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

Nicolette A. Moya, Seongsik Yun, Stefan W. Fleps, Madison M. Martin, Jacob A. Nadel, Lisa R. Beutler, Larry S. Zweifel, Jones G. Parker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)690-699
Number of pages10
JournalNeuropsychopharmacology
Volume48
Issue number4
DOIs
StatePublished - Mar 2023

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology

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