Caffeine is an adenosine A₁ and A₂ receptor antagonist with marked psychomotor stimulant effects. Substantial evidence suggests that the motor stimulant effects of caffeine are mediated by antagonistic interactions between specific adenosine and dopamine (DA) receptor subtypes located in the basal ganglia (Ferre et al., 1997). The aims of the present study were to examine the in vivo and in vitro effects of caffeine on DA D₁ receptors in rat striatum.

DA D₁ receptors in male Wistar rat striatum (150-200g) were labelled with [³H] SCH 23390 and non-specific binding was defined using 1 µM piflutixol. The effect of caffeine on D₁ receptor density was determined in saturation experiments using striatal membranes prepared from rats that were sacrificed 14 days after cessation of treatment with caffeine, 5 mg/kg i.p. twice daily for 4 days. The effects of caffeine, DPCPX (A₁ antagonist), CPA (A₁ agonist) and CGS 21680 (A₂ agonist) on the affinity of DA for high (K_H) and low (K_L) affinity states of the D₁ receptor were examined in competition experiments. Binding data were analysed using GraphPad Prism.

Treatment of rats with low doses of caffeine for 4 days caused a 50% reduction in striatal D₁ receptor density from 21.6 ±2.3 to 11.3 ±1.4 fmol mg^-1 wet wt (mean ±SEM, n=4) (p<0.01, t-test). There was no change in K_d (control: 0.21 ±0.10 nM, caffeine: 0.13 ±0.08 nM). The displacement of [³H] SCH 23390 by DA was best described by a two-site model under control conditions (Table 1). Caffeine, DPCPX and CPA all converted the interaction between DA and D₁ receptors into single, low affinity site. In contrast, CGS 21680 did not alter the two-site interaction of DA (Table 1).

Table 1. Effect of adenosine ligands on affinity of DA for rat striatal D 1 receptors

mean ±SEM; pK_H, pK_L and pK_i are -log of the corresponding K_H, K_L and K_i values.

In summary, in vivo administration of low doses of caffeine caused a significant and persistent reduction in the density of D₁ receptors. In vitro treatment with caffeine prevented DA having a high affinity interaction with D₁ receptors. This latter effect was mimicked by an A₁ agonist, an A₁ antagonist but not by an A₂ agonist.

Ferre S et al., (1997) Trends Neurosci. 20, 482-487

This work was supported by Enterprise Ireland and University College Dublin