Physiological actions and signaling mechanisms of dopamine D1-D5 receptor modulation of working memory circuitry in prefrontal cortex

The neuropharmacology of working memory remains a critical focus of studies regarding prefrontal cortical mechanisms involved in cognitive function and dysfunction. Working memory deficits are consistently observed in neuropsychiatric spectrum disorders, and an imperative consideration in treatment strategies. Prefrontal neurons show characteristic memory-related perisistent activity and this information-contingent post-sensory activity is widely considered to be the neurophysiological and cellular substrate of working memory. Dopamine has an indispensable role in working memory performance and modulation. The D1 family of dopamine receptors, comprising the D1 and D5 receptors, is abundant in prefrontal cortex, and receptor blockade is detrimental to working memory function in behavioral studies. D1 receptor stimulation dose-dependently alters behavioral performance in working memory tasks: low-dose D1 receptor stimulation augments working memory performance, while high doses are deleterious. However, the impact of D1 receptor stimulation on monkey prefrontal mnemonic neurons and memory guided saccades is hitherto unknown. D1 receptors are linked to intracellular biochemical events primarily through the cyclic-adenosine mono-phosphate pathway and also through other secondary mediators. Signaling mechanisms of D1 receptor actions on working memory circuitry have not been characterized.;This dissertation addresses the gap in knowledge between systems-level behavioral and anatomical information available for D1 receptor stimulation and working memory performance, and the physiological mechanisms by which D1 receptors modulate currents, synaptic potentials and the biochemistry of single prefrontal cells. Local stimulation of prefrontal cortical D1 receptors using micro-infusions caused "mnemonic scotomas", with impaired memory performance in selective spatial directions in the contra-lateral hemifield. D1 receptor stimulation, through iontophoresis suppressed prefrontal neuronal activity. At low doses, suppression of spontaneous activity resulted in enhancement of mnemonic selectivity. Higher doses completely suppressed mnemonic activity, collapsing the neuronal memory field. We propose that this differential suppression at different doses is the cellular basis of inverted-U actions of D1 receptors on behavioral performance in working memory tasks. Examination of cAMP and protein kinase C pathway blockers with D1 receptor stimulation indicated the involvement of the cAMP cascade in these effects.;This work delineates the physiological correlates of behavioral effects of dopamine D1 receptors and their intracellular mediators, and opens new avenues for therapeutic intervention in neurobiological ailments of cognition.