Alteration of dopamine transport in the striatum and nucleus accumbens of ovariectomized and estrogen-primed rats following N-(p-isothiocyanatophenethyl) spiperone (NIPS) treatment.
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 microg, 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'-(gamma-thiotriphosphate) ([35S]-GTPgammaS) binding and [3H]-dopamine uptake. A decrease in E(max) for ligand potentiated [35S]-GTPgammaS 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]-GTPgammaS 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.
Thompson
T L
TL
Division of Basic Sciences, Mercer University School of Medicine, Macon, GA 31207, USA. thompson_tl@mercer.edu
Bridges
S R
SR
Weirs
W J
WJ
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D004347:Drug Interactions / Q000502:physiology; D004967:Estrogens / Q000378:metabolism; D004971:Estrus / Q000187:drug effects / Q000378:metabolism; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010052:Ovariectomy; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D013134:Spiperone / Q000031:analogs & derivatives / Q000494:pharmacology*; D013462:Sulfur Radioisotopes / Q000493:pharmacokinetics; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium / Q000493:pharmacokinetics
D002352:Carrier Proteins; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D004967:Estrogens; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D013462:Sulfur Radioisotopes; D014316:Tritium; C068824:N-(4-isothiocyanatophenethyl)spiperone; D019257:Quinpirole; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013134:Spiperone; D004298:Dopamine