Endogenous DA-mediated feedback inhibition of DA neurons: involvement of both D(1)- and D(2)-like receptors.
To investigate the role of D(1)-like receptors in endogenous dopamine (DA)-mediated feedback control of DA neurons in vivo, single unit recordings were made from rat nigral DA cells using low cerveau isolé preparations. The D(2) antagonist raclopride, but not the D(1) antagonist SCH23390, increased baseline activity of DA neurons, suggesting that spontaneously released DA acts primarily through D(2)-like receptors to inhibit DA cells. However, feedback inhibition induced by an increased DA release by D-amphetamine (1 mg/kg, i.v.) was partially reversed by SCH23390. The same inhibition, on the other hand, was always completely reversed by raclopride, suggesting that the D(1)-mediated portion of the inhibition depends upon co-activation of D(2)-like receptors. In rats with forebrain hemitransections, D-amphetamine-induced inhibition was markedly decreased and the remaining inhibition was not blocked by SCH23390, supporting the suggestion that D(1)-D(2) co-activation-induced inhibition is mediated through long feedback pathways. In chloral hydrate-anesthetized rats, D-amphetamine-induced inhibition was also insensitive to SCH23390; however, the degree of the inhibition was not reduced. Combined with previous studies, these data suggest that chloral hydrate not only inactivates the D(1) feedback pathway but also enables the D(2) feedback pathway to operate independently of D(1)-like receptors. Conversely, in parkinsonian animals D(1) receptor activation alone has been reported to inhibit DA cells. Taken together, these results suggest that a major portion of endogenous DA-mediated feedback inhibition is due to concurrent activation of D(1)- and D(2)-like receptors. However, this D(1)-D(2) interdependence may alter under certain conditions and may play a role in the pathophysiology of Parkinson's disease.
Shi
W X
WX
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. wei-xing.shi@yale.edu
Pun
C L
CL
Smith
P L
PL
Bunney
B S
BS
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D005246:Feedback; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016548:Prosencephalon / Q000502:physiology*; D020891:Raclopride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*
D001552:Benzazepines; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D020891:Raclopride; D003913:Dextroamphetamine; D004298:Dopamine