Adrenergic pharmacology and cognition: focus on the prefrontal cortex

Abstract

Norepinephrine (NE) has widespread projections throughout the brain, and thus, is ideally positioned to orchestrate neural functions based on arousal state. For example, NE can increase "signal/noise" ratio in the processing of sensory stimuli, and can enhance long-term memory consolidation in the amygdala and hippocampus through actions at alpha-1 and beta adrenoceptors. Over the last 20 years, NE has also been shown to play a powerful role in regulating the working memory and attention functions of the prefrontal cortex (PFC). Moderate levels of NE released under control conditions strengthen prefrontal cortical functions via actions at post-synaptic alpha-2A adrenoceptors with high affinity for NE, while high levels of NE release during stress impair PFC cortical functions via alpha-1 and possibly beta-1 receptors with lower affinity for NE. Thus, levels of NE determine whether prefrontal cortical or posterior cortical systems control our behavior and thought. Understanding these receptor mechanisms has led to new intelligent treatments for neuropsychiatric disorders associated with PFC dysfunction.

Figure 1

The cellular basis of spatial working memory. (A) A neuron with spatially tuned persistent activity during the delay period of a spatial working memory task. Data from Dr. Min Wang. (B) Schematic representation of PFC networks of pyramidal cells that represent the cellular basis of working memory. Networks with shared mnemonic properties (preferred direction) engage in recurrent excitation to maintain information (increase in firing rate) during the delay period in the absence of environmental stimuli. GABAergic interneurons activated by networks firing to non-preferred directions enhance spatial tuning by inhibiting firing to nonpreferred directions. Adapted from Goldman-Rakic.

Figure 2

Norepinephrine (NE) released in the PFC activates different intracellular signaling pathways through distinct adrenoceptors with varying affinities for NE. PFC cognitive function is enhanced by moderate levels of NE engaging post-synaptic α2A receptors with high affinity for NE, while high levels of NE impair PFC cognitive function by engaging α1 and β1 receptors with lower affinity for NE. AC, adenylyl cyclase; LC, locus coeruleus; PLC, phospholipase C; DAG, diacylglycerol.

Figure 3

Differential effects of the adrenergic system on peripheral versus central nervous systems. Epinephrine is released into blood by the adrenal gland in response to stress. NE is released by the sympathetic nervous system and throughout most of brain. Turning off PFC control of behavior during stress may have survival value under conditions of danger by switching control of our behavior from a slow, “reflective” region to more reflexive and instinctual brain areas. However, shutting off the PFC may make us more vulnerable to neuropsychiatric illness.