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

Jett, Julianne D; Morilak, David A

doi:10.1038/npp.2012.216

Cited by 41Stress Responses and CortisolNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

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

Open access

Jett, Julianne D, Morilak, David A·2013·Neuropsychopharmacology

DOI 10.1038/npp.2012.216PMC PMC3572455

Open this paper in CoChat — free account Open PDF

Abstract

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 α(1)-, β(1)-, and β(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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1038/npp.2012.216

Cites

87 of 87 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Both forms of inflexibility occur after chronic stress; only stress-induced attentional set-shifting deficits are prevented by adrenergic receptor agonist cocktail into mPFC, while reversal learning deficits remain.
“Both forms of inflexibility have been reported following chronic stress but only stress-induced attentional set-shifting deficits were prevented by localized infusions of a cocktail of alpha 1, beta 1 and beta 2 adrenergic receptor agonists into the mPFC before each stress session of the chronic treatment period [257], whilst stress-induced reversal learning deficits remain.”
From Prefrontal cortex and depression (2022) · cites this paper as [257]
The Discussion reports that chronic stress impaired both ED set-shifting and reversal learning, and that the mPFC treatment prevented only the set-shifting deficit. But the Figure 4 caption and Experiment 2 identify the infused drugs as α1-, β1-, and β2-adrenergic receptor antagonists, not agonists. The claim reverses the identity of the intervention responsible for the reported effect. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Chronic stress, such as chronic unpredictable stress and repeated restraint stress, produces a deficit in extradimensional set-shifting on the AST in rodents.
“chronic stress (for example, chronic unpredictable stress (CUS) and repeated restraint stress) has been shown to produce a deficit in ED set-shifting on the AST in rodents (Bondi et al 2008, Fucich et al 2016, Jett & Morilak 2013, Liston et al 2006, Morilak et al 2005)”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Jett & Morilak 2013
Blocking α1-adrenergic and β2-adrenergic receptors before each stress session during chronic unpredictable stress protects against detrimental effects of chronic stress on set-shifting capability.
“blocking α1-adrenergic and β2-adrenergic receptors prior to each stress session during a chronic unpredictable stress treatment protected against the detrimental effects of chronic stress on set-shifting capability (Jett & Morilak 2013).”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Jett & Morilak 2013

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The rat brain in stereotaxic coordinates
Palkovits, M. (1983) · Neuropeptides · doi:10.1016/0143-4179(83)90049-5 · Cited by 28,959 · see citing works
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
Stress and the brain: from adaptation to disease
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1683 · Cited by 4,621 · see citing works
The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes
Berridge, C. W., & Waterhouse, B. D. (2003) · Brain Research Reviews · doi:10.1016/s0165-0173(03)00143-7 · Cited by 2,529 · see citing works
Causal Relationship Between Stressful Life Events and the Onset of Major Depression
Kendler, K. S., Karkowski, L. M., & Prescott, C. A. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.6.837 · Cited by 2,486 · cited 2× · see citing works
“Similar treatment strategies may be effective in reducing the risk of relapse of depression or anxiety disorders when faced with subsequent life stress (Kendler et al, 1998, 1999).”
Background
Neural mechanisms of the cognitive model of depression.
Disner, S. G., Beevers, C. G., Haigh, E. A. P., & Beck, A. T. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3027 · Cited by 1,718 · see citing works
Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders
MCEWEN, B. S. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1314.001 · Cited by 1,638 · see citing works
The neuro-symphony of stress
Joëls, M., & Baram, T. Z. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2632 · Cited by 1,521 · see citing works
Medial Frontal Cortex Mediates Perceptual Attentional Set Shifting in the Rat
Birrell, J. M., & Brown, V. J. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-11-04320.2000 · Cited by 1,421 · see citing works
The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission
Popoli, M., Yan, Z., McEwen, B. S., & Sanacora, G. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3138 · Cited by 1,393 · see citing works
Cognitive deficits in depression: Possible implications for functional neuropathology
Austin, M.-P., Mitchell, P., & Goodwin, G. M. (2001) · British Journal of Psychiatry · doi:10.1192/bjp.178.3.200 · Cited by 1,154 · see citing works
Mood disorders and allostatic load
McEwen, B. S. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00177-x · Cited by 1,135 · see citing works
Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons
Woolley, C. S., Gould, E., & McEwen, B. S. (1990) · Brain Research · doi:10.1016/0006-8993(90)90778-a · Cited by 1,020 · see citing works
Stress-Induced Alterations in Prefrontal Cortical Dendritic Morphology Predict Selective Impairments in Perceptual Attentional Set-Shifting
Liston, C., Miller, M. M., Goldwater, D. S., Radley, J. J., Rocher, A. B., Hof, P. R., Morrison, J. H., & McEwen, B. S. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1184-06.2006 · Cited by 968 · see citing works
Learning under stress: how does it work?
Joëls, M., Pu, Z., Wiegert, O., Oitzl, M. S., & Krugers, H. J. (2006) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2006.02.002 · Cited by 947 · see citing works
Role of locus coeruleus in attention and behavioral flexibility
Aston-Jones, G., Rajkowski, J., & Cohen, J. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00140-7 · Cited by 900 · see citing works
Psychosocial stress reversibly disrupts prefrontal processing and attentional control
Liston, C., McEwen, B. S., & Casey, B. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807041106 · Cited by 859 · see citing works
Increased Amygdala and Decreased Dorsolateral Prefrontal BOLD Responses in Unipolar Depression: Related and Independent Features
Siegle, G. J., Thompson, W., Carter, C. S., Steinhauer, S. R., & Thase, M. E. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.05.048 · Cited by 857 · see citing works
Reduced Prefrontal Glutamate/Glutamine and γ-Aminobutyric Acid Levels in Major Depression Determined Using Proton Magnetic Resonance Spectroscopy
Hasler, G., van der Veen, J. W., Tumonis, T., Meyers, N., Shen, J., & Drevets, W. C. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.2.193 · Cited by 846 · see citing works
Role of adrenal stress hormones in forming lasting memories in the brain
McGaugh, J. L., & Roozendaal, B. (2002) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(02)00306-9 · Cited by 818 · see citing works
The Current State of Cognitive Therapy: A 40-Year Retrospective
Beck, A. T. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.9.953 · Cited by 816 · see citing works
Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex
Radley, J. J., Sisti, H. M., Hao, J., Rocher, A. B., McCall, T., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.01.006 · Cited by 769 · see citing works
Chronic stress alters dendritic morphology in rat medial prefrontal cortex
Cook, S. C., & Wellman, C. L. (2004) · Journal of Neurobiology · doi:10.1002/neu.20025 · Cited by 750 · see citing works
Differentiating anxiety and depression: A test of the cognitive content-specificity hypothesis.
Beck, A. T., Brown, G. P., Steer, R. A., Eidelson, J. I., & al, E. (1987) · Journal of Abnormal Psychology · doi:10.1037//0021-843x.96.3.179 · Cited by 707 · see citing works
Emotional bias and inhibitory control processes in mania and depression
MURPHY, F. C., SAHAKIAN, B. J., RUBINSZTEIN, J. S., MICHAEL, A., ROGERS, R. D., ROBBINS, T. W., & PAYKEL, E. S. (1999) · Psychological Medicine · doi:10.1017/s0033291799001233 · Cited by 659 · see citing works
Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat
McAlonan, K., & Brown, V. J. (2003) · Behavioural Brain Research · doi:10.1016/j.bbr.2003.09.019 · Cited by 618 · see citing works
Wisconsin Card Sorting Test performance in patients with focal frontal and posterior brain damage: effects of lesion location and test structure on separable cognitive processes
Stuss, D. T., Levine, B., Alexander, M. P., Hong, J., Palumbo, C., Hamer, L., Murphy, K. J., & Izukawa, D. (2000) · Neuropsychologia · doi:10.1016/s0028-3932(99)00093-7 · Cited by 596 · see citing works
Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration
Wellman, C. L. (2001) · Journal of Neurobiology · doi:10.1002/neu.1079 · Cited by 594 · see citing works
Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggests a role in vigilance
Aston‐Jones, G., Chiang, C., & Alexinsky, T. (1991) · Progress in brain research · doi:10.1016/s0079-6123(08)63830-3 · Cited by 589 · see citing works
Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Comparison of stressors
Magarin˜os, A. M., & McEwen, B. S. (1995) · Neuroscience · doi:10.1016/0306-4522(95)00256-i · Cited by 571 · see citing works
Role of brain norepinephrine in the behavioral response to stress
Morilak, D. A., Barrera, G., Echevarria, D. J., Garcia, A. S., Hernandez, A., Ma, S., & Petre, C. O. (2005) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2005.08.007 · Cited by 570 · see citing works
Self-citation
A Parallel Group Placebo Controlled Study of Prazosin for Trauma Nightmares and Sleep Disturbance in Combat Veterans with Post-Traumatic Stress Disorder
Raskind, M. A., Peskind, E. R., Hoff, D. J., Hart, K. L., Holmes, H. A., Warren, D., Shofer, J. B., O’Connell, J., Taylor, F., Gross, C., et al. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.06.032 · Cited by 554 · see citing works
Differentiating anxiety and depression: A test of the cognitive content-specificity hypothesis.
Beck, A. T., Brown, G. P., Steer, R. A., et al. (1987) · Journal of Abnormal Psychology · doi:10.1037/0021-843x.96.3.179 · Cited by 529 · see citing works
Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory
Yuen, E. Y., Liu, W., Karatsoreos, I. N., Feng, J., McEwen, B. S., & Yan, Z. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906791106 · Cited by 481 · see citing works
Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression
Feyissa, A. M., Chandran, A., Stockmeier, C. A., & Karolewicz, B. (2009) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2008.10.005 · Cited by 421 · see citing works
Locus coeruleus and regulation of behavioral flexibility and attention
(2000) · Progress in Brain Research · doi:10.1016/s0079-6123(00)26013-5 · Cited by 400 · see citing works
Chronic Unpredictable Stress Induces a Cognitive Deficit and Anxiety-Like Behavior in Rats that is Prevented by Chronic Antidepressant Drug Treatment
Bondi, C. O., Rodriguez, G., Gould, G. G., Frazer, A., & Morilak, D. A. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301410 · Cited by 398 · see citing works
Self-citation
Stressful Life Events and Major Depression: Risk Period, Long-Term Contextual Threat, and Diagnostic Specificity
KENDLER, K. S., KARKOWSKI, L. M., & PRESCOTT, C. A. (1998) · The Journal of Nervous & Mental Disease · doi:10.1097/00005053-199811000-00001 · Cited by 380 · see citing works
Glucocortcoids mediate the stress-induced extracellular accumulation of glutamate
Moghaddam, B., Bolinao, M. L., Stein-Behrens, B., & Sapolsky, R. (1994) · Brain Research · doi:10.1016/0006-8993(94)91622-5 · Cited by 378 · see citing works
Stress and emotional memory: a matter of timing
Joëls, M., Fernández, G., & Roozendaal, B. (2011) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2011.04.004 · Cited by 372 · see citing works
Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: Role of corticosterone-mediated apical dendritic atrophy
Liu, R.-J., & Aghajanian, G. K. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706679105 · Cited by 346 · see citing works
Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability
Bluhm, M. D. L., & Morilak, D. A. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.09.031 · Cited by 325 · see citing works
Self-citation
Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory
Yuen, E. Y., Liu, W., Karatsoreos, I. N., Ren, Y., Feng, J., McEwen, B. S., & Yan, Z. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.50 · Cited by 324 · see citing works
Stress and brain noradrenaline: a review.
Glavin, G. (1985) · Neuroscience and Biobehavioral Reviews · doi:10.1016/0149-7634(85)90048-x · Cited by 322 · see citing works
Prefrontal Cortical Dysfunction in Depression Determined by Wisconsin Card Sorting Test Performance
Merriam, E. P., Thase, M. E., Haas, G. L., Keshavan, M. S., & Sweeney, J. A. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.5.780 · Cited by 278 · see citing works
Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats
Venero, C., & Borrell, J. (1999) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1999.00668.x · Cited by 277 · see citing works
Neuro-Psychopharmacology.
GRINKER, R. R. (1960) · Archives of General Psychiatry · doi:10.1001/archpsyc.1960.03590120120017 · Cited by 269 · see citing works
Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression
Fales, C. L., Barch, D. M., Rundle, M. M., Mintun, M. A., Mathews, J., Snyder, A. Z., & Sheline, Y. I. (2009) · Journal of Affective Disorders · doi:10.1016/j.jad.2008.04.027 · Cited by 266 · see citing works
Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders
Morilak, D. A., & Frazer, A. (2004) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145704004080 · Cited by 252 · see citing works
Self-citation
Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress.
Cecchi, M., Khoshbouei, H., Javors, M., & Morilak, D. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00062-3 · Cited by 243 · see citing works
Self-citation
Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam
Bagley, J., & Moghaddam, B. (1997) · Neuroscience · doi:10.1016/s0306-4522(96)00435-6 · Cited by 231 · see citing works
Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting
McGaughy, J., Ross, R. S., & Eichenbaum, H. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.01.064 · Cited by 226 · see citing works
The neuropharmacology of serotonin and noradrenaline in depression
Nutt, D. (2002) · International Clinical Psychopharmacology · doi:10.1097/00004850-200206001-00002 · Cited by 222 · see citing works
5-HT2A receptor or α1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex
Marek, G. J., & Aghajanian, G. K. (1999) · European Journal of Pharmacology · doi:10.1016/s0014-2999(98)00945-5 · Cited by 221 · see citing works
Locus coeruleus-evoked responses in behaving rats: A clue to the role of noradrenaline in memory
Sara, S. J., Vankov, A., & Hervé, A. (1994) · Brain Research Bulletin · doi:10.1016/0361-9230(94)90159-7 · Cited by 221 · see citing works
Effects of locus coeruleus inactivation on electroencephalographic activity in neocortex and hippocampus
Berridge, C. W., Page, M. E., Valentino, R. J., & Foote, S. L. (1993) · Neuroscience · doi:10.1016/0306-4522(93)90507-c · Cited by 214 · see citing works
Multiple neurochemical and behavioral consequences of stressors: Implications for depression
Anisman, H., & Zacharko, R. M. (1990) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(90)90039-5 · Cited by 196 · see citing works
Alpha-receptor-mediated facilitation of somatosensory cortical neuronal responses to excitatory synaptic inputs and iontophoretically applied acetylcholine
Waterhouse, B. (1981) · Neuropharmacology · doi:10.1016/0028-3908(81)90020-4 · Cited by 184 · see citing works
Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat
Tait, D. S., Brown, V. J., Farovik, A., Theobald, D. E., Dalley, J. W., & Robbins, T. W. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05612.x · Cited by 179 · see citing works
Noradrenergic Innervation of the Dorsal Medial Prefrontal Cortex Modulates Hypothalamo-Pituitary-Adrenal Responses to Acute Emotional Stress
Radley, J. J., Williams, B., & Sawchenko, P. E. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0552-08.2008 · Cited by 148 · see citing works
Modulatory effects of norepinephrine, acting on alpha1 receptors in the central nucleus of the amygdala, on behavioral and neuroendocrine responses to acute immobilization stress
Cecchi, M., Khoshbouei, H., & Morilak, D. A. (2002) · Neuropharmacology · doi:10.1016/s0028-3908(02)00292-7 · Cited by 147 · see citing works
Self-citation
NMDA Receptor Blockade Alters Stress-Induced Dendritic Remodeling in Medial Prefrontal Cortex
Martin, K. P., & Wellman, C. L. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhr021 · Cited by 138 · see citing works
Prevention of stress-induced morphological and cognitive consequences
McEwen, B. S., Conrad, C. D., Kuroda, Y., Frankfurt, M., Magariños, A. M., & McKittrick, C. R. (1997) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(97)00064-3 · Cited by 137 · see citing works
Forebrain norepinephrine: role in controlled information processing in the rat.
Cole, B. J., & Robbins, T. W. (1992) · PubMed · Cited by 134 · see citing works
Executive dysfunction in depression: The Wisconsin Card Sorting Test
Channon, S. (1996) · Journal of Affective Disorders · doi:10.1016/0165-0327(96)00027-4 · Cited by 129 · see citing works
Corticotropin-Releasing Factor in the Basolateral Amygdala Enhances Memory Consolidation via an Interaction with the -Adrenoceptor-cAMP Pathway: Dependence on Glucocorticoid Receptor Activation
Roozendaal, B., Schelling, G., & McGaugh, J. L. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1336-08.2008 · Cited by 115 · see citing works
Stress, glucocorticoids and glutamate release: Effects of antidepressant drugs
Musazzi, L., Racagni, G., & Popoli, M. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.05.002 · Cited by 113 · see citing works
Norepinephrine Release in Medial Amygdala Facilitates Activation of the Hypothalamic‐Pituitary‐Adrenal Axis in Response to Acute Immobilisation Stress
Ma, S., & Morilak, D. A. (2005) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2005.01279.x · Cited by 111 · see citing works
Self-citation
Abnormal Cingulate and Prefrontal Cortical Neurochemistry in Major Depression After Electroconvulsive Therapy
Merkl, A., Schubert, F., Quante, A., Luborzewski, A., Brakemeier, E., Grimm, S., Heuser, I., & Bajbouj, M. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.08.009 · Cited by 106 · see citing works
Chronic cold stress sensitizes brain noradrenergic reactivity and noradrenergic facilitation of the HPA stress response in Wistar Kyoto rats
Pardon, M., Ma, S., & Morilak, D. A. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02355-2 · Cited by 97 · see citing works
Self-citation
Stress-induced norepinephrine release in the rat prefrontal cortex measured by microdialysis
Nakane, H., Shimizu, N., & Hori, T. (1994) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1994.267.6.r1559 · Cited by 95 · see citing works
Chronic Intermittent Cold Stress Sensitises the Hypothalamic‐Pituitary‐Adrenal Response to a Novel Acute Stress by Enhancing Noradrenergic Influence in the Rat Paraventricular Nucleus
Ma, S., & Morilak, D. A. (2005) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2005.01372.x · Cited by 94 · see citing works
Self-citation
Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by α1-adrenergic receptors in medial prefrontal cortex
Bondi, C. O., Jett, J. D., & Morilak, D. A. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.04.016 · Cited by 88 · see citing works
Self-citation
Interactions between noradrenaline and corticosteroids in the brain: from electrical activity to cognitive performance
Krugers, H. J., Karst, H., & Joëls, M. (2012) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2012.00015 · Cited by 77 · see citing works
Single-unit and physiological analyses of brain norepinephrine function in behaving animals.
Jacobs, B. L., Abercrombie, E., Fornal, C., Levine, E., Morilak, D. A., & Stafford, I. (1991) · Progress in Brain Research · doi:10.1016/s0079-6123(08)63805-4 · Cited by 70 · see citing works
Self-citation
Pre- and Postsynaptic -Adrenergic Activation Enhances Excitatory Synaptic Transmission in Layer V/VI Pyramidal Neurons of the Medial Prefrontal Cortex of Rats
Ji, X.-H., Cao, X., Zhang, C.-L., Feng, Z.-J., Zhang, X.-H., Ma, L., & Li, B.-M. (2007) · Cerebral Cortex · doi:10.1093/cercor/bhm177 · Cited by 68 · see citing works
Neuronal Protein Kinase Signaling Cascades and Excitotoxic Cell Death
Skaper, S. D., Facci, L., & Strijbos, P. J. L. M. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb03606.x · Cited by 60 · see citing works
Stress and β-adrenergic receptor binding in the rat's brain
Nomura, S., Watanabe, M., Ukei, N., & Nakazawa, T. (1981) · Brain Research · doi:10.1016/0006-8993(81)91133-1 · Cited by 58 · see citing works
Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation by chronic treatment with desipramine
Bondi, C. O., Barrera, G., Lapiz, M. D. S., Bedard, T., Mahan, A., & Morilak, D. A. (2007) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2006.11.015 · Cited by 56 · see citing works
Self-citation
Modulatory Actions of Norepinephrine on Neural Circuits
Woodward, D. J., Moises, H. C., Waterhouse, B. D., Yeh, H. H., & Cheun, J. E. (1991) · Advances in experimental medicine and biology · doi:10.1007/978-1-4684-5907-4_16 · Cited by 54 · see citing works
Interhemispheric Regulation of the Medial Prefrontal Cortical Glutamate Stress Response in Rats
Lupinsky, D., Moquin, L., & Gratton, A. P. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1187-10.2010 · Cited by 49 · see citing works
Differential modulatory effects of norepinephrine on synaptically driven responses of layer V barrel field cortical neurons
Waterhouse, B. D., Mouradian, R., Sessler, F. M., & Lin, R. C. S. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02261-7 · Cited by 45 · see citing works
Chronic stress modulation of prefrontal cortical NMDA receptor expression disrupts limbic structure-prefrontal cortex interaction
Lee, Y., & Goto, Y. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07750.x · Cited by 42 · see citing works
Excitatory amino acids and neurotoxicity.
Bruno, V., Scapagnini, U., & Canonico, P. L. (1994) · PubMed · Cited by 29 · see citing works
Treatment of nightmares in the context of posttraumatic stress disorder
Gehrman, P., & Harb, G. C. (2010) · Journal of Clinical Psychology · doi:10.1002/jclp.20730 · Cited by 26 · see citing works
Blockade of autoreceptor-mediated inhibition of norepinephrine release by atipamezole is maintained after chronic reuptake inhibition
Bluhm, M. D. L., Zhao, Z., Bondi, C. O., O’Donnell, J. M., & Morilak, D. A. (2007) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145707007651 · Cited by 12 · see citing works
Self-citation
Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders
(2000) · doi:10.1002/1520-6394(2000)12:1+

Flagged first, then by citations

Sorted by citations

Prefrontal cortex and depression
Pizzagalli, D. A., & Roberts, A. C. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01101-7 · Cited by 644 · see citing works
Chronic stress and brain plasticity: Mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders
Radley, J., Morilak, D., Viau, V., & Campeau, S. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.06.018 · Cited by 339 · see citing works
Self-citation
Prefrontal cortex executive processes affected by stress in health and disease
Girotti, M., Adler, S. M., Bulin, S. E., Fucich, E. A., Paredes, D., & Morilak, D. A. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.07.004 · Cited by 176 · see citing works
Self-citation
Effects of chronic stress on cognitive function – From neurobiology to intervention
Girotti, M., Bulin, S. E., & Carreno, F. R. (2024) · Neurobiology of Stress · doi:10.1016/j.ynstr.2024.100670 · Cited by 141 · see citing works
Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex
Jett, J. D., Bulin, S. E., Hatherall, L. C., McCartney, C. M., & Morilak, D. A. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.01.017 · Cited by 92 · see citing works
Self-citation
Treatment of cognitive dysfunction in major depressive disorder—a review of the preclinical evidence for efficacy of selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors and the multimodal-acting antidepressant vortioxetine
Pehrson, A. L., Leiser, S. C., Gulinello, M. E., Dale, E., Li, Y., Waller, J. A., & Sánchez, C. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.07.044 · Cited by 94 · see citing works
Effects of stress on behavioral flexibility in rodents
Hurtubise, J. L., & Howland, J. G. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.04.007 · Cited by 79 · see citing works
Acute stress impairs set-shifting but not reversal learning
Butts, K. A., Floresco, S. B., & Phillips, A. G. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.06.007 · Cited by 77 · see citing works
Anxiety and depression: A top‐down, bottom‐up model of circuit function
LeDuke, D. O., Borio, M., Miranda, R. L., & Tye, K. M. (2023) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14997 · Cited by 76 · see citing works
Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway
Jett, J. D., Boley, A. M., Girotti, M., Shah, A., Lodge, D. J., & Morilak, D. A. (2015) · Psychopharmacology · doi:10.1007/s00213-015-3957-3 · Cited by 75 · see citing works
Self-citation
Neurocognitive Disorders in Heart Failure: Novel Pathophysiological Mechanisms Underpinning Memory Loss and Learning Impairment
Toledo, C., Andrade, D. C., Díaz, H. S., Inestrosa, N. C., & Rio, R. D. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01655-0 · Cited by 58 · see citing works
GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex
Kaushal, R., Taylor, B. K., Jamal, A. B., Zhang, L., Ma, F., Donahue, R. R., & Westlund, K. N. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.08.005 · Cited by 55 · see citing works
Adverse effects of early-life stress: focus on the rodent neuroendocrine system
Lee, S. H., & Jung, E. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.377587 · Cited by 43 · see citing works
Sustained corticosterone rise in the prefrontal cortex is a key factor for chronic stress-induced working memory deficits in mice
Dominguez, G., Henkous, N., Prévot, T. D., David, V., Guillou, J., Belzung, C., Mons, N. E., & Béracochéa, D. (2019) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100161 · Cited by 41 · see citing works
Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal
Ashare, R. L., & Schmidt, H. D. (2014) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2014.908180 · Cited by 40 · see citing works
The role of medial prefrontal cortex projections to locus ceruleus in mediating the sex differences in behavior in mice with inflammatory pain
Cárdenas, A., Papadogiannis, A., & Dimitrov, E. L. (2021) · The FASEB Journal · doi:10.1096/fj.202100319rr · Cited by 32 · see citing works
Norepinephrine and corticosterone in the medial prefrontal cortex and hippocampus predict PTSD ‐like symptoms in mice
Kao, C. ‐., Stalla, G. K., Stalla, J., Wotjak, C. T., & Anderzhanova, E. A. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.12860 · Cited by 32 · see citing works
Activation of α1‐adrenoceptors enhances excitatory synaptic transmission via a pre‐ and postsynaptic protein kinase C ‐dependent mechanism in the medial prefrontal cortex of rats
Luo, F., Tang, H., Li, B., & Li, S. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12495 · Cited by 27 · see citing works
Activity in the Ventral Medial Prefrontal Cortex Is Necessary for the Therapeutic Effects of Extinction in Rats
Fucich, E. A., Paredes, D., Saunders, M. O., & Morilak, D. A. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0635-17.2017 · Cited by 27 · see citing works
Self-citation
Therapeutic effects of extinction learning as a model of exposure therapy in rats
Fucich, E. A., Paredes, D., & Morilak, D. A. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.127 · Cited by 24 · see citing works
Self-citation
The impact of social stress during adolescence or adulthood and coping strategy on cognitive function of female rats
Snyder, K., Barry, M. E., Plona, Z., Ho, A., Zhang, X., & Valentino, R. J. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.02.047 · Cited by 25 · see citing works
Effects of Yoga and Aerobic Exercise on Verbal Fluency in Physically Inactive Older Adults: Randomized Controlled Trial (FitForAge)
Welford, P., Östh, J., Hoy, S., Rossell, S. L., Pascoe, M. C., Diwan, V. K., & Hallgren, M. Å. (2023) · Clinical Interventions in Aging · doi:10.2147/cia.s359185 · Cited by 22 · see citing works
Acute restraint stress augments the rewarding memory of cocaine through activation of α1 adrenoceptors in the medial prefrontal cortex of mice
Wada, S., Yanagida, J., Sasase, H., Zhang, T., Li, X., Kamii, H., Domoto, M., Deyama, S., Hinoi, E., Yamanaka, A., et al. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.107968 · Cited by 20 · see citing works
Repeated Social Stress Increases Reward Salience and Impairs Encoding of Prediction by Rat Locus Coeruleus Neurons
Chaijale, N., Snyder, K., Arner, J., Curtis, A. L., & Valentino, R. J. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.200 · Cited by 18 · see citing works
The long-term effect of maternal dietary protein restriction on 5-HT1A receptor function and behavioral responses to stress in adulthood
Ye, W., Pitlock, M. D., Javors, M. A., Thompson, B. J., Lechleiter, J. D., & Hensler, J. G. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.03.038 · Cited by 17 · see citing works
Adolescent Corticosterone and TrkB Pharmaco-Manipulations Sex-Dependently Impact Instrumental Reversal Learning Later in Life
Barfield, E. T., & Gourley, S. L. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2017.00237 · Cited by 16 · see citing works
Vortioxetine reverses medial prefrontal cortex-mediated cognitive deficits in male rats induced by castration as a model of androgen deprivation therapy for prostate cancer
Sharp, A. M., Lertphinyowong, S., Yee, S. S., Paredes, D., Gelfond, J., Johnson‐Pais, T. L., Leach, R. J., Liss, M. A., Risinger, A. L., Sullivan, A. C., et al. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05274-4 · Cited by 11 · see citing works
Self-citation
Brain activation and subjective anxiety during an anticipatory anxiety task is related to clinical outcome during prazosin treatment for alcohol use disorder
Wilcox, C. E., Adinoff, B. H., Clifford, J. M., Ling, J. M., Witkiewitz, K. A., Mayer, A. R., Boggs, K. M., Eck, M., & Bogenschutz, M. P. (2020) · NeuroImage Clinical · doi:10.1016/j.nicl.2020.102162 · Cited by 11 · see citing works
Neurochemical modulation of stress-induced cognitive inflexibility in a rat model of an attentional set-shifting task
Nikiforuk, A., & Popik, P. (2013) · Pharmacological Reports · doi:10.1016/s1734-1140(13)71508-1 · Cited by 10 · see citing works
Patients with sickle-cell disease exhibit greater functional connectivity and centrality in the locus coeruleus compared to anemic controls
Bhatt, R. R., Zeltzer, L. K., Coloigner, J., Wood, J. C., Coates, T. D., & Labus, J. S. (2019) · NeuroImage Clinical · doi:10.1016/j.nicl.2019.101686 · Cited by 9 · see citing works
Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure
Shao, M., Botvinov, J., Banerjee, D., Girirajan, S., & Lüscher, B. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02832-x · Cited by 9 · see citing works
Peripheral CD4 + T cells mediate the destructive effects of maternal separation on prefrontal myelination and cognitive functions
Xiong, R., Hu, Y., Wang, M., Han, T., Hu, Y., Ma, C., & Li, B. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2412995122 · Cited by 7 · see citing works
Variable Response of Norepinephrine Transporter to Traumatic Stress and Relationship to Hyperarousal
Nwokafor, C., Serova, L. I., Tanelian, A., Nahvi, R. J., & Sabban, E. L. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.725091 · Cited by 9 · see citing works
Noradrenergic stimulation of α1 adrenoceptors in the medial prefrontal cortex mediates acute stress-induced facilitation of seizures in mice
Niitani, K., Ito, S., Wada, S., Izumi, S., Nishitani, N., Deyama, S., & Kaneda, K. (2023) · Scientific Reports · doi:10.1038/s41598-023-35242-0 · Cited by 8 · see citing works
Impaired Latent Inhibition in GDNF-Deficient Mice Exposed to Chronic Stress
Buhusi, M. C., Brown, C. K., & Buhusi, C. V. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2017.00177 · Cited by 6 · see citing works
Type-7 metabotropic glutamate receptors negatively regulate α1-adrenergic receptor signalling
Iacovelli, L., Menna, L. D., Peterlik, D., Stangl, C., Orlando, R., Molinaro, G., Blasi, A. D., Bruno, V., Battaglia, G., Flor, P. J., et al. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.10.018 · Cited by 4 · see citing works
A Role for Microglia in Repeated Stress-Induced Functional Changes in the Medial Prefrontal Cortex in Rodents
Kitaoka, S. (2013) · Journal of Neurological Disorders · doi:10.4172/2329-6895.1000123
Cognitive Flexibility in the Context of Stress and Depressive Disorders
Gabrys, R. L. (2017) · doi:10.22215/etd/2017-11965
Neural mechanisms underlying stress-induced enhancement of cocaine craving behaviors
Kaneda, K., Deyama, S., Li, X., Zhang, T., & Sasase, H. (2020) · Folia Pharmacologica Japonica · doi:10.1254/fpj.19147
Involvement of a stress-responsive orbito-striatal projection in impulsive action in male rats
Girotti, M., Boehmer-Cortez, M. G., Tuite, K., & Morilak, D. A. (2025) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyaf043
Self-citation
Connectome gradient dysfunction in earthquake-induced posttraumatic stress disorder and its association with gene expression and neurotransmitter profiles
Zhang, X., Liu, W., Chen, L., Zuo, C., Lan, H., Li, L., Kemp, G. J., Lui, S., Suo, X., & Gong, Q. (2026) · Psychological Medicine · doi:10.1017/s0033291726105388

Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by α1-adrenergic receptors in medial prefrontal cortex
Bondi, C. O., Jett, J. D., & Morilak, D. A. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.04.016 · Cited by 88 · see citing works
Self-citation
Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex
Jett, J. D., Bulin, S. E., Hatherall, L. C., McCartney, C. M., & Morilak, D. A. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.01.017 · Cited by 92 · see citing works
Self-citation
Chronic Stress Effects on the Functional Activation of the Medial Prefrontal Cortex (mPFC) Following Two Short-Term Memory Paradigms
Le, B. Q. (2017) · Arizona State University Library Digital Repository (Arizona State University)
Dissociable roles for cortical and subcortical structures in memory encoding and retrieval
Baxter, M. G., Browning, P. G. F., Gaffan, D., Wilson, C. R. E., & Mitchell, A. S. (2009) · Neuroscience Research · doi:10.1016/j.neures.2009.09.1499
Neurochemical and behavioral effects of chronic unpredictable stress
Matuszewich, L., McFadden, L. M., Friedman, R. D., & Frye, C. A. (2014) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000061 · Cited by 18 · see citing works

Authors: Jett, J. D., & Morilak, D. A.
Affiliations: The University of Texas at San Antonio Health Science Center (US)
Corresponding author: Morilak, David A
ORCID: Jett, Julianne D
Morilak, David A
Venue: Neuropsychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2012-11-07
Volume: 38
Issue: 4
Pages: 585-595
ISSN: 0893-133X (ISSN-L)
1740-634X
DOI: 10.1038/npp.2012.216
PMC: PMC3572455
OpenAlex: W2072437917
Cited by: 41
References: 86
Citations by year: 2026: 1 · 2025: 2 · 2024: 2 · 2023: 4 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 3
FWCI: 1.46
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Neuropsychopharmacology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Mental Health (MH053851, R29MH053851, R01MH053851)
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: chronic unpredictable mild stress, medial prefrontal cortex, norepinephrine, adrenergic antagonists, set-shifting, cognitive impairment, stress-related psychiatric disorders
MeSH terms: Adrenergic beta-Antagonists, Animals, Chronic Disease, Cognition, Cognition Disorders, Male, Norepinephrine, Stress, Psychological, Rats, Sprague-Dawley, Prefrontal Cortex, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks