The dopamine d1-d2 receptor heteromer in striatal medium spiny neurons: evidence for a third distinct neuronal pathway in Basal Ganglia - PubMed (original) (raw)

The dopamine d1-d2 receptor heteromer in striatal medium spiny neurons: evidence for a third distinct neuronal pathway in Basal Ganglia

Melissa L Perreault et al. Front Neuroanat. 2011.

Abstract

Dopaminergic signaling within the basal ganglia has classically been thought to occur within two distinct neuronal pathways; the direct striatonigral pathway which contains the dopamine D1 receptor and the neuropeptides dynorphin (DYN) and substance P, and the indirect striatopallidal pathway which expresses the dopamine D2 receptor and enkephalin (ENK). A number of studies have also shown, however, that D1 and D2 receptors can co-exist within the same medium spiny neuron and emerging evidence indicates that these D1/D2-coexpressing neurons, which also express DYN and ENK, may comprise a third neuronal pathway, with representation in both the striatonigral and striatopallidal projections of the basal ganglia. Furthermore, within these coexpressing neurons it has been shown that the dopamine D1 and D2 receptor can form a novel and pharmacologically distinct receptor complex, the dopamine D1-D2 receptor heteromer, with unique signaling properties. This is indicative of a functionally unique role for these neurons in brain. The aim of this review is to discuss the evidence in support of a novel third pathway coexpressing the D1 and D2 receptor, to discuss the potential relevance of this pathway to basal ganglia signaling, and to address its potential value, and that of the dopamine D1-D2 receptor heteromer, in the search for new therapeutic strategies for disorders involving dopamine neurotransmission.

Keywords: basal ganglia; dopamine D1–D2 receptor heteromer; dynorphin; enkephalin; striatonigral; striatopallidal; substance P.

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Figures

Figure 1

Figure 1

Classical model of the basal ganglia circuitry and associated mesolimbic structures. The major projections of D1R-only striatonigral and D2R-only striatopallidal neurons are depicted. In this model, the D1R and D2R exhibit complete segregation. Inhibitory (dotted lines) and excitatory (solid lines) pathways are shown. NAc, nucleus accumbens; CP, caudate putamen; VP, ventral pallidum; GP, globus pallidus; EPN, entopeduncular nucleus; STN, subthalamic nucleus; SNr, substantia nigra reticulata; SNc, substantia nigra compacta; VTA, ventral tegmental area.

Figure 2

Figure 2

The dopamine D1 and D2 receptor are colocalized with dynorphin and enkephalin in rat nucleus accumbens shell. (A,B) Confocal images showing D1R and D2R colocalization with dynorphin (DYN) or enkephalin (ENK; white arrows). The D1R was also expressed individually with DYN (yellow arrows). (C,D) Neurons coexpressing DYN and ENK also expressed the D1R or the D2R (white arrows).

Figure 3

Figure 3

Dopamine D1 and D2 receptors form D1–D2 receptor heteromers in rat globus pallidus. Fluorescence resonance energy transfer (FRET), using Alexa 488 and Alexa 350 was used to identify interactions between endogenous D1R and D2R in neurons of rat globus pallidus. An interaction between the D1R and D2R was evident, with a relatively high mean FRET Efficiency (efficiency of energy transfer between the donor and acceptor fluorophores) of ~22%. The receptor antibody-linked fluorophores were calculated to be in close proximity with a relative distance of 5–7 nm (50–70 Å) indicative of D1–D2 receptor heteromer formation.

Figure 4

Figure 4

Model of D1 and D2 receptor-coexpressing projections in the basal ganglia circuitry. Previously reported (solid lines; Deng et al., ; Wang et al., 2006, 2007) projection sites of D1R/D2R or SP/ENK-coexpressing neurons and putative projections of D1R/D2R-DYN/ENK neurons (dashed lines), based on the reported regional distribution of neuronal cell bodies and presynaptic D1R and D2R colocalization (Perreault et al., 2010).

References

    1. Aizman O., Brismar H., Uhlen P., Zettergren E., Levey A. I., Forssberg H., Greengard P., Aperia A. (2000). Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons. Nat. Neurosci. 3, 226–230 - PubMed
    1. Anderson K. D., Reiner A. (1990). Extensive co-occurrence of substance P and dynorphin in striatal projection neurons: an evolutionarily conserved feature of basal ganglia organization. J. Comp. Neurol. 295, 339–369 - PubMed
    1. Anderson S. M., Famous K. R., Sadri-Vakili G., Kumaresan V., Schmidt H. D., Bass C. E., Terwilliger E. F., Cha J. H., Pierce R. C. (2008). CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nat. Neurosci. 11, 344–353 - PubMed
    1. Andringa G., Drukarch B., Leysen J. E., Cools A. R., Stoof J. C. (1999). The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors. Eur. J. Pharmacol. 364, 33–41 - PubMed
    1. Arnt J., Hyttel J., Sanchez C. (1992). Partial and full dopamine D1 receptor agonists in mice and rats: relation between behavioural effects and stimulation of adenylate cyclase activity in vitro. Eur. J. Pharmacol. 213, 259–267 - PubMed

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