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A novel dopamine D1 receptor agonist excites delay-dependent working memory-related neuronal firing in primate dorsolateral prefrontal cortex.

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 ?-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 ?-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.

SUBMITTER: Wang M

PROVIDER: S-EPMC6475613 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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A novel dopamine D1 receptor agonist excites delay-dependent working memory-related neuronal firing in primate dorsolateral prefrontal cortex.

Wang Min M Datta Dibyadeep D Enwright John J Galvin Veronica V Yang Sheng-Tao ST Paspalas Constantinos C Kozak Rouba R Gray David L DL Lewis David A DA Arnsten Amy F T AFT

Neuropharmacology 20190308

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-3 ...[more]

PMID: 30858103

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Project description:Background: Normal aging is associated with working memory decline. A decrease in working memory performance is associated with age-related changes in functional activation patterns in the dorsolateral prefrontal cortex (DLPFC). Cognitive training can improve cognitive performance in healthy older adults. We implemented a cognitive training study to assess determinants of generalization of training gains to untrained tasks, a key indicator for the effectiveness of cognitive training. We aimed to investigate the association of resting-state functional connectivity (FC) of DLPFC with working memory performance improvement and cognitive gains after the training. Method: A sample of 60 healthy older adults (mean age: 68 years) underwent a 4-week neuropsychological training, entailing a working memory task. Baseline resting-state functional MRI (rs-fMRI) images were acquired in order to investigate the FC of DLPFC. To evaluate training effects, participants underwent a neuropsychological assessment before and after the training. A second follow-up assessment was applied 12 weeks after the training. We used cognitive scores of digit span backward and visual block span backward tasks representing working memory function. The training group was divided into subjects who had and who did not have training gains, which was defined as a higher improvement in working memory tasks than the control group (N = 19). Results: A high FC of DLPFC of the right hemisphere was significantly associated with training gains and performance improvement in the visuospatial task. The maintenance of cognitive gains was restricted to the time period directly after the training. The training group showed performance improvement in the digit span backward task. Conclusion: Functional activation patterns of the DLPFC were associated with the degree of working memory training gains and visuospatial performance improvement. Although improvement through cognitive training and acquisition of training gains are possible in aging, they remain limited.

Dataset Information

A novel dopamine D1 receptor agonist excites delay-dependent working memory-related neuronal firing in primate dorsolateral prefrontal cortex.

Publications

A novel dopamine D1 receptor agonist excites delay-dependent working memory-related neuronal firing in primate dorsolateral prefrontal cortex.

Similar Datasets

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