Effect of amphetamine-induced dopamine release on radiotracer binding to D-1 and D-2 receptors in rat brain striatal slices

Abstract

The in vivo binding of positron emission tomography (PET) and single photon emission computer tomography (SPECT) radiotracers to dopamine D-2 receptors in the striatum can be influenced by competition with endogenous dopamine. The present study was undertaken to determine if a similar inhibition of radiotracer binding to dopamine receptors could be observed following pharmacologically-evoked dopamine release in rat brain striatal slices. Striatal slices were incubated in a large volume of oxygenated Krebs saline and exposed to amphetamine or methamphetamine to evoke dopamine release within the slice. Amphetamine and methamphetamine, at concentrations up to 30 muM, reduced [H-3]raclopride binding in the slices by 77% and 86%, respectively, with 50% inhibition at 1.6 muM amphetamine or 3.0 muM methamphetamine. Neither drug produced a significant effect on binding of [H-3]SCH 23390 in the slices. This suggests that dopamine was able to interfere with radiotracer binding to D-2 but not D-1 receptors. The dopamine uptake blockers, cocaine and methylphenidate, had relatively little effect by themselves on [H-3]raclopride binding but, by inhibiting amphetamine-induced dopamine release, significantly reduced inhibition of [H-3]raclopride binding by a low (3 muM) amphetamine concentration. At a higher (30 muM) amphetamine concentration the inhibition of [H-3]raclopride binding was not antagonized by uptake blockers and data obtained from homogenate binding experiments indicated a direct displacement of [H-3]raclopride binding by amphetamine at this concentration. In conclusion the data obtained in the present study demonstrate that the effects of amphetamine on striatal radiotracer accumulation observed in PET and SPECT can also be observed in brain slices in vitro and, at least at low amphetamine concentrations, are mediated by competition with released dopamine.