Modulating D1 rather than D2 receptor-expressing spiny-projection neurons corresponds to optimal antipsychotic effect

Yun, Seongsik; Yang, Ben; Martin, Madison M; Yeh, Nai-Hsing; Contractor, Anis; Parker, Jones Griffith

doi:10.1101/2021.08.03.454992

Cited by 5 publications

(6 citation statements)

References 66 publications

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“…While the D1 agonist SKF38393 may have enhanced the negatively valenced sensory property of medial accumbens shell dopamine by elevating the activity of neurons expressing D1 receptors, it is equally likely that the relevant feature of this manipulation was broader reshaping of accumbal physiology. Consistently, recent work [80][81][82][83] describes unintuitive responses of striatal neurons to modulation of dopamine neurotransmission. The relationship between input stimulation, the profile of ventral striatal activity that follows, and motivated behaviour is complex, poorly described, and a major hurtle to treating psychopathologies characterized by striatal dysfunction.…”

Section: Discussionsupporting

confidence: 60%

A disengaging property of medial accumbens shell dopamine

Valyear,

Eustachon,

Alymova

et al. 2023

Preprint

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Electrical stimulation of the medial forebrain bundle vigorously reinforces self-stimulation behaviour, yet rodents perform operant responses to terminate this stimulation. Whether distinct neural substrates underpin the reinforcing and sensory properties of electrical brain stimulation is a question that has hampered the development of efficacious treatment for psychopathology. The accumbens shell emerged as a substrate subserving the reinforcing and therapeutic properties of electrical medial forebrain bundle stimulation. Here, we examine whether there are dissociable reinforcing and sensory properties of medial accumbens shell dopamine and probe the substrates underlying these properties. Using a novel self-stimulation procedure, transgenic DAT-Cre mice expressing channelrhodopsin-II in ventral tegmental area dopamine neurons were trained to hold-down a lever to engage, and then release the lever to disengage, optogenetic stimulation of dopaminergic inputs to the medial accumbens shell through an implanted optic fiber. The cumulative and mean duration of hold-downs show divergent frequency responses identifying dissociable reinforcing and sensory properties of dopamine’s actions in the medial accumbens shell. At higher stimulation frequencies the cumulative duration of hold-downs grows, whereas the mean duration of hold-downs wanes. Dopamine agonists reduced the cumulative duration of self-stimulation hold-downs, but only a D1 agonist produced this reduction through decreases in the mean duration of hold-downs, which were lengthened with a D2 antagonist. Intense dopamine activity within the medial accumbens shell may achieve negative valence, disengaging behaviour through augmented neurotransmission at D1 receptors which proposes an adjuvant pharmacotherapy to enhance the treatment of binge eating and alcohol use disorder with electrical accumbens stimulation.

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Section: Discussionsupporting

confidence: 60%

A disengaging property of medial accumbens shell dopamine

Valyear,

Eustachon,

Alymova

et al. 2023

Preprint

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“…Because antipsychotics do not principally target them, striatal D1Rs could contribute to the treatment-resistant symptoms. Consistent with this idea, we recently found that clozapine, a highly efficacious antipsychotic drug with some pro-cognitive effects, preferentially normalized activity in D1R-expressing spiny projection neurons (SPNs) in the DMS under hyperdopaminergic conditions (50,51). By contrast, haloperidol affected both D1-and D2-SPN activity following amphetamine treatment (50).…”

Section: Discussionmentioning

confidence: 81%

“…Consistent with this idea, we recently found that clozapine, a highly efficacious antipsychotic drug with some pro-cognitive effects, preferentially normalized activity in D1R-expressing spiny projection neurons (SPNs) in the DMS under hyperdopaminergic conditions (50,51). By contrast, haloperidol affected both D1-and D2-SPN activity following amphetamine treatment (50). These data potentially explain why haloperidol partially rescued working memory in capsaicin-treated TRPV1 mice, and suggests that drugs that preferentially normalize D1-SPN activity may have greater therapeutic advantages over drugs like haloperidol that principally block D2Rs (50).…”

Section: Discussionmentioning

confidence: 81%

“…By contrast, haloperidol affected both D1- and D2-SPN activity following amphetamine treatment (50). These data potentially explain why haloperidol partially rescued working memory in capsaicin-treated TRPV1 mice, and suggests that drugs that preferentially normalize D1-SPN activity may have greater therapeutic advantages over drugs like haloperidol that principally block D2Rs (50).…”

Section: Discussionmentioning

confidence: 99%

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

Moya

Yun

Fleps

et al. 2022

Preprint

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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.

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“…With respect to non-glutamatergic approaches, despite many similarities with the phenotype of dopamine D 2 receptor antagonists in preclinical studies, multiple PDE10 inhibitors failed due to lack of efficacy in clinical development. Recent speculation attributes failures of such inhibitors to their only modulating indirect spiny projection neurons in the striatum and / or the additional effects on cyclic GMP with respect to modulation of cyclic AMP by dopamine D 2 receptor antagonists [31].…”

Section: The Past and The Present Of Schizophrenia Drug Developmentmentioning

confidence: 99%

Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics

et al. 2022

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Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective—with the exception of clozapine—against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.

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Modulating D1 rather than D2 receptor-expressing spiny-projection neurons corresponds to optimal antipsychotic effect

Cited by 5 publications

References 66 publications

A disengaging property of medial accumbens shell dopamine

A disengaging property of medial accumbens shell dopamine

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

Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics

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