Agonist-induced D1 Receptor Mediation of Spatial and Temporal Working Memory
Open Access
- Author:
- Cimino, Jack
- Graduate Program:
- Neuroscience
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- March 29, 2023
- Committee Members:
- Yang Yang, Thesis Advisor/Co-Advisor
Richard Bernard Mailman, Thesis Advisor/Co-Advisor
Alistair Barber, Committee Member - Keywords:
- Dopamine
Prefrontal Cortex
D1 Receptor
Working Memory
Parkinson's
Novel Object Recognition
T-Maze
CY208243
2MDHX
Spatial
Temporal
Fischer Rat
Sprague-Dawley
Aging
Ageing
cAMP
Beta Arrestin
catecholamine
agonist
antagonist
dopamine agonist
PF6256142 - Abstract:
- Dopamine D1 receptors are enriched in brain areas (i.e. the medial prefrontal cortex (mPFC)) that play critical roles in cognitive function. The mPFC declines with age, leading to weaker cognitive function, especially working memory (WM). The PFC, in addition to WM, is also known to work with the medial temporal lobe (MTL) for encoding of episodic memory. Consequently, age-related cognitive decline has been found to impact both WM performance and temporal order memory. D1 receptor agonists have been shown to improve age-related cognitive deficits, but the signaling mechanisms responsible are poorly understood. To explore this issue, we evaluated three D1 agonists [2-methyldihydrexidine (2MDHX); CY208243 (CY208); and PF6256142 (PF6142)] that have different D1 signaling profiles that we assessed using in vitro pharmacological experiments. It was hypothesized that these signaling differences might influence their actions on modulating WM. First, we compared the effects of 2MDHX and CY208 in the Tmaze task. 2MDHX and CY208 differed significantly in affecting WM performance in the Tmaze, with 2MDHX causing favorable outcomes at lower doses. Interestingly, both 2MDHX and CY208 were associated with the rats preferring the right arm instead of left for the T-maze task. Second, we compared 2MDHX and PF6142 using the Temporal Novel Object Recognition (NOR) task to determine if either ligand was superior at improving age-related declines in performance. 2MDHX did not differ significantly from PF6142 in this latter task when data were pooled together from all three age groups of rats. Interestingly, the analyses on the older rats, however, showed that 2MDHX and PF6142 differed, with PF6142 having improved WM performance significantly compared to the other. Although there are significant differences in the signaling bias (functional selectivity) of these three compounds, all can activate the canonical cAMP signaling system, suggesting this is the most important pathway for performance in these working memory tasks.