Dopamine dynamics and cocaine sensitivity differ between striosome and matrix compartments of the striatum

doi:10.1016/j.neuropharm.2016.03.049

Neuropharmacology

Volume 108, September 2016, Pages 275-283

https://doi.org/10.1016/j.neuropharm.2016.03.049 Get rights and content

Highlights

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The striatum consists of neurochemically-distinct striosome & matrix compartments.
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Dopamine release differs between striosome and matrix compartments.
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This difference is region dependent and partially DAT-mediated.
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This difference is not attributable to dopamine D2 or nACh receptors.

Abstract

The striatum is typically classified according to its major output pathways, which consist of dopamine D1 and D2 receptor-expressing neurons. The striatum is also divided into striosome and matrix compartments, based on the differential expression of a number of proteins, including the mu opioid receptor, dopamine transporter (DAT), and Nr4a1 (nuclear receptor subfamily 4, group A, member 1). Numerous functional differences between the striosome and matrix compartments are implicated in dopamine-related neurological disorders including Parkinson's disease and addiction. Using Nr4a1-eGFP mice, we provide evidence that electrically evoked dopamine release differs between the striosome and matrix compartments in a regionally-distinct manner. We further demonstrate that this difference is not due to differences in inhibition of dopamine release by dopamine autoreceptors or nicotinic acetylcholine receptors. Furthermore, cocaine enhanced extracellular dopamine in striosomes to a greater degree than in the matrix and concomitantly inhibited dopamine uptake in the matrix to a greater degree than in striosomes. Importantly, these compartment differences in cocaine sensitivity were limited to the dorsal striatum. These findings demonstrate a level of exquisite microanatomical regulation of dopamine by the DAT in striosomes relative to the matrix.

Graphical abstract

Introduction

The striatum has been characterized according to its two major output pathways: the direct pathway (dopamine D1 receptor-expressing neurons) and the indirect pathway (dopamine D2 receptor-expressing neurons) (Gerfen et al., 1990). The striatum can also be classified into two neurochemically-distinct compartments, the striosome and matrix, based on the differential expression of several proteins, including the mu opioid receptor (MOR), acetylcholinesterase, dopamine transporter (DAT), and Nr4a1 (nuclear receptor subfamily 4, group A, member 1) (Crittenden and Graybiel, 2011, Davis and Puhl, 2011, Graybiel and Ragsdale, 1978, Herkenham and Pert, 1981). The matrix compartment comprises approximately 85% of the striatum (Johnston et al., 1990, Mikula et al., 2009) and functions as part of the sensorimotor and associative circuits; in contrast, the striosome compartment comprises approximately 15% of the striatum and is associated with limbic circuits (Eblen and Graybiel, 1995, Gerfen, 1984, Jimenez-Castellanos and Graybiel, 1987, Kincaid and Wilson, 1996). However, these ratios vary across the rostro-caudal extent of the striatum (Davis and Puhl, 2011). Striosome projection neurons are primarily direct pathway neurons developmentally, while matrix projection neurons are either direct or indirect pathway (Fujiyama et al., 2011), though some controversy remains and may be attributable to species differences (Levesque and Parent, 2005). Interestingly, it is theorized that only striatal projection neurons originating in striosomes innervate the substantia nigra pars compacta (SNc) and in this way may globally influence dopamine release in the striatum (Fujiyama et al., 2011, Gerfen et al., 1987, Watabe-Uchida et al., 2012).

Midbrain dopaminergic innervation of the striatum follows a topographical pattern where the dorsal striatum (DS) is innervated primarily by the substantia nigra (and to a lesser extent the lateral ventral tegmental area) and the ventral striatum (VS) is innervated primarily by the ventral tegmental area (VTA) (Beier et al., 2015, Ikemoto, 2007, Lammel et al., 2008). The dopaminergic innervation of the matrix compartment reflects this topographical pattern, but striosomal dopamine originates largely from the SNc and to a lesser extent the substantia nigra pars reticulata (Gerfen et al., 1987, Jimenez-Castellanos and Graybiel, 1987, Langer and Graybiel, 1989, Prensa and Parent, 2001). Related to these differences in compartmental dopamine innervation, numerous animal models of Parkinson's disease and dystonia show preferential loss of dopamine terminals or striatal projection neurons in either the striosome or matrix compartments (see Crittenden and Graybiel (2011) for review). Similarly, imbalances in chronic drug-induced immediate early gene expression between striosome and matrix compartments underlie psychostimulant-induced stereotypies (Canales and Graybiel, 2000, Capper-Loup et al., 2002, Jedynak et al., 2012). Given the differences in compartmental dopamine origin and the putative roles of striosome and matrix compartments in numerous dopamine-related neurological disorders, we hypothesized that dopamine signaling between striatal compartments would differ.

Nr4a1 (also known as Nur77 and NGFIB; Entrez Gene ID: 15370) is a nuclear receptor protein initially identified in silico by Davis and Puhl (2011) as a marker for striosomes. Therefore, in the current study, we used fast-scan cyclic voltammetry (FSCV) and Nr4a1-eGFP transgenic mice to identify striosomes and to directly compare dopamine release between the striosome and matrix compartments of the striatum. We found that electrically evoked dopamine release differed between striosome and matrix compartments in a region-specific manner and that these differences could not be attributed to nicotinic acetylcholine receptor (nAChR) antagonism or dopamine D2 autoreceptor inhibition of the dopamine terminal. We further found that cocaine-enhanced dopamine levels and uptake inhibition differed between striosome and matrix compartments in the dorsal, but not ventral, striatum. These findings demonstrate a previously undescribed compartment difference in cocaine mediated regulation of dopamine dynamics in the striatum.

Section snippets

Subjects

Nr4a1-eGFP mice were obtained from GENSAT and backcrossed with C57BL6J mice (The Jackson Laboratory) for at least six generations. At weaning, visual genotyping with a blue LED and GFP filter-equipped goggles (Electron Microscopy Sciences) was performed. Drd2^loxp/loxp mice were obtained from The Jackson Laboratory and crossed with Adora2A-Cre mice (KG139, GENSAT). The A2ACre/Drd2^loxp pups were then crossed with Drd2^loxp/loxp mice to generate A2ACre/Drd2^loxp/loxp (KO) and Drd2^loxp/loxp mice

Nr4a1-eGFP is enhanced in striosomes and colocalizes with DAT

Nr4a1-eGFP was expressed throughout the striatum as previously described (Davis and Puhl, 2011) and colocalized extensively with immunoreactivity for the MOR, a striosomal marker (Fig. 1A and B). We also examined the colocalization of Nr4a1-eGFP with DAT throughout the striatum. We observed extensive colocalization of Nr4a1 with DAT in the DS. The degree of colocalization in the VS, however, was negligible (Fig. 1B).

Evoked dopamine release differs between striosome and matrix compartments

We employed FSCV to directly compare dopamine release between striatal

Discussion

We found that dopamine release differed between striosome and matrix compartments of the striatum in a regionally-distinct manner such that in the DS, dopamine release in striosomes was less than in the matrix, and in the VS, the opposite was true. We also found that cocaine differentially affects dopamine dynamics between striosome and matrix compartments. Specifically, cocaine enhanced dopamine overflow to a greater degree in striosomes than in proximal matrix regions. Concurrently, cocaine

Disclosures

The authors declare no competing financial interests.

Acknowledgements

The authors would like to thank Drs. Carmelo Sgobio and Joseph Cheer for their comments on the manuscript.

This work was supported by NIAAA R01 AA016022 (AGS) and the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biomedical Research (MID, YM, and DML) (Grant Number: ZIA AA000407).

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Indeed, it is known that the striosome and matrix compartments within the striatum have functional differences in dopamine release (for review see, Brimblecomb and Cragg, 2016). This relationship of release to compartment does appear to vary across the ventral and dorsal portions of the striatum with higher release associated with the matrix compartment in dorsal striatum but this relationship is reversed in the ventral portion (Brimblecomb and Cragg, 2015, 2016; Salinas et al., 2016). However, the extent of contribution and the specific role of the dopamine transporters in relation to this difference in dopamine release is yet to be resolved.
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Dopamine dynamics and cocaine sensitivity differ between striosome and matrix compartments of the striatum

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Subjects

Nr4a1-eGFP is enhanced in striosomes and colocalizes with DAT

Evoked dopamine release differs between striosome and matrix compartments

Discussion

Disclosures

Acknowledgements

Cell

Cell Rep.

Neurochem. Int.

Neurobiol. Learn. Mem.

Exp. Neurol.

Trends Neurosci.

Trends Neurosci.

Cell

Brain Res.

Brain Res. Rev.

Neuroscience

Brain Res. Dev. Brain Res.

Neuroscience

Neuron

Brain Res.

Brain Res.

Neuron

Neuron

J. Neurosci. Methods

J. Neurosci. Methods

Cocaine inhibition of nicotinic acetylcholine receptors influences dopamine release

Front. Synaptic Neurosci.

PKA-dependent phosphorylation of ribosomal protein S6 does not correlate with translation efficiency in striatonigral and striatopallidal medium-sized spiny neurons

J. Neurosci.

Substance P weights striatal dopamine transmission differently within the striosome-matrix axis

J. Neurosci.

A measure of striatal function predicts motor stereotypy

Nat. Neurosci.

Concurrent activation of dopamine D1 and D2 receptors is required to evoke neural and behavioral phenotypes of cocaine sensitization

J. Neurosci.

Differences in dopamine clearance and diffusion in rat striatum and nucleus accumbens following systemic cocaine administration

J. Neurochem.

Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments

Front. Neuroanat.

Chronic methylphenidate exposure during adolescence reduces striatal synaptic responses to ethanol

Eur. J. Neurosci.

Targeted expression of mu-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward

Nat. Neurosci.