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Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons

Nature Neuroscience volume 26, pages 1417–1428 (2023)Cite this article

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Abstract

Elevated dopamine transmission in psychosis is assumed to unbalance striatal output through D1- and D2-receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by blocking D2 receptors (D2Rs). In this study, we found that amphetamine-driven dopamine release unbalanced D1-SPN and D2-SPN Ca2+ activity in mice, but that antipsychotic efficacy was associated with the reversal of abnormal D1-SPN, rather than D2-SPN, dynamics, even for drugs that are D2R selective or lacking any dopamine receptor affinity. By contrast, a clinically ineffective drug normalized D2-SPN dynamics but exacerbated D1-SPN dynamics under hyperdopaminergic conditions. Consistent with antipsychotic effect, selective D1-SPN inhibition attenuated amphetamine-driven changes in locomotion, sensorimotor gating and hallucination-like perception. Notably, antipsychotic efficacy correlated with the selective inhibition of D1-SPNs only under hyperdopaminergic conditions—a dopamine-state-dependence exhibited by D1R partial agonism but not non-antipsychotic D1R antagonists. Our findings provide new insights into antipsychotic drug mechanism and reveal an important role for D1-SPN modulation.

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Fig. 1: Effects of amphetamine treatment on D1-SPN/D2-SPN Ca2+ activity in freely behaving mice.
Fig. 2: Effects of antipsychotic drugs or a failed drug candidate on behavior and D1-SPN/D2-SPN dynamics.
Fig. 3: Effects of drugs lacking dopamine receptor affinity on behavior and D1-SPN/D2-SPN dynamics.
Fig. 4: Inhibiting D1-SPNs is sufficient to rescue amphetamine-driven behaviors.
Fig. 5: Effects of D1R-targeted compounds on behavior and D1-SPN/D2-SPN dynamics.
Fig. 6: Antipsychotic efficacy is better explained by a drug’s effects on D1-SPN than D2-SPN activity levels.

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Data availability

We have provided Source Data underlying each figure and statistical conclusion. Source data are provided with this paper.

Code availability

The software code used to process our Ca2+ movies (https://bahanonu.github.io/ciatah/) as well as MARS (https://github.com/neuroethology/MARS) and the training code that we used for behavioral classification (https://github.com/neuroethology/MARS_Developer) and manual annotation (https://github.com/neuroethology/bentoMAT) are freely available online. The code used to analyze individual behaviors is available at https://github.com/arinpamukcu/parkerlab/.

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Acknowledgements

We thank B. Ahanonu for assistance in data processing, P. J. Conn for providing VU0467154, J. I. Sanders and A. Kepecs for guidance in setting up the task to measure HALIP and L. Pinto for help with psychometric modeling of behavior. S.Y., B.Y., J.D.A., M.M.M., S.W.F. and J.G.P. were funded by National Institute of Mental Health (NIMH) K01MH113132, National Institute of Neurological Disorders and Stroke R01NS122840 and the Whitehall Foundation. A.P. and A.K. were funded by Aligning Science Across Parkinson’s ASAP-020551 through the Michael J. Fox Foundation for Parkinson’s Research. N.-H.Y. and A.C. were funded by NIMH R01MH099114.

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Authors and Affiliations

  1. Department of Neuroscience, Northwestern University, Chicago, IL, USA

    Seongsik Yun, Ben Yang, Justin D. Anair, Madison M. Martin, Stefan W. Fleps, Arin Pamukcu, Nai-Hsing Yeh, Anis Contractor, Ann Kennedy & Jones G. Parker

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Contributions

S.Y. performed all imaging, behavior experiments and histological experiments. B.Y. performed surgeries and assisted with imaging experiments. J.D.A. performed surgeries and assisted with the HALIP experiment. M.M.M. and S.W.F. performed mouse surgeries and oversaw mouse breeding. A.P. and A.K. performed analyses of pose estimation and the rates of activity associated with specific behaviors. N.-H.Y. and A.C. conducted electrophysiology experiments. S.Y. and J.G.P. designed all experiments, performed all data analysis and wrote the manuscript, with input from the co-authors.

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Correspondence to Jones G. Parker.

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Extended data

Extended Data Fig. 1 Histological validation and characterization of normal D1-/D2-SPN ensemble dynamics and hM4Di-mCherry functionality.

a, Representative coronal brain sections of DMS and substantia nigra reticulata (SNr) from GCaMP7f-expressing D1- or A2A-Cre mice (green: anti-GFP; blue: DAPI nuclear stain; scale bar: 1 mm). White lines indicate the position of the implanted microendoscope and boundaries of brain areas. b, Ca2+ event rates in D1- and D2-SPNs across increasing running speed bins. c, Co-activity (Jaccard index) of D1- or D2-SPN pairs during movement (locomotor speed >= 0.5 cm·s−1) versus the separation of cell pairs, normalized to temporally shuffled datasets (dashed line). Cyan shading indicates proximal (25–125 μm) cell pairs. d, Co-activity of proximal D1- and D2-SPN pairs across increasing running speed bins, normalized to temporally shuffled comparisons (dashed line). e, Ca2+ event amplitudes in D1- and D2-SPNs across increasing locomotor speed bins (for b–e, N = 18 D1-Cre and N = 17 A2A-Cre mice; data were averaged across all recordings following vehicle only treatment; **P < 0.01 comparing D1-SPNs to D2-SPNs; Two-way ANOVA with Holm-Sidak’s multiple comparison test). f, Representative coronal brain sections of DMS and subtantia nigra from hM4Di-mCherry expressing D1-Cre mice (red: mCherry; blue: DAPI nuclear stain; scale bar: 1 mm). g, We performed patch-clamp electrophysiological recordings from hM4Di-mCherry-expressing neurons in the DMS of D1-Cre mice. h, Representative traces of action potential responses to 250 pA current injection. i, Number of evoked action potentials following vehicle, DCZ or CNO treatment (N = 4 cells; *P < 0.05 compared to vehicle treatment; One-way ANOVA with Holm-Sidak’s multiple comparison test). All data are mean ± s.e.m. Exact P values for these and all other analyses are in the Supplementary Table. All N values refer to number of mice for all figures unless otherwise specified.

Source data

Extended Data Fig. 2 Antipsychotic drug dose selection based on locomotor activity.

a–c, Locomotor activity in untethered, C57BL6/J mice during 15 min following vehicle or drug treatment and 45 min following amphetamine treatment (see Fig. 2a). Effects of haloperidol, olanzapine, clozapine, or MP-10 (a), xanomeline, VU0467154, or SEP-363856 (b), and SKF39393, SCH23390, or SCH39166 (c) on baseline and amphetamine-driven locomotion. The ‘low’ and ‘high’ doses we subsequently used for Ca2+ imaging experiments are indicated in red. Data are expressed as mean ± s.e.m. (****P < 10−4 ***P < 10−3, **P < 10−2 and *P < 0.05 for comparison to vehicle treatment; ####P < 10−4 and ##P < 10−2 compared to vehicle + amphetamine treatment; One-way ANOVA with Holm-Sidak’s multiple comparison test).

Source data

Extended Data Fig. 3 Effects of drug treatments on D1-/ D2-SPN dynamics under baseline conditions.

a–f, Bar plots depict the mean ± s.e.m Ca2+ event rates (a, c, e) and proximal co-activity (b, d, f) of D1- and D2-SPNs, normalized to values following vehicle only treatment during periods of rest (left) or movement (right) following haloperidol, olanzapine, clozapine, or MP-10 (a, b), xanomeline, VU0467154, or SEP-363856 (c, d), and SKF39393, SCH23390, or SCH39166 (e, f) treatment. Heat maps display either the effects of drugs on the ratio of D1- to D2-SPN Ca2+ event rates (D1/D2; left in a, c, e) or the ratio of drug to vehicle treatment on the rates (Drug/Vehicle; right in a, c, e) or proximal co-activity (b, d, f) of D1- and D2-SPN activity during periods or rest (left) or movement (right) (****P < 10−4, ***P < 10−3, **P < 10−2 and *P < 0.05 compared to vehicle treatment; One-way ANOVA with Holm-Sidak’s multiple comparison test).

Source data

Extended Data Fig. 4 Antipsychotic drug effects on D1-/D2-SPN Ca2+ dynamics under baseline conditions as a function of locomotor speed.

a, b, Drug effects on D1- (a) and D2-SPN (b) Ca2+ event rates across different speed bins following vehicle or drug only treatment. c, d, Drug effects on the proximal co-activity of D1- (c) and D2-SPNs (d) across different speed bins following vehicle or drug only treatment. Data are represented as mean ± s.e.m. (****P < 10−4, ***P < 10−3, **P < 10−2 and *P < 0.05 for comparison to vehicle treatment; Two-way ANOVA with Holm-Sidak’s multiple comparison test).

Source data

Extended Data Fig. 5 Drug effects on D1-/D2-SPN Ca2+ event amplitudes under normal and hyperdopaminergic conditions.

a–c, Mean ± s.e.m. Ca2+ event amplitudes of D1- and D2-SPNs across all speeds following treatment with haloperidol, olanzapine, clozapine, or MP-10 (a), xanomeline, VU0467154, or SEP-363856 (b), and SKF39393, SCH23390, or SCH39166 (c), normalized to values following vehicle only treatment. Data are from periods before (top) or after (bottom) amphetamine treatment. Heat maps depict the mean D1- and D2-SPN Ca2+ event amplitudes, normalized to values following vehicle only treatment (Drug/Vehicle) and the vehicle-normalized values, normalized to the corresponding value following vehicle + amphetamine treatment (Drug/Amph; ****P < 10−4, ***P < 10−3, **P < 10−2 and *P < 0.05 for comparison to vehicle treatment; ####P < 10−4, ###P < 10−3, ##P < 10−2 and #P < 0.05 compared vehicle + amphetamine treatment; One-way ANOVA with Holm-Sidak’s multiple comparison test).

Source data

Extended Data Fig. 6 Antipsychotic drug effects on D1-/D2-SPN Ca2+ dynamics as a function of locomotor speed under hyperdopaminergic conditions.

a, b, Drug effects on Ca2+ event rates of D1- (a) and D2-SPNs (b) across different speed bins following vehicle or drug + amphetamine treatment. c, d, Drug effects on the proximal co-activity of D1- (c) and D2-SPNs (d) across different speed bins following vehicle or drug + amphetamine treatment. Data are represented as mean ± s.e.m. (****P < 10−4, ***P < 10−3, **P < 10−2 and *P < 0.05 for comparison to vehicle + amphetamine treatment; Two-way ANOVA with Holm-Sidak’s multiple comparison test).

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Extended Data Fig. 7 Longitudinal stability of D1-/D2-SPN dynamics under normal and hyperdopaminergic conditions.

a, b, Ca2+ event rates (left), proximal co-activity (middle) and Ca2+ event amplitudes (right) of D1- (top) and D2-SPNs (bottom) across all locomotor speed bins and drug treatment blocks following vehicle (a) or amphetamine only (b) treatment. Data are represented as mean ± s.e.m. (***P < 10−3, **P < 10−2 and *P < 0.05 compared to naive; One-way ANOVA with Holm-Sidak’s multiple comparison test).

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Extended Data Fig. 8 Drug effects on the time spent engaged in specific behaviors and their associated D1- and D2-SPN activity levels.

a, b, Proportion of time engaged in specific behaviors (a) and the D1- and D2-SPN Ca2+ event rates associated with those behaviors (b) following vehicle or amphetamine treatment. c, The predicted and actually observed Ca2+ event rates of D1- and D2-SPNs following amphetamine treatment during periods of rest or movement, normalized to values following vehicle treatment. Predicted values were computed from a weighted average of the event rates associated with each behavior following vehicle treatment in (b) and the proportion of time spent engaged in each behavior following amphetamine treatment in (a), where the specific behaviors were grouped into resting and moving types for comparison to the observed data here and reported in the main text (Figs. 1 and 2). d, Proportion of time spent in categorized resting and moving behaviors following vehicle, vehicle + amphetamine, or drug + amphetamine treatment. e, The predicted and actually observed Ca2+ event rates of D1- and D2-SPNs following drug + amphetamine treatment during periods of rest or movement, normalized to values following vehicle treatment. Predicted values were computed from the data in (b) and (d) as described in (c). All data are expressed as mean ± s.e.m. (****P < 10−4, ***P < 10−3, **P < 10−2 and *P < 0.05 compared to vehicle treatment (a, b) or predicted values (c, e); two-tailed Wilcoxon signed-rank test; ++++P < 10−4 and +++P < 10−3 comparing vehicle to vehicle + amphetamine treatment and ####P < 10−4, ###P < 10−3, ##P < 10−2 and #P < 0.05 comparing drug + amphetamine to vehicle + amphetamine treatment (d); One-way ANOVA with Holm-Sidak’s multiple comparison test).

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Extended Data Fig. 9 Dopamine receptor-independent drug effects on D1-/D2-SPN Ca2+ dynamics as a function of locomotor speed under normal and hyperdopaminergic conditions.

a, b, Drug effects on D1- (a) and D2-SPN (b) Ca2+ event rates across different speed bins following vehicle or drug only treatment. c, d, Drug effects on the proximal co-activity of D1- (c) and D2-SPNs (d) across different speed bins following vehicle or drug only treatment. e, f, Drug effects on Ca2+ event rates of D1- (e) and D2-SPNs (f) across different speed bins following vehicle or drug + amphetamine treatment. g, h, Drug effects on the proximal co-activity of D1- (g) and D2-SPNs (h) across different speed bins following vehicle or drug + amphetamine treatment. Data are represented as mean ± s.e.m. (****P < 10−4, ***P < 10−3, **P < 10−2 and *P < 0.05 for comparison to vehicle treatment (a–d) or to vehicle + amphetamine treatment (e–h); Two-way ANOVA with Holm-Sidak’s multiple comparison test).

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Extended Data Fig. 10 D1R-targeted drug effects on D1-/D2-SPN Ca2+ dynamics as a function of locomotor speed under normal and hyperdopaminergic conditions.

a, b, Drug effects on D1- (a) and D2-SPN (b) Ca2+ event rates across different speed bins following vehicle or drug only treatment. c, d, Drug effects on the proximal co-activity of D1- (c) and D2-SPNs (d) across different speed bins following vehicle or drug only treatment. e, f, Drug effects on Ca2+ event rates of D1- (e) and D2-SPNs (f) across different speed bins following vehicle or drug + amphetamine treatment. g, h, Drug effects on the proximal co-activity of D1- (g) and D2-SPNs (h) across different speed bins following vehicle or drug + amphetamine treatment. Data are represented as mean ± s.e.m. (****P < 10−4, ***P < 10−3, **P < 10−2 and *P < 0.05 for comparison to vehicle treatment (a–d) or to vehicle + amphetamine treatment (e–h); Two-way ANOVA with Holm-Sidak’s multiple comparison test).

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Supplementary information

Reporting Summary

Supplementary Table 1

Summary table of n and P values of all statistical comparisons.

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Yun, S., Yang, B., Anair, J.D. et al. Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons. Nat Neurosci 26, 1417–1428 (2023). https://doi.org/10.1038/s41593-023-01390-9

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