.