Irreversible receptor inactivation reveals differences in dopamine receptor reserve between A9 and A10 dopamine systems: an electrophysiological analysis.
Partial receptor inactivation was used as a tool to examine whether differences in receptor reserve exist between the dopamine receptor populations which mediate responses of substantia nigra (A9) and ventral tegmental area (A10) dopamine neurons to dopamine agonist drugs. The irreversible receptor inactivator, N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline (EEDQ), was administered to rats intraperitoneally at a dose of 6 mg/kg (in an ethanol-water vehicle). Approximately 24 h after EEDQ treatments, extracellular, single-unit recording experiments were carried out. In the first series of experiments, dose-response curves were constructed for the inhibition of A9 and A10 dopamine cell firing by intravenous administration of the potent dopamine agonist, R-(-)-N-n-propylnorapomorphine (NPA). For the A9 dopamine cell group, EEDQ pretreatments caused a 3-fold rightward shift in the NPA dose-response curve (ED50S, 0.3 vs 0.8 micrograms/kg for vehicle- and EEDQ-treated rats, respectively), but there was no change in the maximum attainable response (greater than 95% inhibition of cell firing). For A10 neurons, the same EEDQ treatments produced a greater rightward shift in the dose-response curve to NPA (ED50s, 0.6 vs 5.4 micrograms/kg for vehicle- and EEDQ-treated rats), and also depressed the maximum response by about 25% relative to the control (vehicle) curve. The dose-response curves from each region were subjected to Furchgott analysis to determine relative receptor occupancy-response relationships for NPA. For the A9 system, a steep, hyperbolic occupancy-response plot revealed that a 50% inhibitory response required only 4% receptor occupancy, while complete (greater than 95%) inhibition of cell firing required about 30% occupancy. This suggests about a 70% receptor reserve for this agonist in inhibiting A9 dopamine cell firing. The occupancy-response curve for A10 cells was less steep with 50% and maximal (greater than 95%) responses occurring when 11 and 70% of receptors were occupied by the agonist, indicating only about a 30% reserve for A10 cell responses to NPA. While the level of 'spare' receptors differed substantially between the two areas, calculated pseudo-KA values were similar (7.7 micrograms/kg for A9 cells and 5.5 micrograms/kg for A10 cells), suggesting no regional differences in receptor affinity. To explore where the differences in receptor reserve might reside, a second series of studies evaluated the effects of iontophoretically applied dopamine and NPA on both cell groups in vehicle- and EEDQ-treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)
Cox
R F
RF
Pharmacology Section, College of Pharmacy and Allied Health Professions, Northeastern University, Boston, MA 02115.
Waszczak
B L
BL
D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists; D004594:Electrophysiology / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000502:physiology*
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D011804:Quinolines; D011954:Receptors, Dopamine; C009074:N-n-propylnorapomorphine; C000470:EEDQ; D006220:Haloperidol; D001058:Apomorphine; D004298:Dopamine