title: Inhibition of substantia nigra dopamine cell firing by R(-)-N-n-propylnorapomorphine: electrophysiological and autoradiographic studies after regional inactivation of dopamine receptors by microinjection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.
abstract: The irreversible receptor inactivator, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), was injected into rat striatum or substantia nigra to study potential contributions of dopamine receptors in each area to the inhibition of substantia nigra (A9) dopamine cell firing by i.v. R(-)-N-n-propylnorapomorphine (NPA), a dopamine agonist. Extracellular, single unit recording studies showed that the numbers of active dopamine cells, basal firing rates and responses to i.v. R(-)-NPA were unchanged a day after striatal EEDQ injections, despite significant losses of striatal D1 and D2 receptors (confirmed by autoradiography). These results indicate that striatal receptors do not control the basal activity of A9 neurons, nor do they mediate inhibitions of firing by R(-)-NPA. Microinjections of EEDQ into substantia nigra, however, inactivated 75-78% of nigral D1 and D2 receptors and reduced the number of active dopamine cells and slightly increased firing rates. Moreover, dose-response curves to R(-)-NPA were shifted 10-fold to the right and the maximum inhibitory response was depressed. Furchgott analysis of the dose-response curves yielded a steep occupancy-response curve with maximum (> 95%) inhibition of firing at only 24% receptor occupation (i.e., 76% reserve). Thus, the substantial (approximately 70%) receptor reserve previously shown to exist for inhibition of dopamine cell firing by i.v. R(-)-NPA20,21 appears to be intrinsic to the nigra. To assess contributions of nigral D1 and D2 receptors to this response, selective inactivation of each receptor subtype was achieved (confirmed autoradiographically) by treating rats with SCH 23390 (4 mg/kg) or S(-)eticlopride (2 mg/kg), respectively, 30 min before intranigral EEDQ. Selective D2, but not D1, receptor inactivation produced rightward shifts and depressed the maximum of the R(-)-NPA dose-response curve in a manner like that observed after non-selective inactivation of nigral dopamine receptors. Unexpectedly, pretreatment with SCH 23390 (to protect D1 receptors) also produced a modest rightward shift in the R(-)-NPA dose-response curve, suggesting a slight role for D1 receptors in this response. These results indicate that inhibition of A9 dopamine cell firing by i.v. R(-)-NPA is mediated by dopamine receptors located in substantia nigra, but not striatum and confirm the predominant role of nigral D2 receptors.
authors.affiliation: Pharmacology Section, Bouve College of Pharmacy and Health Sciences, Northeastern University, Boston, MA 02115.
authors.forename: R F
authors.initials: RF
authors.lastname: Cox
authors.forename: B L
authors.initials: BL
authors.lastname: Waszczak
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001345:Autoradiography; D015259:Dopamine Agents / Q000494:pharmacology*; D008297:Male; D008845:Microinjections; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects*
chemical_list: D015259:Dopamine Agents; D011804:Quinolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C009074:N-n-propylnorapomorphine; C000470:EEDQ; D001058:Apomorphine