Modulatory Actions of Norepinephrine on Neural Circuits

Woodward, Donald J.; Moises, Hylan C.; Waterhouse, Barry D.; Yeh, Hermes H.; Cheun, J.E.

doi:10.1007/978-1-4684-5907-4_16

Cited by 96 publications

(91 citation statements)

References 20 publications

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“…Nonetheless, b-receptors have been shown to facilitate glutamate signaling in the mPFC, and to enhance signal-to-noise ratio of evoked synaptic responses in many brain regions (Woodward et al, 1991;Ji et al, 2008). In addition, chronic stress downregulates b-adrenergic receptor binding in the cortex (Nomura et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

Jett

Morilak

2012

Neuropsychopharmacol

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Cognitive impairments associated with dysfunction of the medial prefrontal cortex (mPFC) are prominent in stress-related psychiatric disorders. We have shown that enhancing noradrenergic tone acutely in the rat mPFC facilitated extra-dimensional (ED) set-shifting on the attentional set-shifting test (AST), whereas chronic unpredictable stress (CUS) impaired ED. In this study, we tested the hypothesis that the acute facilitatory effect of norepinephrine (NE) in mPFC becomes detrimental when activated repeatedly during CUS. Using microdialysis, we showed that the release of NE evoked in mPFC by acute stress was unchanged at the end of CUS treatment. Thus, to then determine if repeated elicitation of this NE activity in mPFC during CUS may have contributed to the ED deficit, we infused a cocktail of a 1 -, b 1 -, and b 2 -adrenergic receptor antagonists into the mPFC prior to each CUS session, then tested animals drug free on the AST. Antagonist treatment prevented the CUS-induced ED deficit, suggesting that NE signaling during CUS compromised mPFC function. We confirmed that this was not attributable to sensitization of adrenergic receptor function following chronic antagonist treatment, by administering an additional microinjection into the mPFC immediately prior to ED testing. Acute antagonist treatment did not reverse the beneficial effects of chronic drug treatment during CUS, nor have any effect on baseline ED performance in chronic vehicle controls. Thus, we conclude that blockade of noradrenergic receptors in mPFC protected against the detrimental cognitive effects of CUS, and that repeated elicitation of noradrenergic facilitatory activity is one mechanism by which chronic stress may promote mPFC cognitive dysfunction.

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Section: Discussionmentioning

confidence: 99%

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

Jett

Morilak

2012

Neuropsychopharmacol

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“…What role might p-adrenergic stimulation of adenosine accumulation play in the physiology of norepinephrine? Since Woodward and colleagues proposed that the function of the norepinephrine projection to cortex is to increase the signal-to-noise relationship for significant stimuli, this hypothesis has become widely accepted as useful in understanding the function of norepinephrine (Woodward et al, 1979;Foote et al, 1983). It has received considerable support in studies (Haas and Konnerth, 1982;Madison and Nicoll, 1982) that provided a cellular basis for the strengthening of strong inputs that is one role for norepinephrine required by the Woodward hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Beta-adrenergic receptor-mediated regulation of extracellular adenosine in cerebral cortex in culture

Knowles

et al. 1994

J. Neurosci.

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Adenosine is an important inhibitory neuromodulator in the CNS, yet the sources of extracellular adenosine have yet to be well characterized. In this study we show that beta-adrenergic stimulation of cortical cultures results in the extracellular accumulation of cAMP as well as adenosine, and that the extracellular adenosine derives from extracellular cAMP. The concentration dependence of isoproterenol in evoking cAMP secretion was determined by radioimmunoassay, and the EC50 for this effect was found to be approximately 100 nM. In order to investigate the effect of beta-adrenergic stimulation on the regulation of extracellular adenosine, the effect of isoproterenol in stimulating the extracellular accumulation of adenine-containing compounds was examined by HPLC. Isoproterenol stimulated cAMP secretion in both astrocyte cultures and astrocyte-rich mixed cultures of astrocytes and neurons. However, no extracellular cAMP was detectable in neuron- enriched astrocyte-poor cultures. Extracellular adenosine increased in response to isoproterenol in the astrocyte-rich mixed cultures, but not in the neuron-enriched astrocyte-poor cultures. After 30 min exposure to isoproterenol, the concentration of adenosine in the extracellular medium increased by 47% in 56 experiments in the mixed astrocyte-rich cultures. In order to establish whether the adenosine that accumulates in response to isoproterenol stimulation actually derives from extracellular cAMP, phosphodiesterase inhibitors were tested for their ability to block isoproterenol-stimulated adenosine accumulation. Isobutylmethylxanthine (IBMX; 100 microM), RO 20–1724 (180 microM), carbazeran (10 microM), dipyridamole (10 microM), and trifluoperazine (10 microM) had no inhibitory effect on the isoproterenol-stimulated accumulation of extracellular adenosine. However 100 microM IBMX plus 180 microM RO 20–1724 effectively blocked isoproterenol-stimulated adenosine accumulation and, as expected, increased extracellular cAMP. As a further test of the origin of isoproterenol-stimulated adenosine accumulation, we attempted to block this phenomenon by blocking cAMP secretion itself. For this purpose probenecid, a known inhibitor of cAMP secretion in many different cell types, was used. We found that probenecid at 1 mM blocked isoproterenol-stimulated adenosine accumulation. These studies suggest that one potentially important source of extracellular adenosine in the cerebral cortex is endogenous extracellular cAMP, secreted from astrocytes in response to beta- adrenergic receptor stimulation. Since the receptors of neuromodulators other than norepinephrine may also be coupled to adenylyl cyclase in the cerebral cortex, there may be several neuromodulatory systems that regulate extracellular adenosine levels by this mechanism.

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“…The locus coeruleus is known to possess a high level of D2 receptors (Yokoyama eta!., 1994), which tend to inhibit cell -28- activity. During training, a transient noradrenergic or cholinergic burst due to a dopamine dip may suppress recently active cells but excite cells which have not recently been active, Noradrenaline has been found to both suppress synaptic transmission and enhance responsiveness to stimuli (Woodward et aL, 1979;Hasselmo et aL, 1997), The model dopamine dip effect here is similar to a reset signal in Adaptive Resonance Theory, or ART (Carpenter and Grossberg, 1991;Grossberg, 1999), which allows new cells to become active and learn to be activated by the existing input pattern, It docs this by first suppressing previously active cells and then exciting a new cell (or cells) which has not recently been active, Then it trains the newly activated cell to respond to the input pattern. In this way, a dopamine dip can cause the SEF input layer to Jearn a new contlgural cue representation (CCR) of the active SEF afferents from working memory representations in dorsolateral PFC A CCR is a clustered representation of an afferent pattern, Learning-selective cells, which are most active during the early stages of new task learning) have been found in the SEF (Chen & Wise, 1995a), Although the dopamine dip corresponds to failure in the current trial, the resulting newly trained CCR expands the set of input layer representations such that the activity of the input layer becomes sufficient to uniquely determine an appropriate response to the novel situation as well as to previously learned situations.…”

Section: During Training a Reactive Pro-saccade To The Anti-saccade mentioning

confidence: 99%

How laminar frontal cortex and basal ganglia circuits interact to control planned and reactive saccades

Brown

Bullock

Grossberg³

2004

Neural Networks

247

281

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Modulatory Actions of Norepinephrine on Neural Circuits

Cited by 96 publications

References 20 publications

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

Beta-adrenergic receptor-mediated regulation of extracellular adenosine in cerebral cortex in culture

How laminar frontal cortex and basal ganglia circuits interact to control planned and reactive saccades

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