Abstract
Noradrenergic (NE) α1-adrenoceptors (α1-AR) contribute to arousal mechanisms, and play an important role in therapeutic medications, e.g. for treating Post-Traumatic Stress Disorder (PTSD). However, little is known about how α1-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 α1-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 α1-AR antagonist, HEAT, had mixed effects, reducing firing 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 α1-AR agonists phenylephrine and cirazoline suppressed Delay cell firing, and this was blocked by co-administration of HEAT. These results indicate an inverted-U dose response for α1-AR actions, with mixed excitatory actions under basal conditions, and suppressed firing with high levels of α1-AR stimulation, e.g. with stress exposure. Immunoelectron microscopy revealed α1-AR expression both pre-synaptically in axons and axon terminals, and post-synaptically in spines and dendrites, as well as in astrocytes. It is possible that α1-AR excitatory effects arise from pre-synaptic excitation of glutamate release, while post-synaptic actions suppress firing through calcium-PKC opening of potassium channels on spines. The latter may predominate under stressful conditions, leading to loss of dlPFC regulation during uncontrollable stress.
SIGNIFICANCE STATEMENT
Noradrenergic stimulation of α1-AR is implicated in Post-Traumatic 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 α1-AR to prefrontal cortical physiology in primates has received little attention. This study found that α1-ARs are located near prefrontal synapses, and that α1-AR stimulation has mixed effects under basal conditions. However, high levels of α1-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 NE release in brain, and why blocking α1-AR e.g. with prazosin, may be helpful in the treatment of PTSD.
Footnotes
The authors declare no competing financial interests.
We thank Lisa Ciavarella, Tracy Sadlon, Sam Johnson and Michelle Wilson for their technical expertise. This work was supported by NIH grants Pioneer Award DP1AG047744-01 to AFTA and DA02399 and EY002593 to PR.
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