PPubMed19 Jan 2023Cited 73×

Segregation of D1 and D2 dopamine receptors in the striatal direct and indirect pathways: An historical perspective

Charles R. Gerfen

Abstract

The direct and indirect striatal pathways form a cornerstone of the circuits of the basal ganglia. Dopamine has opponent affects on the function of these pathways due to the segregation of the D1- and D2-dopamine receptors in the spiny projection neurons giving rise to the direct and indirect pathways. An historical perspective is provided on the discovery of dopamine receptor segregation leading to models of how the direct and indirect affect motor behavior.

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D1 and D2 dopamine receptors are segregated in striatal direct and indirect pathways, producing opposite effects on motor behavior and gene expression.

What’s new

i.Provides a comprehensive historical overview of the discovery of D1/D2 receptor segregation in striatal pathways.
ii.Integrates anatomical, pharmacological, and gene‑expression data showing opponent functional effects of D1 and D2 receptors.
iii.Links receptor segregation to motor behavior models and Parkinson’s disease mechanisms.
iv.Summarizes experimental findings on how selective D1 and D2 agonists differentially regulate neuropeptide and immediate‑early gene expression.

How they did it

The work is a literature review that synthesizes findings from anatomical tracing, pharmacological agonist treatments, in‑situ hybridization, and gene‑expression studies across multiple animal models.

What they found

Continuous D2 agonist quinpirole reverses the 6‑OHDA‑induced increase in enkephalin labeling.
Intermittent D1 agonist treatment reverses the 6‑OHDA‑induced decrease in substance P labeling.
Combined D1 (SKF38393, 1.0 mg/kg) and D2 (quinpirole, 1.0 mg/kg) agonists reduce zif268 levels in D2‑cells and increase them in D1‑cells compared with D1‑agonist alone.
Electrical stimulation of the nigrostriatal pathway induces c‑fos throughout striatum but phosphorylated ERK1/2 only in the nucleus accumbens.

Caveats

✕Relies on previously published studies; no new experimental data were generated.
✕Unresolved questions remain about the precise cortical and thalamic input segregation to dSPNs and iSPNs.
✕Quantitative synthesis of effect sizes across studies is limited.

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