Effect of permanently charged and uncharged dopaminergic agonists on the potassium-induced release of [3H]acetylcholine from striatal slices.

The effects of chemical analogs of dopamine, which are permanently charged or which lack a net positive charge, on the potassium-evoked release of [3H]acetylcholine from mouse striatal slices were studied in order to determine whether a positive charge on the dopamine agonist molecule is required to activate dopaminergic receptors. The striatal slices were first preincubated with [3H]choline, transferred to a superfusion chamber, and then superfused in physiological medium. [3H]Acetylcholine release was evoked by exposure of the slices to a high potassium medium and potential dopamine agonist drugs were added to the medium 10 min before superfusing with high potassium. A permanently charged quaternary ammonium analog and dimethylselenonium analog of dopamine inhibited the potassium-evoked release of [3H]acetylcholine, and this inhibition was antagonized by sulpiride, a dopamine receptor antagonist. However, this inhibition was not antagonized by reserpine and alpha-methyl-p-tyrosine, which was shown to completely antagonize the inhibitory effect of amphetamine, an indirectly acting amine. This suggests that the charged dopamine analogs are acting directly on dopaminergic receptors. In contrast to the permanently charged dopamine analogs, analogs of dopamine with no net positive charge produced no inhibition of the potassium-evoked [3H]acetylcholine release. These in vitro observations are in agreement with a behavioral model in which a permanently uncharged monomethylsulfide analog of dopamine was ineffective in eliciting circling behavior after its unilateral injection into the striatum of rats in which dopamine neurons were previously lesioned by the injection of 6-hydroxydopamine into the medial forebrain bundle. In contrast, under these same conditions, the intrastriatal injection of the charged quaternary ammonium or dimethylsulfonium analog of dopamine elicited intense contralateral circling. These results suggest that the charged form of a dopamine agonist molecule is required to bind to and activate the dopamine receptor regulating [3H]acetylcholine release and circling behavior.