Selective Nigrostriatal Dopamine Excess Impairs Behaviors Linked to the Cognitive and Negative Symptoms of Psychosis

Abstract

BACKGROUND: Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work for positive symptoms by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms. Further, broadly increasing dopamine release improves cognitive function. These observations fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms, but this has never been tested with dopamine pathway specificity. METHODS: We selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of male and female Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively ac-tivate these neurons, validated this approach with fiber photometry, and assessed its effects on social and cogni-tive function. We combined this manipulation with antipsychotic treatment (haloperidol) and compared the path-way-specific manipulation to treatment with the non-selective dopamine releaser amphetamine. RESULTS: Selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired behavioral processes linked to negative and cognitive symptoms (social drive and working memory). Haloperidol normalized locomo-tion, 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. CONCLUSIONS: Excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Previous studies using non-selective approaches to release dopamine likely overlooked these contributions of excess dopamine to psychosis. Future therapies should address this disre-garded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.

Chronically elevated corticosterone impairs dopaminergic transmission in the dorsomedial striatum by sex-divergent mechanisms

“…A custom MATLAB script was used to calculate dLight1.3b area-under-the-curve (AUC). Briefly, dLight1.3b fluorescence was normalized by fitting it with the isosbestic fluorescence curve, filtered with a 1 second median filter, downsampled to 1Hz, then dLight1.3b AUC was calculated in one-minute bins for the entire trace, and normalized to the average 1-minute AUC of the drug-free period by subtraction (26). Locomotor activity was recorded using Noldus Ethovision XT 16.…”