Dopamine D-2 autoreceptors regulating the release of dopamine from cultured rat fetal dopaminergic neurons do not desensitize upon sustained activation: implications for the combined pharmaco- and grafting therapy in parkinsonian patients

F L Van Muiswinkel, B Drukarch, H W Steinbusch, J C Stoof

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Cultured rat fetal mesencephalic dopaminergic neurons exhibit specific high-affinity uptake for [3H]dopamine (DA) and express DA D-2 autoreceptors, functionally coupled to the inhibition of depolarization evoked [3H]DA release. In this study, we examined the effect of short- and long-term sustained agonist exposure on the responsiveness of these DAD-2 receptors, expressed on cultured fetal mesencephalic dopaminergic neurons. Therefore, cultures were incubated in the absence or presence of the selective D-2 receptor agonist LY 171555 (Quinpirole, 1 microM) before the DA D-2 receptor-mediated inhibition of depolarization-induced [3H]DA release was determined. Short-term preincubation of cultures for 4 h did not lead to any change in the K(+)-evoked [3H]DA release nor to a change in the efficacy of LY 171555 (1 microM) to inhibit this release. Similar results were obtained after long-term agonist exposure for 6 days. Only after exposure for 12 consecutive days was a small reduction of the LY 171555 mediated inhibitory effect on DA release observed, while the IC50 value was slightly shifted to the right as compared to control cultures. Additionally, in pretreated cultures, a statistically significant increase was observed in the depolarization-induced release of [3H]DA in the absence of drugs. In the same model, activation of muscarinic acetylcholine (M-ACh) receptors was shown to potentiate the depolarization-induced release of [3H]DA. Preincubation for 4 h with the muscarinic agonist carbachol (100 microM) induced a strong reduction in the M-ACh receptor-mediated effect on [3H]DA release, indicative of a rapid desensitization of M-ACh receptors. It is concluded that, while no functional desensitization of DA D-2 autoreceptors is apparent, the depolarization-induced release of DA from cultured fetal dopaminergic neurons is enhanced upon long-term sustained activation of DA D-2 receptors.

Original languageEnglish
Pages (from-to)218-27
Number of pages10
JournalExperimental Neurology
Volume125
Issue number2
DOIs
Publication statusPublished - Feb 1994

Cite this

@article{ccb8b0be6dcf4bd789f9c9421f2c24a8,
title = "Dopamine D-2 autoreceptors regulating the release of dopamine from cultured rat fetal dopaminergic neurons do not desensitize upon sustained activation: implications for the combined pharmaco- and grafting therapy in parkinsonian patients",
abstract = "Cultured rat fetal mesencephalic dopaminergic neurons exhibit specific high-affinity uptake for [3H]dopamine (DA) and express DA D-2 autoreceptors, functionally coupled to the inhibition of depolarization evoked [3H]DA release. In this study, we examined the effect of short- and long-term sustained agonist exposure on the responsiveness of these DAD-2 receptors, expressed on cultured fetal mesencephalic dopaminergic neurons. Therefore, cultures were incubated in the absence or presence of the selective D-2 receptor agonist LY 171555 (Quinpirole, 1 microM) before the DA D-2 receptor-mediated inhibition of depolarization-induced [3H]DA release was determined. Short-term preincubation of cultures for 4 h did not lead to any change in the K(+)-evoked [3H]DA release nor to a change in the efficacy of LY 171555 (1 microM) to inhibit this release. Similar results were obtained after long-term agonist exposure for 6 days. Only after exposure for 12 consecutive days was a small reduction of the LY 171555 mediated inhibitory effect on DA release observed, while the IC50 value was slightly shifted to the right as compared to control cultures. Additionally, in pretreated cultures, a statistically significant increase was observed in the depolarization-induced release of [3H]DA in the absence of drugs. In the same model, activation of muscarinic acetylcholine (M-ACh) receptors was shown to potentiate the depolarization-induced release of [3H]DA. Preincubation for 4 h with the muscarinic agonist carbachol (100 microM) induced a strong reduction in the M-ACh receptor-mediated effect on [3H]DA release, indicative of a rapid desensitization of M-ACh receptors. It is concluded that, while no functional desensitization of DA D-2 autoreceptors is apparent, the depolarization-induced release of DA from cultured fetal dopaminergic neurons is enhanced upon long-term sustained activation of DA D-2 receptors.",
keywords = "Animals, Atropine, Brain Tissue Transplantation, Carbachol, Cells, Cultured, Dopamine, Dopamine Agents, Ergolines, Fetal Tissue Transplantation, Fetus, Mesencephalon, Neurons, Parkinson Disease, Potassium, Quinpirole, Rats, Receptors, Dopamine D2, Receptors, Muscarinic, Journal Article",
author = "{Van Muiswinkel}, {F L} and B Drukarch and Steinbusch, {H W} and Stoof, {J C}",
year = "1994",
month = "2",
doi = "10.1006/exnr.1994.1025",
language = "English",
volume = "125",
pages = "218--27",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Dopamine D-2 autoreceptors regulating the release of dopamine from cultured rat fetal dopaminergic neurons do not desensitize upon sustained activation

T2 - implications for the combined pharmaco- and grafting therapy in parkinsonian patients

AU - Van Muiswinkel, F L

AU - Drukarch, B

AU - Steinbusch, H W

AU - Stoof, J C

PY - 1994/2

Y1 - 1994/2

N2 - Cultured rat fetal mesencephalic dopaminergic neurons exhibit specific high-affinity uptake for [3H]dopamine (DA) and express DA D-2 autoreceptors, functionally coupled to the inhibition of depolarization evoked [3H]DA release. In this study, we examined the effect of short- and long-term sustained agonist exposure on the responsiveness of these DAD-2 receptors, expressed on cultured fetal mesencephalic dopaminergic neurons. Therefore, cultures were incubated in the absence or presence of the selective D-2 receptor agonist LY 171555 (Quinpirole, 1 microM) before the DA D-2 receptor-mediated inhibition of depolarization-induced [3H]DA release was determined. Short-term preincubation of cultures for 4 h did not lead to any change in the K(+)-evoked [3H]DA release nor to a change in the efficacy of LY 171555 (1 microM) to inhibit this release. Similar results were obtained after long-term agonist exposure for 6 days. Only after exposure for 12 consecutive days was a small reduction of the LY 171555 mediated inhibitory effect on DA release observed, while the IC50 value was slightly shifted to the right as compared to control cultures. Additionally, in pretreated cultures, a statistically significant increase was observed in the depolarization-induced release of [3H]DA in the absence of drugs. In the same model, activation of muscarinic acetylcholine (M-ACh) receptors was shown to potentiate the depolarization-induced release of [3H]DA. Preincubation for 4 h with the muscarinic agonist carbachol (100 microM) induced a strong reduction in the M-ACh receptor-mediated effect on [3H]DA release, indicative of a rapid desensitization of M-ACh receptors. It is concluded that, while no functional desensitization of DA D-2 autoreceptors is apparent, the depolarization-induced release of DA from cultured fetal dopaminergic neurons is enhanced upon long-term sustained activation of DA D-2 receptors.

AB - Cultured rat fetal mesencephalic dopaminergic neurons exhibit specific high-affinity uptake for [3H]dopamine (DA) and express DA D-2 autoreceptors, functionally coupled to the inhibition of depolarization evoked [3H]DA release. In this study, we examined the effect of short- and long-term sustained agonist exposure on the responsiveness of these DAD-2 receptors, expressed on cultured fetal mesencephalic dopaminergic neurons. Therefore, cultures were incubated in the absence or presence of the selective D-2 receptor agonist LY 171555 (Quinpirole, 1 microM) before the DA D-2 receptor-mediated inhibition of depolarization-induced [3H]DA release was determined. Short-term preincubation of cultures for 4 h did not lead to any change in the K(+)-evoked [3H]DA release nor to a change in the efficacy of LY 171555 (1 microM) to inhibit this release. Similar results were obtained after long-term agonist exposure for 6 days. Only after exposure for 12 consecutive days was a small reduction of the LY 171555 mediated inhibitory effect on DA release observed, while the IC50 value was slightly shifted to the right as compared to control cultures. Additionally, in pretreated cultures, a statistically significant increase was observed in the depolarization-induced release of [3H]DA in the absence of drugs. In the same model, activation of muscarinic acetylcholine (M-ACh) receptors was shown to potentiate the depolarization-induced release of [3H]DA. Preincubation for 4 h with the muscarinic agonist carbachol (100 microM) induced a strong reduction in the M-ACh receptor-mediated effect on [3H]DA release, indicative of a rapid desensitization of M-ACh receptors. It is concluded that, while no functional desensitization of DA D-2 autoreceptors is apparent, the depolarization-induced release of DA from cultured fetal dopaminergic neurons is enhanced upon long-term sustained activation of DA D-2 receptors.

KW - Animals

KW - Atropine

KW - Brain Tissue Transplantation

KW - Carbachol

KW - Cells, Cultured

KW - Dopamine

KW - Dopamine Agents

KW - Ergolines

KW - Fetal Tissue Transplantation

KW - Fetus

KW - Mesencephalon

KW - Neurons

KW - Parkinson Disease

KW - Potassium

KW - Quinpirole

KW - Rats

KW - Receptors, Dopamine D2

KW - Receptors, Muscarinic

KW - Journal Article

U2 - 10.1006/exnr.1994.1025

DO - 10.1006/exnr.1994.1025

M3 - Article

VL - 125

SP - 218

EP - 227

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 2

ER -