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Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction

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Abstract

Background and rationale

Reinstatement of the function of working memory, the cardinal cognitive process essential for human reasoning and judgment, is potentially the most intractable problem for the treatment of schizophrenia. Since deficits in working memory are associated with dopamine dysregulation and altered D1 receptor signaling within prefrontal cortex, we present the case for targeting novel drug therapies towards enhancing prefrontal D1 stimulation for the amelioration of the debilitating cognitive deficits in schizophrenia.

Objectives

This review examines the role of dopamine in regulating cellular and circuit function within prefrontal cortex in order to understand the significance of the dopamine dysregulation found in schizophrenia and related non-human primate models. By revealing the associations among prefrontal neuronal function, dopamine and D1 signaling, and cognition, we seek to pinpoint the mechanisms by which dopamine modulates working memory processes and how these mechanisms may be exploited to improve cognitive function.

Results and conclusions

Dopamine deficiency within dorsolateral prefrontal cortex leads to abnormal recruitment of this region by cognitive tasks. Both preclinical and clinical studies have demonstrated a direct relationship between prefrontal dopamine function and the integrity of working memory, suggesting that insufficient D1 receptor signaling in this region results in cognitive deficits. Moreover, working memory deficits can be ameliorated by treatments that augment D1 receptor stimulation, indicating that this target presents a unique opportunity for the restoration of cognitive function in schizophrenia.

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Authors and Affiliations

  1. Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510, USA

    Patricia S. Goldman-Rakic

  2. Departments of Psychiatry and Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA

    Stacy A. Castner & Graham V. Williams

  3. MIICRO Inc., Chicago, IL 60607, USA

    Stacy A. Castner & Graham V. Williams

  4. Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden

    Torgny H. Svensson

  5. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA

    Larry J. Siever

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  1. Patricia S. Goldman-Rakic
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  2. Stacy A. Castner
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  3. Torgny H. Svensson
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  4. Larry J. Siever
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  5. Graham V. Williams
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Correspondence to Graham V. Williams.

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Dr. Patricia S. Goldman-Rakic passed away July 31, 2003. This review is dedicated to her memory and to her vision of the origins and treatment of cognitive deficits in schizophrenia.

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Goldman-Rakic, P.S., Castner, S.A., Svensson, T.H. et al. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology 174, 3–16 (2004). https://doi.org/10.1007/s00213-004-1793-y

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