RATIONALE:
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. OBJECTIVE: 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. METHODS: 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. RESULTS:
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. CONCLUSION: 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.
