Endogenous DA‐mediated feedback inhibition of DA neurons: Involvement of both D1‐ and D2‐like receptors

Abstract

To investigate the role of D1-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 D2 antagonist raclopride, but not the D1 antagonist SCH23390, increased baseline activity of DA neurons, suggesting that spontaneously released DA acts primarily through D2-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 D1-mediated portion of the inhibition depends upon co-activation of D2-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 D1-D2 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 D1 feedback pathway but also enables the D2 feedback pathway to operate independently of D1-like receptors. Conversely, in parkinsonian animals D1 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 D1- and D2-like receptors. However, this D1–D2 interdependence may alter under certain conditions and may play a role in the pathophysiology of Parkinson's disease. Synapse 35:111–119, 2000. © 2000 Wiley-Liss, Inc.