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Functional roles of dopamine D2 and D3 autoreceptors on nigrostriatal neurons analyzed by antisense knockdown in vivo.

ABSTRACT: Two different 19-mer antisense oligodeoxynucleotides complementary to the initial coding regions of dopamine D2 or D3 receptor mRNA were infused unilaterally into the substantia nigra of rats for 3-6 d to suppress synthesis of D2 and/or D3 receptors on substantia nigra dopaminergic neurons, thereby producing specific reductions of D2 and/or D3 receptors. Autoradiographic receptor binding revealed that D2 and D3 antisense oligodeoxynucleotides specifically and significantly reduced D2 or D3 binding in the ipsilateral substantia nigra, respectively, without affecting dopamine receptor binding in the neostriatum. Either D2 or D3 antisense oligodeoxynucleotides greatly attenuated the ability of apomorphine to inhibit dopaminergic neurons in vivo, an effect that was potentiated by simultaneous administration of D2 and D3 antisenses. Despite these effects, neither the rate nor the pattern of spontaneous activity of antisense-treated nigrostriatal neurons differed from those in the control groups. The proportion of antidromic responses consisting of full spikes from antisense-treated rats was significantly greater, and the mean antidromic threshold was significantly lower than in controls, indicating that autoreceptor knockdown increased both somatodendritic and terminal excitability. These data demonstrate that selective reduction of specific dopamine receptor subtypes by antisense infusion can be effected in vivo, and that nigrostriatal neurons express both D2 and D3 autoreceptors at their somatodendritic and axon terminal regions. Although the somatodendritic and terminal autoreceptors modulate dendritic and terminal excitability, respectively, the interaction of endogenously released dopamine with somatodendritic autoreceptors does not appear to exert a significant effect on spontaneous activity in anesthetized rats.

SUBMITTER: Tepper JM

PROVIDER: S-EPMC6573500 | biostudies-literature | 1997 Apr

REPOSITORIES: biostudies-literature

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Functional roles of dopamine D2 and D3 autoreceptors on nigrostriatal neurons analyzed by antisense knockdown in vivo.

Tepper J M JM Sun B C BC Martin L P LP Creese I I

The Journal of neuroscience : the official journal of the Society for Neuroscience 19970401 7

Two different 19-mer antisense oligodeoxynucleotides complementary to the initial coding regions of dopamine D2 or D3 receptor mRNA were infused unilaterally into the substantia nigra of rats for 3-6 d to suppress synthesis of D2 and/or D3 receptors on substantia nigra dopaminergic neurons, thereby producing specific reductions of D2 and/or D3 receptors. Autoradiographic receptor binding revealed that D2 and D3 antisense oligodeoxynucleotides specifically and significantly reduced D2 or D3 bindi ...[more]

PMID: 9065512

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Project description:Dopamine D2 and D3 autoreceptors are located on pre-synaptic terminals and are known to control the release and synthesis of dopamine. Dopamine D3 receptors have a fairly restricted pattern of expression in the mammalian brain. Their localization in the nucleus accumbens core and shell is of particular interest because of their association with the rewarding properties of drugs of abuse. Using background subtracted fast scan cyclic voltammetry, we investigated the effects of dopamine D2 and D3 agonists on electrically stimulated dopamine release and uptake rates in the mouse caudate-putamen and nucleus accumbens core and shell. The dopamine D2 agonists (-)-quinpirole hydrochloride and 5,6,7,8-Tetrahydro-6-(2-propen-1-yl)-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride (B-HT 920) had the same dopamine release inhibition effects on caudate-putamen and nucleus accumbens (core and shell) based on their EC(50) and efficacies. This suggests that the dopamine D2 autoreceptor functionality is comparable in all three striatal regions investigated. The dopamine D3 agonists (4aR,10bR)-3,4a,4,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride ((+)-PD 128907) and (+/-)-7-Hydroxy-2-dipropylaminotetralin hydrobromide (7-OH-DPAT) had a significantly greater effect on dopamine release inhibition in the nucleus accumbens shell than in caudate-putamen. This study confirms that, the dopamine D3 autoreceptor functionality is greater in the nucleus accumbens shell followed by the nucleus accumbens core, with the caudate-putamen having the least. Neither dopamine D2 nor D3 agonists affected the uptake rates in nucleus accumbens but concentrations greater than 0.3 muM lowered the uptake rate in caudate-putamen. To validate our method of evaluating dopamine D2 and D3 autoreceptors, sulpiride (D2 antagonist) and nafadotride (D3 antagonist) were used to reverse the effects of the dopamine agonists to approximately 100% of the pre-agonist dopamine release concentration. Finally, these results demonstrate a functional voltammetric assay that characterizes dopamine D2-like agonist as either D2- or D3-preferring agonists by taking advantage of the unique receptor density within the striatum.

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Functional roles of dopamine D2 and D3 autoreceptors on nigrostriatal neurons analyzed by antisense knockdown in vivo.

Publications

Functional roles of dopamine D2 and D3 autoreceptors on nigrostriatal neurons analyzed by antisense knockdown in vivo.

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