[³H]Threo‐(±)‐Methylphenidate Binding to 3,4‐Dihydroxyphenylethylamine Uptake Sites in Corpus Striatum: Correlation with the Stimulant Properties of Ritalinic Acid Esters

Abstract: Saturable and stereoselective binding sites for [³H]threo‐(±)‐methylphenidate were characterized in rat brain membranes. The highest density of [³H]threo‐(±)‐ methylphenidate binding sites was found in the synapto somal fraction of corpus striatum. Scatchard analysis revealed a single class of noninteracting binding sites with an apparent dissociation constant (K_D) of 235 nM and a maximum number of binding sites (B_max) of 13.4 pmol/mg protein. Saturable, high‐affinity binding of [³H]threo‐(±)‐methylphenidate to striatal synaptosomal membranes was dependent on the presence of sodium ions. A good correlation (r = 0.88; p < 0.001) was observed between the potencies of various psychotropic drugs in displacing [³H]threo‐(±)‐methylphenidate from these sites and their potencies as inhibitors of [³H]3,4‐dihydroxyphenylethyl‐ amine ([³H]dopamine) uptake into striatal synaptosomes. A good correlation (r = 0.85; p < 0.001) was also observed between the potencies of a series of ritalinic acid esters in inhibiting [³H]threo‐(±)‐methylphenidate binding to striatal synaptosomal membranes and their potencies as motor stimulants in mice. These observations suggest that the binding sites for [³H]threo‐(±)‐methyl‐phenidate described here are associated with a dopamine uptake or transport complex, and that these sites may mediate the motor stimulant properties of ritalinic acid esters such as methylphenidate.