Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia
Author:
Abi-Dargham Anissa12345, Javitch Jonathan A2, Slifstein Mark1, Anticevic Alan3, Calkins Monica E4, Cho Youngsun T3, Fonteneau Clara3, Gil Roberto1, Girgis Ragy2, Gur Raquel E4, Gur Ruben C4, Grinband Jack2, Kantrowitz Joshua2, Kohler Christian4, Krystal John3, Murray John3, Ranganathan Mohini3, Santamauro Nicole3, Van Snellenberg Jared1, Tamayo Zailyn3, Wolf Daniel4, D’Souza Deepak, Srihari Vinod, Gueorguieva Ralitza, Patel Prashant, Forselius-Bielen Kimberlee, Lu Jing, Butler Audrey, Fram Geena, Afriyie-Agyemang Yvette, Selloni Alexandria, Cadavid Laura, Gomez-Luna Sandra, Gupta Aarti, Radhakrishnan Rajiv, Rashid Ali, Aker Ryan, Abrahim Philisha, Bassir Nia Anahita, Surti Toral, Kegeles Lawrence S, Carlson Marlene, Goldberg Terry, Gangwisch James, Benedict Erinne, Govil Preetika, Brazis Stephanie, Mayer Megan, de la Garrigue Nathalie, Fallon Natalka, Baumvoll Topaz, Abeykoon Sameera, Perlman Greg, Bobchin Kelly, Elliott Mark, Schmidt Lyndsay, Rush Sage, Port Allison, Heffernan Zac, Laney Nina, Kantor Jenna, Hohing Thomas, Gray David5, Lieberman Jeffrey2,
Affiliation:
1. Department of Psychiatry, Stony Brook Renaissance School of Medicine, Stony Brook, NY, USA 2. Department of Psychiatry, New York State Psychaitric Institute, Columbia University, New York, NY, USA 3. Department of Psychiatry, Yale University, New Haven, CT, USA 4. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 5. Cerevel Therapeutics Research and Development, Boston, MA, USA
Abstract
Abstract
Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.
Funder
National Institute of Mental Health
Publisher
Oxford University Press (OUP)
Subject
Psychiatry and Mental health
Cited by
10 articles.
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