Motor stimulant effects of caffeine in 6-hydroxydopamine-lesioned rats are dependent on previous stimulation of dopamine receptors: a different role of D1 and D2 receptors.

Caffeine has been reported to induce contralateral rotational behaviour in rats bearing a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway. In order to define the role of dopamine receptors in the mediation of this behaviour, we have evaluated the influence of previous exposure to a dopamine receptor agonist and the importance of the time elapsed from the 6-hydroxydopamine lesion on the rotational behaviour induced by caffeine. Separate groups of rats lesioned with 6-hydroxydopamine 2 weeks previously were exposed to four administrations of the D1/D2 receptor agonist apomorphine (0.3 mg/kg s.c.) (primed) or vehicle (drug-naive). Three days later, all rats received caffeine (30 mg/kg s.c.). Drug-naive 6-hydroxydopamine-lesioned rats did not rotate in response to caffeine, while rats primed with apomorphine rotate contralaterally in response to caffeine. When apomorphine priming was paired to the same environment (hemispherical bowls) where rats received caffeine, rotational behaviour was significantly higher than that obtained in rats primed in an unpaired environment (cylinders). Repeated priming with the D2/D3 receptor agonist quinpirole (0.2 mg/kg s.c.) induced a totally context-dependent contralateral rotation in response to caffeine, while caffeine contralateral rotation was not dependent from the context after repeated priming with the D1 agonist SKF 38393 [1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol hydrochloride, 3 mg/kg s.c.]. Caffeine-mediated contralateral rotation was also evaluated in rats lesioned with 6-hydroxydopamine 12 weeks previously and exposed to four administrations of apomorphine or vehicle. As for rats repeatedly exposed to vehicle or apomorphine 2 weeks after 6-hydroxydopamine lesioning, caffeine failed to induce contralateral rotation in drug-naive rats, while it did induce a partially context-dependent contralateral rotation in apomorphine-primed rats. Different from rats receiving apomorphine priming 2 weeks after 6-hydroxydopamine lesioning, in 12 week-lesioned rats, caffeine also induced contralateral rotation after one priming with apomorphine (0.3 mg/kg s.c.), a condition which fails to induce context-dependent rotation. Administration of selective antagonists of A1 (8-cyclopentyl-1,3-dipropylxanthine), (DPCPX) or A2A (5-amino-2-(2-furyl)-7-(3-phenylpropyl)-pyrazolo[4,3-e]-1 ,2,4-triazolo[5c]pirimidine), (SCH 58261) adenosine receptors failed to induce contralateral rotation either alone or in combination in 12 week-6-hydroxydopamine-lesioned rats repeatedly primed with apomorphine. All together, the results indicate that: (i) caffeine does not induce any contralateral rotation in drug-naive 6-hydroxydopamine-lesioned rats; (ii) priming with a dopamine agonist enables caffeine to induce contralateral rotation, this rotation is, however, context independent only after priming with a selective D1 agonist; (iii) contralateral rotation in response to caffeine is dependent on the time from the 6-hydroxydopamine lesion; (iv) blockade of A1 and A2A adenosine receptors with selective antagonists does not induce contralateral rotational behaviour in 6-hydroxydopamine-lesioned rats.