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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:Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.

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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