title: Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine.
abstract: Dopamine D(3) receptors are structurally highly homologous to other D(2)-like dopamine receptors, but differ from them pharmacologically. D(3) receptors are notably resistant to alkylation by 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which readily alkylates D(2) receptors. We compared EEDQ with N-(p-isothiocyanatophenethyl)spiperone (NIPS), a selective D(2)-like receptor alkylating agent, for effects on D(3) and D(2) receptors in rat brain using autoradiographic analysis. Neither agent occluded D(3) receptors in vivo at doses that produced substantial blockade of D(2) receptors, even after catecholamine-depleting pretreatments. In vitro, however, D(3) receptors were readily alkylated by both NIPS (IC(50)=40 nM) and EEDQ (IC(50)=12 microM). These effects on D(3) sites were blocked by nM concentrations of dopamine, whereas microM concentrations were required to protect D(2) receptors from the alkylating agents. The findings are consistent with the view that alkylation of D(3) receptors in vivo is prevented by its high affinity for even minor concentrations of endogenous dopamine.
authors.affiliation: Mailman Research Center, McLean Division of Massachusetts General Hospital, 115 Mill Street, Belmont, MA, USA. kz@mclean.harvard.edu
authors.forename: K
authors.initials: K
authors.lastname: Zhang
authors.forename: N T
authors.initials: NT
authors.lastname: Weiss
authors.forename: F I
authors.initials: FI
authors.lastname: Tarazi
authors.forename: N S
authors.initials: NS
authors.lastname: Kula
authors.forename: R J
authors.initials: RJ
authors.lastname: Baldessarini
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects; D004298:Dopamine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050637:Receptors, Dopamine D3; D013134:Spiperone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000477:Alkylating Agents; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D018696:Neuroprotective Agents; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C068824:N-(4-isothiocyanatophenethyl)spiperone; D013134:Spiperone; C000470:EEDQ; D004298:Dopamine