Dopamine Depletion Preferentially Impairs D₁ over D₂‐Receptor Regulation of Striatal In Vivo Acetylcholine Release

Abstract

The roles of D2 and D1 dopaminergic receptors on the regulation of striatal acetylcholine (ACh) release in vivo were examined for a period of 120 min after acute (2 h) or prolonged (16 h) depletion of brain dopamine (DA) by alpha-methyl-p-tyrosine. The reduction of DA transmission did not affect basal ACh output after 2 h but markedly lowered ACh release by 16 h (50%). Acute alpha-methyl-p-tyrosine pretreatment prevented the reduction of ACh release by the D1 antagonist SCH 23390 and its increase by the D2 antagonist, remoxipride, consistent with a drastic reduction of DA transmission at both DA receptors. However, 16 h after alpha-methyl-p-tyrosine, the effect of remoxipride on ACh release was restored, but SCH 23390 still had no effect, suggesting that the D2 inhibitory tone on ACh release had recovered, whereas the reduction of the D1 facilitatory influence persisted. The D1 facilitatory control of ACh neurotransmission thus appears to be more sensitive than the D2 inhibitory control to a reduction in DA transmission. The new model of DA-ACh interaction resulting from these data casts fresh light on the relationship between changes in DA transmission and extrapyramidal motor function.

D2Dopamine Receptor-Mediated Modulation of Voltage-Dependent Na+Channels Reduces Autonomous Activity in Striatal Cholinergic Interneurons

“…A major component of the dopaminergic regulation of cholinergic function is mediated by D 2 receptor inhibition of spike-driven Ca 2ϩ influx and acetylcholine release (Lehmann and Langer, 1983;Bertorelli et al, 1992;Stoof et al, 1992;DeBoer et al, 1993;Di Chiara et al, 1994;. However, there are compelling reasons to believe there is more to this story.…”

“…This modulation could account, in part, for conjectured involvement of D 1 -class receptors in generation of the pause (Watanabe and Kimura, 1998). These alterations in intrinsic properties governing autonomous spiking complement the direct D 2 receptormediated inhibition of acetylcholine release (Lehmann and Langer, 1983;Bertorelli et al, 1992;Stoof et al, 1992;DeBoer et al, 1993;Di Chiara et al, 1994;, further reducing the impact of cholinergic interneurons on striatal circuitry.…”

“…Although they appear to receive a sparse dopaminergic innervation (Smith et al, 1994), cholinergic interneurons express both D 2 and D 5 dopamine receptors, making them responsive to volume-transmitted dopamine (Levey et al, 1993;Bergson et al, 1995;. The best characterized effect of dopamine on cholinergic interneurons is mediated by the activation of D 2 receptors, which inhibit N-type Ca 2ϩ channel opening and the Ca 2ϩ -dependent release of acetylcholine (Lehmann and Langer, 1983;Bertorelli et al, 1992;Stoof et al, 1992;DeBoer et al, 1993;Di Chiara et al, 1994;.…”

Involvement of Cholinergic System in Hyperactivity in Dopamine-Deficient Mice

“…DD mice exhibited a decrease in ChAT expression, with a reduction of extracellular ACh levels in the striatum, demonstrating that the cholinergic system was suppressed in DD mice. DA depletion that is induced by α -methyl- p -tyrosine and reserpine was shown to decrease basal ACh release in the striatum ( Bertorelli et al , 1992 ). In addition, ChAT activity has been reported to be normal or reduced in the striatum in PD patients ( Hornykiewicz and Kish, 1987 ).…”

GABAergic Modulation of Striatal Cholinergic Interneurons: An In Vivo Microdialysis Study

“…Synaptic contacts from intrinsic striatal neurons mainly arise from substance P-containing MSp GABAergic neurons (Bolam et al, 1986;Bolam and Izzo, 1988;Martone et al, 1992), although some input may come from enkephalin-containing striatal MSp neurons (Martone et al, 1992). Furthermore, it has been suggested that the effect of systemically administered indirect DA agonists, such as amphetamine, on the striatal ACh output is mediated in part by GABAergk MSp neurons (Consolo et al, 1991Bertorelli et al, 1992) or corticostriatal or thalamostriatal glutamatergic projections (Damsma et al, 1991;DeBoer et al, 1993), which have a direct effect on striatal cholinergic neurons and GABAergic MSp neurons.…”