A novel dopamine D1 receptor agonist excites delay-dependent working memory-related neuronal firing in primate dorsolateral prefrontal cortex. (15th May 2019)

• Record Type: Journal Article
• Authors: Wang, Min; Datta, Dibyadeep; Enwright, John; Galvin, Veronica; Yang, Sheng-Tao; Paspalas, Constantinos; Kozak, Rouba; Gray, David L.; Lewis, David A.; Arnsten, Amy F.T.
• Is Part Of: Neuropharmacology. Volume 150(2019)
• Page Start: 46
• Page End: 58
• Publication Date: 2019-05-15
• Subjects: Schizophrenia -- Cognition -- Pyramidal cell -- GABA interneuron -- Cognition -- Aging; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.03.001
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Decades of research have emphasized the importance of dopamine (DA) D1 receptor (D1R) mechanisms to dorsolateral prefrontal cortex (dlPFC) working memory function, and the hope that D1R agonists could be used to treat cognitive disorders. However, existing D1R agonists all have had high affinity for D1R, and engage β-arrestin signaling, and these agonists have suppressed task-related neuronal firing. The current study provides the first physiological characterization of a novel D1R agonist, PF-3628, with low affinity for D1R –more similar to endogenous DA actions– as well as little engagement of β-arrestin signaling. PF-3628 was applied by iontophoresis directly onto dlPFC neurons in aged rhesus monkeys performing a delay-dependent working memory task. Aged monkeys have naturally-occurring loss of DA, and naturally-occurring reductions in dlPFC neuronal firing and working memory performance. We found the first evidence of excitatory actions of a D1R agonist on dlPFC task-related firing, and this PF-3628 beneficial response was blocked by co-application of a D1R antagonist. These D1R actions likely occur on pyramidal cells, based on previous immunoelectron microscopic studies showing expression of D1R on layer III spines, and current microarray experiments showing that D1R are four times more prevalent in pyramidal cells than in parvalbumin-containing interneurons laser-captured from layer III of the human dlPFC. These results encourage the translation of D1R mechanisms from monkey to human, with the hope PF-3628 and related, novel D1R agonists will be more appropriate for enhancing dlPFC cognitive functions in patients with mental disorders. Highlights: There's great need for a low-affinity D1R agonist that mimics DA excitatory actions. We tested a new noncatechol, low affinity D1R agonist, PF-3628, in aged monkey cortex. PF-3628 excited the dlPFC neurons that maintain information in working memory. D1R are concentrated in human dlPFC layer III pyramidal cells compared to PV cells. PF-3628 and related agonists may be a new path for treating human cognitive disorders.