D1 agonist-induced excitation of substantia nigra pars reticulata neurons: mediation by D1 receptors on striatonigral terminals via a pertussis toxin-sensitive coupling pathway.
Iontophoresis of dopamine or the D1 agonist SKF 38393 has been shown to elicit current-dependent increases in the firing of rat substantia nigra pars reticulata neurons, suggesting a discrete physiological role for the D1 dopamine receptor population in the substantia nigra. The effects of SKF 38393 differed from those of dopamine, however, in that the D1 agonist also augmented inhibitory responses to applied GABA, whereas dopamine and D2-like agonists were previously found to attenuate responses to GABA. The present studies involved various manipulations of the nigral D1 receptors in order to examine the pharmacological specificity, receptor localization, and second messenger coupling underlying the D1 agonist response. The excitatory and GABA-potentiating effects of SKF 38393 were found to be attributable to D1 receptor stimulation, rather than a nonspecific action, since (1) the effect was mimicked by iontophoresis of A-68930, a D1 agonist of a different structural class than SKF 38393, and (2) the response to SKF 38393 was prevented by intranigral injection of the receptor inactivator N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 50 nmol/0.5 microliter) 1 d before, or the D1 antagonist SCH 23390 (1 microgram/microliter) 1 hr before electrophysiological testing. Additional studies revealed that the involved D1 receptors were located presynaptically on striatonigral terminals. For instance, in rats given ipsilateral striatal kainic acid lesions 1 week earlier, application of SKF 38393 failed to elicit the usual increases in cell firing, but loss of the response was observed only among the group of pars reticulata neurons that were shown to be unresponsive to striatal stimulation (i.e., those whose striatonigral inputs had been terminated by the lesion). Finally, to examine the second messenger coupling characteristics of the involved D1 receptors, several membrane-permeable analogs of cAMP were tested iontophoretically in place of SKF 38393. Surprisingly, none of these compounds gave a pattern of response typical of the D1 agonist, raising questions about the involvement of cAMP. Even more suggestive of an unconventional D1 coupling pathway, the excitatory and GABA-potentiating effects of applied SKF 38393 were completely abolished by prior intranigral injection of the G(i)/G(o) protein inactivator, pertussis toxin. Collectively, these results suggest that stimulation of D1 receptors on striatonigral terminals causes an excitation of substantia nigra pars reticulata neurons with an exaggerated responsiveness to GABA, and the effects appear to be mediated by a pertussis toxin-sensitive (i.e., a non-G-like) G-protein and possibly a second messenger other than cAMP.
Martin
L P
LP
Department of Pharmaceutical Sciences, Bouve College of Pharmacy and Health Sciences, Northeastern University, Boston, Massachusetts 02115.
Waszczak
B L
BL
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists; D008297:Male; D009411:Nerve Endings / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D037342:Pertussis Toxin; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D011804:Quinolines; D011954:Receptors, Dopamine; D010566:Virulence Factors, Bordetella; C000470:EEDQ; D000242:Cyclic AMP; D037342:Pertussis Toxin