Caffeine and a selective adenosine A2A receptor antagonist induce reward and sensitization behavior associated with increased phospho-Thr75-DARPP-32 in mice

Caffeine, an antagonist of adenosine A(1) and A(2A) receptor, is the most widely used psychoactive substance in the world. Evidence indicates that caffeine interacts with the neuronal systems involved in drug reinforcing. Although adenosine A(1) and/or A(2A) receptor have been found to play important roles in the locomotor stimulation and probably reinforcing effect of caffeine, the relative contribution of the A(1) and/or A(2A) receptors to the acute and chronic motor activation and reinforcing effects of caffeine has not been completely investigated. The roles of adenosine A(1) and/or A(2A) receptor and the association of phospho-Thr75-dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) in the motor activation and reinforcing effects of caffeine, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A(1) antagonist, and 5-amino-7-(beta-phenylethyl)-2-(8-furyl) pyrazolol [4,3-e]-1,2,4-triazolol [1,5-c] pyrimidine (SCH58261), a selective A(2A) receptor antagonist were examined. Locomotor stimulation and behavioral sensitization of caffeine, DPCPX, and SCH58261 were studied in C57BL/6 male mice following acute and chronic administration. Conditioned place preference (CPP) paradigm was used to evaluate the drug-seeking potential of these compounds. Furthermore, the expression of phospho-Thr75-DARPP-32 in striatal membrane from behaviorally sensitized mice was analyzed by Western blot. Caffeine and SCH58261 but not DPCPX induced CPP and locomotor sensitization in C57BL/6 mice. The locomotor sensitization after chronic treatment was associated with increased DARPP-32 phosphorylation at Thr75 in the striatum. Caffeine-induced reinforcing effect and behavioral sensitization are mediated by antagonism at adenosine A(2A) receptor. These effects are associated with phosphorylation of DARPP-32 at Thr75 in the striatum.