Alteration of dopamine transport in the striatum and nucleus accumbens of ovariectomized and estrogen-primed rats following N-(p-isothiocyanatophenethyl) spiperone (NIPS) treatment

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The ability of N-(p-isothiocyanatophenethyl) spiperone (NIPS, 10 mg/kg, 24 h), a selective, irreversible alkylating agent of the dopamine D 2 receptor, to alter properties of dopamine uptake and clearance in the striatum and nucleus accumbens of ovariectomized and estrogen-primed (estradiol benzoate, 10 μg, 48 h, 24 h) rats was examined using voltammetry. The effectiveness of NIPS was evaluated independently by measuring agonist mediated potentiation of [ 35S]-guanosine 5′-(γ-thiotriphosphate) ([ 35S]-GTPγS) binding and [ 3H]-dopamine uptake. A decrease in E max for ligand potentiated [ 35S]-GTPγS binding and a loss of quinpirole potentiated [ 3H]-dopamine uptake was observed consistent with a NIPS mediated alkylation and functional down-regulation of the dopamine D 2 receptor. This down-regulation was associated with an attenuation of the dose dependent uptake of dopamine in both the striatum and the accumbens. Co-administration of estrogen and NIPS resulted in a further attenuation of dopamine potentiated [ 35S]-GTPγS binding measured in vitro and dopamine uptake measured in vivo. Analysis of the voltammetric profile revealed that clearance and T 50 times were significantly prolonged in animals treated with estrogen and NIPS compared with those treated with NIPS alone. These data are consistent with both a steroid mediated impairment in dopamine autoreceptor/dopamine transporter coupling and an independent action of estrogen at the level of the dopamine transporter.