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The effect of selective nigrostriatal dopamine excess on behaviors linked to the cognitive and negative symptoms of schizophrenia

Abstract

Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms of schizophrenia. These observations and the fact that increasing brain-wide dopamine improves cognition have fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms. However, this idea has never been explicitly tested with DS-pathway specificity. To determine if excess DS dopamine is involved in cognitive and negative symptoms, we selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social interaction and working memory, behavioral constructs related to negative and cognitive symptoms. We combined this manipulation with antipsychotic treatment (haloperidol) and compared it to brain-wide dopamine release via amphetamine treatment. We found that selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired social interaction and working memory. Haloperidol normalized locomotion, but only partially rescued working memory and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. These results suggest that excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.

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Fig. 1: Histological validation of the selective expression of functional TRPV1 in SNc dopamine neurons.
Fig. 2: Recordings of dLight1.3b fluorescence in DMS and mPFC following systemic capsaicin or amphetamine treatment.
Fig. 3: Selectively driving nigrostriatal dopamine transmission dose-dependently increases locomotion in TRPV1, but not control mice.
Fig. 4: Selective nigrostriatal dopamine excess disrupts social and cognitive function.
Fig. 5: Amphetamine treatment fails to disrupt social exploration and working memory, while haloperidol incompletely normalizes these deficits caused by selective nigrostriatal dopamine excess.

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Acknowledgements

We thank Dr. Ben Arenkiel for providing the cDNA plasmid for Trpv1. The authors have no financial disclosures to declare.

Funding

This work was supported by the Whitehall Foundation (JGP) and National Institutes of Mental Health: K01 MH11313201 (JGP) and 2T32 MH067564 (NAM), Neurological Disorders and Stroke R01 NS122840 (JGP), Drug Abuse P30DA048736 (LSZ) and Diabetes and Digestive and Kidney Diseases R01 DK128477 (LRB).

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Conceptualization and methodology: NAM, LRB, LSZ, JGP; Investigation and analysis: NAM, SY, SWF, MMM, JAN, JGP; Writing and editing: NAM and JGP; All authors edited and approved draft prior to submission.

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Correspondence to Jones G. Parker.

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Moya, N.A., Yun, S., Fleps, S.W. et al. The effect of selective nigrostriatal dopamine excess on behaviors linked to the cognitive and negative symptoms of schizophrenia. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01492-1

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