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.