Chronic stimulation of alpha-2A-adrenoceptors with guanfacine protects rodent prefrontal cortex dendritic spines and cognition from the effects of chronic stress
Open accessAbstract
The prefrontal cortex (PFC) provides top-down regulation of behavior, cognition, and emotion, including spatial working memory. However, these PFC abilities are greatly impaired by exposure to acute or chronic stress. Chronic stress exposure in rats induces atrophy of PFC dendrites and spines that correlates with working memory impairment. As similar PFC grey matter loss appears to occur in mental illness, the mechanisms underlying these changes need to be better understood. Acute stress exposure impairs PFC cognition by activating feedforward cAMP-calcium- K+ channel signaling, which weakens synaptic inputs and reduces PFC neuronal firing. Spine loss with chronic stress has been shown to involve calcium-protein kinase C signaling, but it is not known if inhibiting cAMP signaling would similarly prevent the atrophy induced by repeated stress. The current study examined whether inhibiting cAMP signaling through alpha-2A-adrenoceptor stimulation with chronic guanfacine treatment would protect PFC spines and working memory performance during chronic stress exposure. Guanfacine was selected due to 1) its established effects on cAMP signaling at post-synaptic alpha-2A receptors on spines in PFC, and 2) its increasing clinical use for the treatment of pediatric stress disorders. 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. These findings suggest that chronic guanfacine use may have clinical utility by protecting PFC gray matter from the detrimental effects of stress.
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
Cites
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?
Guanfacine can protect PFC circuits from stress exposure, including preventing atrophy due to chronic stress exposure.
“Evidence from both in vivo and in vitro studies show that guanfacine can protect PFC circuits from stress exposure, including preventing atrophy due to chronic stress exposure.”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2015
The Abstract and Discussion (Summary and evaluation of data; page unavailable) report that daily guanfacine prevented stress-related PFC dendritic spine loss and protected working memory in rats. The Introduction reports in vitro findings of spine growth and spinophilin enrichment, but does not say those cell-culture studies tested protection from stress exposure. Thus the chronic-stress protection is supported by the in vivo study, not by both types of study as the citing sentence states. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDaily guanfacine administration prevented spine loss and working memory deficits.
“and daily guanfacine administration prevented spine loss and working memory deficits (Hains et al., 2015), which may help to explain its utility in treating stress-related disorders.”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2015
The Discussion (Summary and evaluation of data) says daily guanfacine protected spine density and working-memory performance in rats exposed to repeated restraint stress. It also says cognitive performance did not completely normalize, so describing working-memory deficits as prevented overstates the result. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInhibition of PKC or PKA signaling can prevent loss of mPFC dendritic spines and working memory abilities during chronic stress exposure.
“Research in rats by Avis Hains has shown that inhibition of PKC or PKA signaling can prevent the loss of mPFC dendritic spines and working memory abilities during chronic stress exposure (Hains et al., 2009, Hains et al., 2015), suggesting that the sustained weakening of synaptic connectivity via K+ channel opening contributes to spine loss.”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2015
The Introduction reports that inhibiting calcium-PKC signaling rescued spine density and working memory during repeated stress, citing Hains et al. (2009). The Discussion reports that guanfacine protected both outcomes in stressed rats, but the 2015 study tested alpha-2A-adrenoceptor stimulation to inhibit cAMP signaling, not PKA inhibition specifically. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredChronic stress reduces PFC spine density in vehicle-treated rats but not in those receiving daily guanfacine treatment.
“Chronic stress (Str) exposure reduces PFC spine density in vehicle-treated rats, but not in those receiving daily guanfacine treatment.”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2015
Daily treatment with guanfacine preserves working memory performance in chronically stressed rats.
“and preserved working memory performance (Hains et al., 2015)”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2015
Chronic stress exposure causes loss of dendritic spines from layer II/III pyramidal cells in rat mPFC.
“With chronic stress exposure, dendritic spines are lost from layer II/III pyramidal cells in rat mPFC”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2015
Daily treatment with guanfacine prevents stress-induced loss of spines in rats.
“daily treatment with guanfacine prevented stress-induced loss of spines”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Hains et al., 2015
Inhibition of cAMP-PKA signaling with the α2A-AR agonist guanfacine is protective of PFC dendritic spines and cognitive function in rats.
“A more recent study found that inhibition of cAMP–PKA signaling with the α2A-AR agonist guanfacine is also protective of PFC dendritic spines and cognitive function in rats97.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [97]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577 · see citing works
Stress signalling pathways that impair prefrontal cortex structure and function
Arnsten, A. F. T. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2648 · Cited by 3,299 · see citing works
Self-citationCellular basis of working memory
Goldman-Rakic, P. S. (1995) · Neuron · doi:10.1016/0896-6273(95)90304-6 · Cited by 2,663 · see citing works
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208 · see citing works
Decreased Dendritic Spine Density on Prefrontal Cortical Pyramidal Neurons in Schizophrenia
Glantz, L. A., & Lewis, D. A. (2000) · Archives of General Psychiatry · doi:10.1001/archpsyc.57.1.65 · Cited by 1,636 · see citing works
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
Chung, W.-S., Clarke, L. E., Wang, G. X., Stafford, B. K., Sher, A., Chakraborty, C., Joung, J., Foo, L. C., Thompson, A., Chen, C., et al. (2013) · Nature · doi:10.1038/nature12776 · Cited by 1,377 · see citing works
Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates
Dalley, J. W., Cardinal, R. N., & Robbins, T. W. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.09.006 · Cited by 1,329 · see citing works
The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease
Stephan, A. H., Barres, B. A., & Stevens, B. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113810 · Cited by 1,113 · see citing works
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
The reduced neuropil hypothesis: a circuit based model of schizophrenia
Selemon, L. D., & Goldman-Rakic, P. S. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00281-9 · Cited by 909 · 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
Repeated Stress Induces Dendritic Spine Loss in the Rat Medial Prefrontal Cortex
Radley, J. J., Rocher, A. B., Miller, M., Janssen, W. G. M., Liston, C., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2006) · Cerebral Cortex · doi:10.1093/cercor/bhi104 · Cited by 820 · 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
Catecholamine receptors on locus coeruleus neurons: Pharmacological characterization
Cedarbaum, J. M., & Aghajanian, G. K. (1977) · European Journal of Pharmacology · doi:10.1016/0014-2999(77)90312-0 · Cited by 714 · see citing works
Qin, S., Hermans, E. J., van Marle, H. J. F., Luo, J., & Fernández, G. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.03.006 · Cited by 675 · see citing works
Wang, M., Ramos, B. P., Paspalas, C. D., Shu, Y., Simen, A., Duque, A., Vijayraghavan, S., Brennan, A., Dudley, A., Nou, E., et al. (2007) · Cell · doi:10.1016/j.cell.2007.03.015 · Cited by 672 · see citing works
Self-citationRelation of Prefrontal Cortex Dysfunction to Working Memory and Symptoms in Schizophrenia
Perlstein, W. M., Carter, C. S., Noll, D. C., & Cohen, J. D. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.7.1105 · Cited by 647 · see citing works
Cannon, T. D., Chung, Y., He, G., Sun, D., Jacobson, A., van Erp, T. G. M., McEwen, S., Addington, J., Bearden, C. E., Cadenhead, K., et al. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.023 · Cited by 599 · see citing works
Murphy, B. L., Arnsten, A. F., Goldman-Rakic, P. S., & Roth, R. H. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.3.1325 · Cited by 590 · see citing works
Self-citationDendritic spine pathology in schizophrenia
Glausier, J. R., & Lewis, D. A. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2012.04.044 · Cited by 581 · see citing works
Wang, M., Yang, Y., Wang, C.-J., Gamo, N. J., Jin, L. E., Mazer, J. A., Morrison, J. H., Wang, X.-J., & Arnsten, A. F. T. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.032 · Cited by 489 · see citing works
Self-citationCytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis
Masi, A., Quintana, D. S., Glozier, N., Lloyd, A. R., Hickie, I. B., & Guastella, A. J. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.59 · Cited by 467 · see citing works
Finlay, J. M., Zigmond, M. J., & Abercrombie, E. D. (1995) · Neuroscience · doi:10.1016/0306-4522(94)00331-x · Cited by 434 · see citing works
Arnsten, A. F. T., Raskind, M. A., Taylor, F. B., & Connor, D. F. (2015) · Neurobiology of Stress · doi:10.1016/j.ynstr.2014.10.002 · Cited by 381 · see citing works
Self-citationRepeated stress alters dendritic spine morphology in the rat medial prefrontal cortex
Radley, J. J., Rocher, A. B., Rodriguez, A., Ehlenberger, D. B., Dammann, M., McEwen, B. S., Morrison, J. H., Wearne, S. L., & Hof, P. R. (2007) · The Journal of Comparative Neurology · doi:10.1002/cne.21588 · Cited by 374 · see citing works
Ansell, E. B., Rando, K., Tuit, K., Guarnaccia, J., & Sinha, R. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.11.022 · Cited by 354 · see citing works
RADLEY, J., ROCHER, A., JANSSEN, W., HOF, P., MCEWEN, B., & MORRISON, J. (2005) · Experimental Neurology · doi:10.1016/j.expneurol.2005.07.008 · Cited by 323 · see citing works
Pace, T. W. W., & Heim, C. M. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2010.10.003 · Cited by 321 · see citing works
Protein kinase C overactivity impairs prefrontal cortical regulation of working memory
Birnbaum, S. G., Yuan, P. X., Wang, M., Vijayraghavan, S., Bloom, A. K., Davis, D. J., Gobeske, K. T., Sweatt, J. D., Manji, H. K., & Arnsten, A. F. T. (2004) · Science · doi:10.1126/science.1100021 · Cited by 318 · see citing works
Self-citationCannon, T. D., Thompson, P. M., van Erp, T. G. M., Toga, A. W., Poutanen, V.-P., HUTTUNEN, M. O., Lönnqvist, J. K., Standerskjold-Nordenstam, C.-G., Narr, K. L., Khaledy, M., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052023499 · Cited by 315 · see citing works
REDD1 is essential for stress-induced synaptic loss and depressive behavior
Ota, K. T., Liu, R.-J., Voleti, B., Maldonado-Aviles, J. G., Duric, V., Iwata, M., Dutheil, S., Duman, C., Boikess, S., Lewis, D. A., et al. (2014) · Nature Medicine · doi:10.1038/nm.3513 · Cited by 267 · see citing works
Pathology of Layer V Pyramidal Neurons in the Prefrontal Cortex of Patients With Schizophrenia
Black, J. E., Kodish, I. M., Grossman, A. W., Klintsova, A. Y., Orlovskaya, D., Vostrikov, V., Uranova, N., & Greenough, W. T. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.4.742 · Cited by 250 · see citing works
Stress-Induced Dendritic Remodeling in the Prefrontal Cortex is Circuit Specific
Shansky, R. M., Hamo, C., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhp003 · Cited by 248 · see citing works
Hains, A. B., Vu, M. A. T., Maciejewski, P. K., van Dyck, C. H., Gottron, M., & Arnsten, A. F. T. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908563106 · Cited by 234 · see citing works
Self-citationEvidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex
Bloss, E. B., Janssen, W. G., Ohm, D. T., Yuk, F. J., Wadsworth, S., Saardi, K. M., McEwen, B. S., & Morrison, J. H. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0839-11.2011 · Cited by 219 · see citing works
Gyoneva, S., & Traynelis, S. F. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.458901 · Cited by 204 · see citing works
Molecular control of locus coeruleus neurotransmission
Nestler, E. J., Alreja, M., & Aghajanian, G. K. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00158-4 · Cited by 155 · see citing works
REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A–DDB1 ubiquitin ligase
Katiyar, S., Liu, E., Knutzen, C. A., Lang, E. S., Lombardo, C. R., Sankar, S., Toth, J. I., Petroski, M. D., Ronai, Z., & Chiang, G. G. (2009) · The EMBO Reports · doi:10.1038/embor.2009.93 · Cited by 150 · see citing works
Taylor, J. R., Birnbaum, S., Ubriani, R., & Arnsten, A. F. T. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-18-j0001.1999 · Cited by 120 · cited 1× · see citing works
“…of stress exposure can be mimicked by activating calcium-protein kinase C (PKC) (Birnbaum et al., 2004) or cAMP-protein kinase A (PKA) signaling (Taylor et al., 1999; Wang et al., 2007) in the PFC. Conversely, inhibiting cAMP signaling via post-synaptic alpha-2A receptors on PFC spines,…”
BackgroundSelf-citationRiedel, B., Browne, K., & SILBERT, B. S. (2013) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0000000000000032 · Cited by 120 · see citing works
Noradrenergic modulation of space exploration in visual neglect
Malhotra, P. A., Parton, A. D., Greenwood, R., & Husain, M. (2006) · Annals of Neurology · doi:10.1002/ana.20701 · Cited by 114 · see citing works
Miner, L. H., Jedema, H. P., Moore, F. W., Blakely, R. D., Grace, A. A., & Sesack, S. R. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4450-05.2006 · Cited by 107 · see citing works
Connor, D. F., Grasso, D. J., Slivinsky, M. D., Pearson, G. S., & Banga, A. (2013) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2012.0119 · Cited by 102 · see citing works
Daily injections alter spine density in rat medial prefrontal cortex
Seib, L. M., & Wellman, C. L. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(02)01287-9 · Cited by 100 · see citing works
The Neurobiology of Thought: The Groundbreaking Discoveries of Patricia Goldman-Rakic 1937-2003
Arnsten, A. F. T. (2013) · Cerebral Cortex · doi:10.1093/cercor/bht195 · Cited by 94 · see citing works
Self-citationRole of Inflammation in Depression: Implications for Phenomenology, Pathophysiology and Treatment
Raison, C. L., & Miller, A. H. (2013) · Modern Trends in Psychiatry · doi:10.1159/000343966 · Cited by 88 · see citing works
No Improvement of Posttraumatic Stress Disorder Symptoms With Guanfacine Treatment
Neylan, T. C. (2006) · American Journal of Psychiatry · doi:10.1176/appi.ajp.163.12.2186 · Cited by 83 · see citing works
Birnbaum, S. G., Podell, D. M., & Arnsten, A. F. T. (2000) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(00)00306-3 · Cited by 81 · see citing works
Self-citationDeBock, F., Kurz, J., Azad, S. C., Parsons, C. G., Hapfelmeier, G., Zieglgänsberger, W., & Rammes, G. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02544.x · Cited by 81 · see citing works
Pharmacokinetics and metabolism of guanfacine in man: a review.
Kiechel, J. R. (1980) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1980.tb04901.x · Cited by 72 · see citing works
McAllister, T. W., McDonald, B. C., Flashman, L. A., Ferrell, R. B., Tosteson, T. D., Yanofsky, N. N., Grove, M. R., & Saykin, A. J. (2011) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2011.06.022 · Cited by 70 · see citing works
Engberg, G., & Eriksson, E. (1991) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/bf00169548 · Cited by 68 · see citing works
MacKenzie, K. F., Wallace, D. A., Hill, E. V., Anthony, D. F., Henderson, D. J. P., Houslay, D. M., Arthur, J. S. C., Baillie, G. S., & Houslay, M. D. (2011) · Biochemical Journal · doi:10.1042/bj20101184 · Cited by 65 · see citing works
Jedema, H., & Grace, A. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300020 · Cited by 61 · see citing works
Davis, L. L., MD, Ward, L. C., PhD, Rasmusson, A. M., Southwick, S. M., Newell, J. M., LCSW, PIP, Frazier, E. C., et al. (2025) · Psychopharmacology Bulletin · doi:10.64719/pb.4275 · Cited by 47 · see citing works
Fox, H. C., & Sinha, R. (2014) · Advances in pharmacology · doi:10.1016/b978-0-12-420118-7.00006-8 · Cited by 46 · see citing works
Common biological mechanisms between bipolar disorder and type 2 diabetes: Focus on inflammation
Sharma, A. N., Bauer, I. E., Sanches, M., Galvez, J. F., Zunta‐Soares, G. B., Quevedo, J., Kapczinski, F. P., & Soares, J. C. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.06.005 · Cited by 36 · see citing works
Differential down-regulation of alpha-2 adrenergic receptor subtypes
Heck, D. A., & Bylund, D. B. (1998) · Life Sciences · doi:10.1016/s0024-3205(98)00091-5 · Cited by 36 · see citing works
Effects of chronic social defeat on expression of dopamine β‐hydroxylase in rat brains
Fan, Y., Chen, P., Li, Y., & Zhu, M. (2013) · Synapse · doi:10.1002/syn.21641 · Cited by 36 · see citing works
β-Adrenergic Receptor Blockade Suppresses Glial Scar Formation
Sutin, J., & Griffith, R. (1993) · Experimental Neurology · doi:10.1006/exnr.1993.1056 · Cited by 36 · see citing works
Guanfacine is an effective countermeasure for hypobaric hypoxia-induced cognitive decline
Kauser, H., Sahu, S., Kumar, S., & Panjwani, U. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.09.023 · Cited by 33 · see citing works
Brady, A. E., Wang, Q., Allen, P. B., Rizzo, M. A., Greengard, P., & Limbird, L. E. (2005) · Molecular Pharmacology · doi:10.1124/mol.104.005215 · Cited by 33 · see citing works
Quintin, L., Buda, M., Hilaire, G., Bardelay, C., GHIGNONE, M., & Pujol, J. F. (1986) · Brain Research · doi:10.1016/0006-8993(86)90743-2 · Cited by 28 · see citing works
Attention deficits following ADEM ameliorated by guanfacine
Singh‐Curry, V., Malhotra, P., Farmer, S. F., & Masud Husain, B. (2010) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2009.195792 · Cited by 26 · see citing works
Morrow, B. A., George, T. P., & Roth, R. H. (2004) · Brain Research · doi:10.1016/j.brainres.2004.08.057 · Cited by 24 · see citing works
Ren, W.-W., Liu, Y., & Li, B.-M. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2011.10.001 · Cited by 23 · see citing works
Rapid induction of REDD1 gene expression in macrophages in response to stress-related catecholamines
Yanagawa, Y., Hiraide, S., Matsumoto, M., & Togashi, H. (2014) · Immunology Letters · doi:10.1016/j.imlet.2013.12.015 · Cited by 16 · see citing works
Hu, J., Vidovic, M., Chen, M., Lu, Q.-Y., & Song, Z. (2008) · Brain Research · doi:10.1016/j.brainres.2007.12.073 · Cited by 16 · see citing works
Arnsten, A. F. T., & Goldman-Rakic, P. S. (1998) · Archives of General Psychiatry · doi:10.1001/archpsyc.55.4.362 · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
1 of the 70 references couldn’t be matched to a known paper.
Research works printed but not linked: 5
- Arnsten A.F.T. Stress signaling pathways that impair prefrontal cortex structure and function Nat. Rev. Neurosci. 10 2009 410 422 PMCID: PMC2907136 19455173 PMC2907136
- Breier A. Wolkowitz O. Pickar D. Stress and schizophrenia: advances in neuropsychiatry and psychopharmacology Tamminga C. Schult S. Schizophrenia Research vol. 1 1991 Raven Press, Ltd. New York
- Engberg G. Eriksson E. Effects of alpha-2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in EEDQ-treated rats Naunyn- Schmiedeb. Arch. Pharmacol. 343 1991 472 477 1652697
- Mazure C.M. Does Stress Cause Psychiatric Illness? 1995 American Psychiatric Press Washington, D.C.
- McKee S. Potenza M. Kober H. Sofouglu M. Arnsten A. Picciotto M. Weinberger A. Ashare R. Sinha R. α2A-AR agonist shows promise for nicotine dependence: enhancing self control during stress J Psychopharmacology 2014 (in press)
Cited by
Sorted by citations
Stress weakens prefrontal networks: molecular insults to higher cognition
Arnsten, A. F. T. (2015) · Nature Neuroscience · doi:10.1038/nn.4087 · Cited by 752 · see citing works
Self-citationMechanisms of radiotherapy-associated cognitive disability in patients with brain tumours
Makale, M., McDonald, C. R., Hattangadi-Gluth, J. A., & Kesari, S. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.185 · Cited by 533 · see citing works
Dendritic Spines in Depression: What We Learned from Animal Models
Qiao, H., Li, M.-X., Xu, C. S., Chen, H.-B., An, S.-C., & Ma, X. (2016) · Neural Plasticity · doi:10.1155/2016/8056370 · Cited by 442 · see citing works
Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes.
Woo, E., Sansing, L. H., Arnsten, A. F. T., & Datta, D. (2021) · Chronic Stress · doi:10.1177/24705470211029254 · Cited by 159 · see citing works
Self-citationAnimal models for posttraumatic stress disorder: An overview of what is used in research
Borghans, B. (2015) · World Journal of Psychiatry · doi:10.5498/wjp.v5.i4.387 · Cited by 120 · see citing works
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 142 · see citing works
The effects of arousal on apical amplification and conscious state
Phillips, W. A., Larkum, M. E., Harley, C. W., & Silverstein, S. M. (2016) · Neuroscience of Consciousness · doi:10.1093/nc/niw015 · Cited by 75 · see citing works
Joyce, M. K. P., Uchendu, S., & Arnsten, A. F. T. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.06.016 · Cited by 86 · see citing works
Self-citationDatta, D., & Arnsten, A. (2019) · Brain Sciences · doi:10.3390/brainsci9050113 · Cited by 78 · see citing works
Self-citationThe genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex
Arnsten, A. F. T., Datta, D., & Wang, M. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00973-3 · Cited by 76 · see citing works
Self-citationArnsten, A. F. T. (2020) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2020.107327 · Cited by 75 · see citing works
Self-citationLi, P., Huang, W., Yan, Y., Cheng, W., Liu, S., Huang, Y., Chen, W., Chen, Y., Gao, Y., Lu, W., et al. (2021) · Medical Science Monitor · doi:10.12659/msm.929027 · Cited by 56 · see citing works
Arnsten, A. F. T., Joyce, M. K. P., & Roberts, A. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.105000 · Cited by 58 · see citing works
Self-citationGuanfacine Extended Release: A New Pharmacological Treatment Option in Europe
Huß, M., Chen, W., & Ludolph, A. G. (2015) · Clinical Drug Investigation · doi:10.1007/s40261-015-0336-0 · Cited by 56 · see citing works
Arnsten, A. F. T., & Wang, M. (2016) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103617 · Cited by 50 · see citing works
Self-citationMechanisms Underlying the Antidepressant Response of Acupuncture via PKA/CREB Signaling Pathway
Jiang, H., Zhang, X., Wang, Y., Zhang, H., Li, J., Yang, X., Zhao, B., Zhang, C., Yu, M., Xu, M., et al. (2017) · Neural Plasticity · doi:10.1155/2017/4135164 · Cited by 51 · see citing works
Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00463-2 · Cited by 45 · see citing works
Effects of Chronic Stress on Cognition in Male SAMP8 Mice
Wang, J., Yuan, J., Pang, J., Ma, J., Han, B., Geng, Y., Shen, L., Wang, H., Ma, Q., Wang, Y., et al. (2016) · Cellular Physiology and Biochemistry · doi:10.1159/000447816 · Cited by 44 · see citing works
Okada, M., Fukuyama, K., Kawano, Y., Shiroyama, T., Suzuki, D., & Ueda, Y. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.02.029 · Cited by 39 · see citing works
Core Differences in Synaptic Signaling Between Primary Visual and Dorsolateral Prefrontal Cortex
Yang, S., Wang, M., Paspalas, C. D., Crimins, J. L., Altman, M. T., Mazer, J. A., & Arnsten, A. F. T. (2017) · Cerebral Cortex · doi:10.1093/cercor/bhx357 · Cited by 38 · see citing works
Self-citationMcGrath, A. G., & Briand, L. A. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.007 · Cited by 37 · see citing works
Arnsten, A. F. T., Woo, E., Yang, S., Wang, M., & Datta, D. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.02.003 · Cited by 35 · see citing works
Self-citationWang, Y., Jiang, H., Meng, H., Lü, J., Li, J., Zhang, X., Yang, X., Zhao, B., Sun, Y., & Bao, T. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.07.021 · Cited by 36 · see citing works
Datta, D., & Arnsten, A. F. T. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00505 · Cited by 36 · see citing works
Self-citationToriumi, K., Miyashita, M., Suzuki, K., Yamasaki, N., Yasumura, M., Horiuchi, Y., Yoshikawa, A., Asakura, M., Usui, N., Itokawa, M., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01381-z · Cited by 34 · see citing works
Musaelyan, K., Yildizoglu, S., Bozeman, J., Preez, A. D., Egeland, M. T., Zunszain, P. A., Pariante, C. M., Fernandes, C., & Thuret, S. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa153 · Cited by 31 · see citing works
Mineur, Y. S., Bentham, M. P., Zhou, W., Plantenga, M. E., McKee, S. A., & Picciotto, M. R. (2015) · Psychopharmacology · doi:10.1007/s00213-015-4001-3 · Cited by 31 · see citing works
Synapse impairment associated with enhanced apoptosis in post‐traumatic stress disorder
Xinzhao, C., Jiang, Y.-F., Wang, J., Liu, Y., Xiao, M., Song, C., Bai, Y., Han, N. Y., & Han, F. (2019) · Synapse · doi:10.1002/syn.22134 · Cited by 29 · see citing works
Arnsten, A. F. T., Ishizawa, Y., & Xie, Z. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02057-4 · Cited by 28 · see citing works
Self-citationScientific Rationale for the Treatment of Cognitive Deficits from Long COVID
Zadeh, A. F., Arnsten, A. F. T., & Wang, M. (2023) · Neurology International · doi:10.3390/neurolint15020045 · Cited by 27 · see citing works
Self-citationRen, M., Hu, Z., Chen, Q., Jaffe, A. E., Li, Y., Sadashivaiah, V., Zhu, S., Rajpurohit, N., Shin, J. H., Xia, W., et al. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0530-1 · Cited by 22 · see citing works
Sandiego, C. M., Matuskey, D., Lavery, M. E., McGovern, E. M., Huang, Y. H., Nabulsi, N., Ropchan, J. R., Picciotto, M. R., Morris, E. D., McKee, S. A., et al. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.223 · Cited by 21 · see citing works
Guanfacine promotes neuronal survival in medial prefrontal cortex under hypobaric hypoxia
Kauser, H., Sahu, S., & Panjwani, U. (2016) · Brain Research · doi:10.1016/j.brainres.2016.01.053 · Cited by 19 · see citing works
Mahalakshmi, A. M., Ray, B., Tuladhar, S., Hediyal, T. A., Raj, P., Rathipriya, A. G., Qoronfleh, M. W., Essa, M. M., & Chidambaram, S. B. (2021) · Cells · doi:10.3390/cells10123405 · Cited by 16 · see citing works
Freund, N., Jordan, C. J., Lukkes, J. L., Norman, K. J., & Andersen, S. L. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5096-0 · Cited by 16 · see citing works
Moyano, P. M., Sanjuan, J., García, J. M., Anadón, M. J., Lobo, M., Pelayo, A., García, J., Frejo, M. T., & del Pino, J. (2019) · Food and Chemical Toxicology · doi:10.1016/j.fct.2019.110961 · Cited by 16 · see citing works
Gandy, H. M., Hollis, F., Hernandez, C. M., & McQuail, J. A. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1306496 · Cited by 13 · see citing works
Liu, Y., Zhao, H., Li, Q., Cui, H.-W., & Huang, G. (2022) · Aging and Disease · doi:10.14336/ad.2022.1211 · Cited by 15 · see citing works
Animal models for the discovery of novel drugs for post-traumatic stress disorder
Zoladz, P. R. (2020) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2020.1820982 · Cited by 12 · see citing works
Datta, D., & Arnsten, A. F. T. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14477 · Cited by 11 · see citing works
Self-citationPeng, S., Li, B., Xi, K., Wang, J., & Zhu, J. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.11.060 · Cited by 10 · see citing works
Arnsten, A. F. T., Perone, I., Wang, M., Yang, S., Uchendu, S., Bolat, D., & Datta, D. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1610350 · Cited by 7 · see citing works
Self-citationHernández‐Hernández, E., Miralles, A., Esteban, S., & García-Fuster, M. J. (2017) · Journal of Psychopharmacology · doi:10.1177/0269881117742667 · Cited by 7 · see citing works
Baskin, B. M., Dhonnchadha, B. Á. N., Dwoskin, L. P., & Kantak, K. M. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4681-y · Cited by 6 · see citing works
Yang, C., Tang, J., Liang, X., Qi, Y., Luo, Y., Xie, Y., Wang, J., Jiang, L. H., Zhou, C., Huang, C., et al. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112765 · Cited by 5 · see citing works
van Staden, C., Weinshenker, D., Finger‐Baier, K., Botha, T. L., Brand, L., & Wolmarans, D. W. (2024) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000808 · Cited by 4 · see citing works
Enhancement of Function of the Prefrontal Cortex to Improve Symptoms of Schizophrenia
Sarma Bardoloi, P. (2020) · Acta Scientific Neurology · doi:10.31080/asne.2020.03.0183 · Cited by 4 · see citing works
Datta, D. (2023) · The Journals of Gerontology Series A · doi:10.1093/gerona/glad134 · Cited by 3 · see citing works
The Cellular Mechanisms of Executive Functions and Working Memory
Lightbourne, T. C., & Arnsten, A. F. T. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803676-1.00002-7 · Cited by 1 · see citing works
Self-citationWang, M., Galvin, V. C., Joyce, M. K. P., Datta, D., Yang, S., Disney, A. A., & Arnsten, A. F. T. (2026) · Biological Psychiatry · doi:10.1016/j.biopsych.2026.06.008 · Cited by 1 · see citing works
Self-citationCunha, C., Todorov, G. I., Mayilvahanan, K., & Cunha, C. (2020) · Journal of Brain and Nerves · doi:10.31487/j.jbn.2020.01.06
Arnsten, A. F. T. (2020) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780190069162.013.4
Self-citationLos peregrinos noruegos también se dirigieron a Santiago
Njerve, E. (1996) · Peregrino: revista del Camino de Santiago
The circuit mechanisms of working memory: Key roles of the dorsolateral prefrontal cortex
Arnsten, A. F. T., & Martínez-Trujillo, J. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-15754-7.00038-9
Self-citationA CRH-HCN theory of obsessive-compulsive disorder (OCD)
Rappoport, A. (2025) · Elsevier eBooks · doi:10.1016/b978-0-44-345008-2.00011-4
Juárez, J., la Torre, A. C. H. D., & Yepez, J. E. (2025) · Pharmacological Research - Reports · doi:10.1016/j.prerep.2025.100060
Fisher, E., Beaudin, S. A., Strupp, B. J., & Smith, D. R. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111517
Additional file 4 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853519
Additional file 3 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853516
Additional file 5 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853522
Additional file 7 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853528
Additional file 9 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853534
Additional file 1 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853510
Additional file 2 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853513
Additional file 8 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853531
Additional file 6 of Pharmacological rescue of cognitive function in a mouse model of chemobrain
Nguyen, L. D., Fischer, T. T., & Ehrlich, B. E. (2021) · Figshare · doi:10.6084/m9.figshare.14853525
Rodent models of posttraumatic stress disorder
Pinna, G. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-29090-9.00015-5
Exploring a Mechanism-Based Therapeutic Approach for ZC4H2 Haploinsufficiency
Crowder, C. M., Fehrmann, N., Foksinska, A., Nicholl, A., Eckenrode, M., Crouse, A. B., Zygmunt, A., & Might, M. (2026) · Drug repurposing · doi:10.58647/drugrepo.25.1.0010
van Staden, C., Weinshenker, D., Finger‐Baier, K., Botha, T. L., Brand, L., & Wolmarans, D. W. (2026) · Behavioural Brain Research · doi:10.1016/j.bbr.2026.116448
Yamamuro, K., Yamauchi, T., & Makinodan, M. (2026) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2026.1915506
- Authors
- Hains, A. B., Yabe, Y., & Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Corresponding author
- Arnsten, Amy F.T.
- Venue
- Neurobiology of Stress
- Publisher
- Elsevier BV
- Published
- 2015
- Volume
- 2
- Pages
- 1-9
- ISSN
- 2352-2895 (ISSN-L)
- PMC
- PMC4316374
- OpenAlex
- W2070844974
- Cited by
- 70
- References
- 70
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 14 · 2020: 8 · 2019: 6 · 2018: 2 · 2017: 8 · 2016: 6 · 2015: 4
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neurobiology of Stress (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- PHS (RL1AA017536, U54RR024350)
- Shire Pharmaceuticals
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- guanfacine, chronic stress, prefrontal cortex, dendritic spines, dendritic atrophy, working memory, cAMP signaling, prelimbic cortex, restraint stress, synaptic plasticity, gray matter loss
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
