Potentiation of amphetamine-mediated responses in caffeine-sensitized rats involves modifications in A2A receptors and zif-268 mRNAs in striatal neurons

Subchronic intermittent administration of caffeine induces sensitization of motor behaviour and promotes cross-sensitization to amphetamine motor activity. In order to evaluate the possible mechanisms at the basis of these effects, modifications in A2A receptor and zif-268 mRNAs were evaluated in rats subchronically treated with caffeine (15 mg/kg i.p.) and challenged with caffeine (15 mg/kg i.p.) or amphetamine (0.5, 1 mg/kg s.c.) 3 days after discontinuation of treatment. Results showed that the sensitized motor response to caffeine was associated with a decrease of adenosine A2A receptor and zif-268 mRNA levels in the striatum and nucleus accumbens, whereas cross-sensitization to amphetamine was linked to a more pronounced increase of zif-268 mRNA levels in the striatum, but not in the nucleus accumbens. Single-cell analysis showed that zif-268 mRNA modifications occurred in Enk(+) striatopallidal neurons after acute or subchronic treatment with caffeine and in Enk(-) striatonigral neurons after acute amphetamine administration. Potentiation of amphetamine effects was not associated with modifications of amphetamine-induced dopamine release in nucleus accumbens in caffeine-pretreated rats compared with vehiclepretreated rats. Results demonstrate that sensitization to caffeine and cross-sensitization to amphetamine are associated with post-synaptic neuroadaptive changes in selective neuronal populations of the striatum.