Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex

Abstract

Noradrenergic (NE) ␣1-adrenoceptors (␣1-ARs) contribute to arousal mechanisms and play an important role in therapeutic medications such as those for the treatment of posttraumatic stress disorder (PTSD). However, little is known about how ␣1-AR stimulation influences neuronal firing in the dorsolateral prefrontal cortex (dlPFC), a newly evolved region that is dysfunctional in PTSD and other mental illnesses. The current study examined the effects of ␣1-AR manipulation on neuronal firing in dlPFC of rhesus monkeys performing a visuospatial working memory task, focusing on the "delay cells" that maintain spatially tuned information across the delay period. Iontophoresis of the ␣1-AR antagonist HEAT (2-{[␤-(4-hydroxyphenyl)ethyl]aminomethyl}-1-tetralone) had mixed effects, reducingfiring in a majority of neurons but having nonsignificant excitatory effects or no effect in remaining delay cells. These data suggest that endogenous NE has excitatory effects in some delay cells under basal conditions. In contrast, the ␣1-AR agonists phenylephrine and cirazoline suppressed delay cell firing and this was blocked by coadministration of HEAT. These results indicate an inverted-U dose response for ␣1-AR actions, with mixed excitatory actions under basal conditions and suppressed firing with high levels of ␣1-AR stimulation such as with stress exposure. Immunoelectron microscopy revealed ␣1-AR expression presynaptically in axons and axon terminals and postsynaptically in spines, dendrites, and astrocytes. It is possible that ␣1-AR excitatory effects arise from presynaptic excitation of glutamate release, whereas postsynaptic actions suppress firing through calcium-protein kinase C opening of potassium channels on spines. The latter may predominate under stressful conditions, leading to loss of dlPFC regulation during uncontrollable stress. Significance StatementNoradrenergic stimulation of ␣1-adrenoceptors (␣1-ARs) is implicated in posttraumatic stress disorder (PTSD) and other mental disorders that involve dysfunction of the prefrontal cortex, a brain region that provides top-down control. However, the location and contribution of ␣1-ARs to prefrontal cortical physiology in primates has received little attention. This study found that ␣1-ARs are located near prefrontal synapses and that ␣1-AR stimulation has mixed effects under basal conditions. However, high levels of ␣1-AR stimulation, as occur with stress, suppress neuronal firing. These findings help to explain why we lose top-down control under conditions of uncontrollable stress when there are high levels of noradrenergic release in brain and why blocking ␣1-AR, such as with prazosin, may be helpful in the treatment of PTSD.

Transient astrocytic Gq signaling underlies remote memory enhancement

“…Whereas these studies did not report in vivo effects on astrocytic and neuronal activity, we showed rapid reduction of neuronal activity and depression of evoked response after astrocytic Gq activation ( Fig. 3 ), in line with the recent monkey prefrontal cortex study with α1AR agonists 53 . Aside from the preparation differences, one important aspect of the current study is the use of transgenic mice that minimizes concerns on tissue inflammation caused by virus-injection and slice preparation.…”

Loss of Prefrontal Cortical Higher Cognition with Uncontrollable Stress: Molecular Mechanisms, Changes with Age, and Relevance to Treatment

“…High levels of dopamine (DA) D1R and norepinephrine (NE) α1-AR stimulation in the PFC impair working memory performance by driving feedforward calcium-cAMP-K + signaling [66,67,68,69], as schematically illustrated in Figure 3. Both α1R (Figure 3A; [70]) and D1R [57,71] have been localized on dendritic spines in layer III of primate dlPFC, and their activation drives feedforward calcium-cAMP signaling (Figure 3B). Thus, stimulation of α1R or D1R reduces the task-related firing of dlPFC neurons in monkeys performing a working memory task, while blockade or closure of HCN channels rescues firing [68,69,70,72].…”

“…Both α1R (Figure 3A; [70]) and D1R [57,71] have been localized on dendritic spines in layer III of primate dlPFC, and their activation drives feedforward calcium-cAMP signaling (Figure 3B). Thus, stimulation of α1R or D1R reduces the task-related firing of dlPFC neurons in monkeys performing a working memory task, while blockade or closure of HCN channels rescues firing [68,69,70,72]. These stress signaling pathways may interact with neuroinflammation, which may remove the brakes on the stress response by inhibiting PDE4s, as illustrated in Figure 3B.…”

“…Sp = spine, Ax = axon terminal, Mit = mitochondrion. Figure 3A adapted from Reference [70]. ( B ) Schematic drawing showing that uncontrollable stress induces cortisol and catecholamine release; high levels of NE and DA activate α1-AR and D1R, which drive feedforward, calcium-cAMP opening of HCN and KCNQ channels to reduce cell firing.…”

Synthesis and Characterization of Carbon-11 Labeled Iloperidone for Imaging of α1-Adrenoceptor in Brain

“…Over the past decade, α 1 -adrenoceptor has gained interest due to its biological functions in regulating both positively motivated behaviors and stress reactions (Selken and Nichols, 2007;Stone et al, 2007). The α 1adrenoceptor has been implicated in numerous neuronal diseases, such as Alzheimer's disease, Parkinson's disease, schizophrenia, substance abuse, and affective disorders (Maletic et al, 2017;Wu et al, 2017;Akinaga et al, 2019;Datta et al, 2019). Consequently, a great deal of interests lay in the development of α 1 -adrenoceptor modulators, which has opened a new avenue for identifying novel CNS disease modifying therapeutics.…”