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Review
. 2022 Jan;27(1):436-444.
doi: 10.1038/s41380-021-01253-4. Epub 2021 Aug 12.

How changes in dopamine D2 receptor levels alter striatal circuit function and motivation

Eleanor H Simpson  1   2 , Eduardo F Gallo  3 , Peter D Balsam  4   5   6   7 , Jonathan A Javitch  5   8   9 , Christoph Kellendonk  10   11   12
Affiliations
Review

How changes in dopamine D2 receptor levels alter striatal circuit function and motivation

Eleanor H Simpson et al. Mol Psychiatry. 2022 Jan.

Abstract

It was first posited, more than five decades ago, that the etiology of schizophrenia involves overstimulation of dopamine receptors. Since then, advanced clinical research methods, including brain imaging, have refined our understanding of the relationship between striatal dopamine and clinical phenotypes as well as disease trajectory. These studies point to striatal dopamine D2 receptors, the main target for all current antipsychotic medications, as being involved in both positive and negative symptoms. Simultaneously, animal models have been central to investigating causal relationships between striatal dopamine D2 receptors and behavioral phenotypes relevant to schizophrenia. We begin this article by reviewing the circuit, cell-type and subcellular locations of dopamine D2 receptors and their downstream signaling pathways. We then summarize results from several mouse models in which D2 receptor levels were altered in various brain regions, cell-types and developmental periods. Behavioral, electrophysiological and anatomical consequences of these D2 receptor perturbations are reviewed with a selective focus on striatal circuit function and alterations in motivated behavior, a core negative symptom of schizophrenia. These studies show that D2 receptors serve distinct physiological roles in different cell types and at different developmental time points, regulating motivated behaviors in sometimes opposing ways. We conclude by considering the clinical implications of this complex regulation of striatal circuit function by D2 receptors.

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Conflict of interest statement

Conflict of interest: The authors declare that they have no conflicts of interest.

Figures

Figure 1.
Figure 1.
A. Schematic of the basal ganglia circuitry. The striatum receives excitatory input from the cortex (Ctx) and thalamus (Thm). Neurons of the striatonigral pathway innervate substantia nigra (GPi) and internal globus pallidum (GPi), resulting in disinhibition of thalamocortical function. Striatonigral pathway neurons also send inhibitory projections to the canonical target of the striatopallidal pathway, the external globus pallidum (GPe). GPe neurons project to classical striatopallidal downstream targets such as the subthalamic nucleus (STN) that lead to activation of the SNr/GPi and thalamocortical inhibition. In addition, GPe neurons project to striatum, thalamus, and cortex. Although there are quantitative differences in the strengths of projections the organization of dorsal and ventral striatal circuitry is similar. B. Within striatum, different neuronal populations express D2Rs, including cholinergic interneurons (CINs) and spiny projection neurons (SPNs) of the striatopallidal pathway, which exhibit somatodendritic as well as axonal presence of D2Rs. In addition, D2Rs may be found in axon terminals of glutamatergic and dopaminergic afferents.
Figure 2.
Figure 2.. Signaling pathways elicited by D2R activation.
Canonical G protein-mediated signaling leads to inhibition of adenylyl cyclase (AC) and PKA activity. Activation of βγ subunits results in increased Ca2+ and PKC activation, as well as activation of G protein-coupled inwardly rectifying K+ channels (GIRK) and inhibition of voltage-gated Ca2+ channels (VGCC). G-protein independent signaling downstream of D2Rs can be mediated by β-arrestin, which inhibits Akt activity to increase GSK-3β function.
Figure 3.
Figure 3.. Schematic diagram of the operant progressive ratio (PR) task.
In this task mice press a lever an increasing number of times to earn food reinforcement (left). In this example, the lever press requirement is doubled after each reinforcer earned (bottom). The D2R-OE transgenic mice show reduced cumulative survival (proportion of mice that are still pressing the lever as a function of session time) compared to wildtype littermates or D2R-OE mice treated with doxycycline (Dox) to switch off the transgene (Right).
See this image and copyright information in PMC

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References

    1. Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999; 46(1): 56–72. - PubMed
    1. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.[comment]. Proceedings of the National Academy of Sciences of the United States of America 2000; 97(14): 8104–8109. - PMC - PubMed
    1. Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A et al. The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment: Meta-analysis of Imaging Studies. Arch Gen Psychiatry 2012; 66(1): 13–20. - PMC - PubMed
    1. Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A. Pathway-Specific Dopamine Abnormalities in Schizophrenia. Biol Psychiatry 2017; 81(1): 31–42. - PMC - PubMed
    1. Kegeles LS, Abi-Dargham A, Frankle WG, Gil R, Cooper TB, Slifstein M et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 2010; 67(3): 231–239. - PubMed

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