A focus on norepinephrine

A role for NE/NA is detailed in Biomarker Symptom Profiles for Schizophrenia and Schizoaffective Psychosis (2015) :

“…finely-tuned relative-strengths between noradrenaline, adrenaline and dopamine (NA, AD and DA) levels are critical in differentiating symptom-formation in schizophrenia and schizoaffective disorder. The graduated difference between the elevated NA biomarker and the level of DA appears to turn symptom correlates from manic (with high DA) to disorganized and distracted (high NA and somewhat lower AD and DA), to depressive and negative (low DA ± high NA, or low DA alone), to dissociative symptoms such as experiencing “blank periods” that are characterised by generally low or absent catecholamine correlates. DA gives high frequency conditioning to glutaminergic synapses in order to potentiate goal-directed sensory information flow around the cortex, whilst high NA raises arousal and vigilance and AD promotes flight. In moderate amounts NA also promotes sensory attention, however disproportionately excessive amounts of NA are reported to suppresses and disrupt DA-facilitated information flow around the cortex. In this project the elevated NA biomarker correlated strongly with symptom severity as measured by the Symptom Intensity Rating (SIR) index. Elevated NA also correlated significantly with symptoms representing sensory flow disruption and symptoms indicative of sensory-disconnectivity within the cortex, such as impaired attention and cognitive disorganisation.”

Berridge and Arnsten (2015) discuss catecholaminergic mechanisms in the prefrontal cortex and proven strategies for enhancing higher cognitive function.

“Catecholamines exert inverted-U shaped modulatory actions within the PFC. Thus, optimal function is associated with moderate levels of catecholamine signaling while both inadequate and excessive signaling are associated with functional impairment”

Monaco et al. (2015) expand on PFC-dependent working memory:

“In the context of prefrontal-dependent working memory, two major neuromodulatory systems, the adrenergic and dopaminergic, are involved in regards to how they can influence NMDA receptor-mediated function. Beginning with the adrenergic system, activation of α1- and α2-adrenergic receptors can have bidirectional effects on prefrontal-dependent performance. That is, infusion of the α1 agonist phenylephrine into the primate dlPFC impairs delay-response performance; however, guanfacine, an α2 agonist, improves working memory performance (Mao et al., 1999 and Wang et al., 2007b). When norepinephrine, the endogenous agonist of adrenergic receptors, is experimentally or naturally depleted, spatial working memory performance can be restored following administration of α2 agonists (Arnsten and Goldman-Rakic, 1985 and Rama et al., 1996). These findings suggest an important role of norepinephrine-mediated signaling in prefrontal-dependent working memory function. More specifically, adrenergic receptor activation has been found to reduce NMDA currents in prefrontal cortical neurons (Liu et al., 2006), but it remains to be determined how unique subtypes of adrenergic receptors regulate NMDA receptors to affect working memory function and their possible links to neuropsychiatric diseases.”

Mather et al. (2015) provide a mechanism by which norepinephrine and glutamate may interact at the emotion-cognition interface:

Norepinephrine ignites local hot spots of neuronal excitation: How arousal amplifies selectivity in perception and memory.

Existing brain-based emotion-cognition theories fail to explain arousal’s ability to both enhance and impair cognitive processing. In the Glutamate Amplifies Noradrenergic Effects (GANE) model outlined in this paper, we propose that arousal-induced norepinephrine (NE) released from the locus coeruleus (LC) biases perception and memory in favor of salient, high priority representations at the expense of lower priority representations. This increase in gain under phasic arousal occurs via synaptic self-regulation of NE based on glutamate levels. When the LC is phasically active, elevated levels of glutamate at the site of prioritized representations increase local NE release, creating “NE hot spots.” At these local hot spots, glutamate and NE release are mutually enhancing and amplify activation of prioritized representations. This excitatory effect contrasts with widespread NE suppression of weaker representations via lateral and auto-inhibitory processes. On a broader scale, hot spots increase oscillatory synchronization across neural ensembles transmitting high priority information. Furthermore, key brain structures that detect or pre-determine stimulus priority interact with phasic NE release to preferentially route such information through large-scale functional brain networks. A surge of NE before, during or after encoding enhances synaptic plasticity at sites of high glutamate activity, triggering local protein synthesis processes that enhance selective memory consolidation. Together, these noradrenergic mechanisms increase perceptual and memory selectivity under arousal. Beyond explaining discrepancies in the emotion-cognition literature, GANE reconciles and extends previous influential theories of LC neuromodulation by highlighting how NE can produce such different outcomes in processing based on priority.

“Under phasic arousal, local glutamate signals corresponding to a highly activated percept interact with NE to create a hot spot of even higher levels of activity, while lower priority representations are either neglected or further suppressed. These self-regulating hot spots are further aided by NE’s recruitment of brain structures and large-scale functional networks that determine which stimuli deserve attention. NE directs blood flow and energetic resources to brain regions transmitting prioritized information. It supports selective memory consolidation via initiation of LTP and LTD. Through all of these processes, NE increases the gain of prioritized information in the brain, such that things that matter stand out even more and are remembered even better, while the mundane or irrelevant recede even more into the background and are ignored or forgotten.”

The norepinephrine (NE) “hot spot” mechanism. (1A) Spillover glutamate (green dots) from highly active neurons interacts with nearby depolarized NE varicosities in a positive feedback loop involving NMDA and other glutamate receptors that leads to greater local NE release (maroon dots). The glutamatergic NMDA receptors require concomitant depolarization of noradrenergic axons (lightning symbol). Thus, hot spots amplify prioritized inputs most effectively under phasic arousal. (1B) Glutamate also recruits nearby astrocytes to release serine, glycine (orange dots), and additional glutamate. (2) Greater NE release creates concentration levels sufficient to activate low-affinity β-adrenoreceptors, which enhances neuron excitability. (3) Via activation of β and α2A auto-receptors, NE can stimulate or inhibit additional NE release, respectively. (4) Within hot spots, NE engages β-adrenoceptors on pre-synaptic glutamate terminals to increase glutamate release. (5) Finally, NE binding to post-synaptic β-adrenoceptors also inhibits the slow after hypolarization, enabling the neuron to fire for even longer. [source]

The temporal dynamics of emotional memory formation, along with the neurobiological correlates of the stress response (including the role of NE), are discussed by Cadle and Zoladz (2015).

A role for DA and NE in response to novelty is discussed by Schomaker and Meeter (2015).

Potential therapeutic interventions include:

Clonidine:

“…even a single low dose of clonidine administered to stably medicated patients with schizophrenia not only significantly increases their levels of P50 suppression but also normalizes them. The results indicate that α2-noradrenergic agonists are capable of normalizing levels of P50 gating, which has a potentially high clinical relevance for the medical treatment of schizophrenia” [1]

There is preliminary evidence that clonidine may be an effective alternative to neuroleptics, particularly for patients for whom the dopaminergic blocking action of the neuroleptics is undesirable [2]

Chronic guanfacine use may have clinical utility in protecting PFC gray matter from the detrimental effects of stress:

“Daily guanfacine treatment compared to vehicle control was found to prevent dendritic spine loss in layer II/III pyramidal neurons of prelimbic PFC in rats exposed to chronic restraint stress. Guanfacine also protected working memory performance; cognitive performance correlated with dendritic spine density.” [3]

Noradrenergic regulation of fear and drug-associated memory reconsolidation [4] and the pharmacological mechanisms of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders [5] are of potential interest.  

Some trials in healthy individuals:

Guanfacine, but not clonidine, improves planning and working memory performance in humans.
Clonidine, but not guanfacine, impairs choice reaction time performance in young healthy volunteers.
Differences in psychic performance with guanfacine and clonidine in normotensive subjects.

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