Antipsychotic Drugs Rapidly Induce Dopamine Neuron Depolarization Block in a Developmental Rat Model of Schizophrenia
Open accessAbstract
Repeated administration of antipsychotic drugs to normal rats has been shown to induce a state of dopamine neuron inactivation known as depolarization block, which correlates with the ability of the drugs to exhibit antipsychotic efficacy and extrapyramidal side effects in schizophrenia patients. Nonetheless, in normal rats depolarization block requires weeks of antipsychotic drug administration, whereas schizophrenia patients exhibit initial effects soon after initiating antipsychotic drug treatment. We now report that, in a developmental disruption rat model of schizophrenia [methyl-azoxymethanol acetate (20 mg/kg, i.p.) injected into G17 pregnant female rats, with offspring tested as adults], the extant hyperdopaminergic state combines with the excitatory actions of a first- (haloperidol; 0.6 mg/kg, i.p.) and a second- (sertindole; 2.5 mg/kg, i.p.) generation antipsychotic drug to rapidly induce depolarization block in ventral tegmental area dopamine neurons. Acute injection of either antipsychotic drug induced an immediate reduction in the number of spontaneously active dopamine neurons (cells per electrode track; termed population activity). Repeated administration of either antipsychotic drug for 1, 3, 7, 15, and 21 d continued to reduce dopamine neuron population activity. Both acute and repeated effects on population activity were reversed by acute apomorphine injections, which is consistent with the reversal of dopamine neuron depolarization block. Although this action may account for the effects of D2 antagonist drugs on alleviating psychosis and the lack of development of tolerance in humans, the drugs appear to do so by inducing an offsetting deficit rather than attacking the primary pathology present in schizophrenia.
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Animal research has demonstrated that acute stressors including aversive stimuli induce a pronounced activation of the dopamine system in terms of dopamine neuron population activity and amphetamine-induced behaviours.
“Animal research has demonstrated that acute stressors including aversive stimuli induce a pronounced activation of the dopamine system in terms of dopamine neuron population activity (i.e. the numbers of neurons firing) and with regard to amphetamine-induced behaviours (Valenti et al., 2011).”
From The effects of psychosocial stress on dopaminergic function and the acute stress response (2019) · cites this paper as Valenti et al., 2011
Acute and repeated stress activates the entire dopamine system projecting to much of the striatum, in particular the associative (dorsal) striatum where object salience is important.
“Acute and repeated stress activates the entire dopamine system projecting to much of the striatum (Valenti et al., 2011), in particular the associative (dorsal) striatum where object salience is important”
From The effects of psychosocial stress on dopaminergic function and the acute stress response (2019) · cites this paper as Valenti et al., 2011
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Cites
Carlsson, A., & Lindqvist, M. (1963) · Acta Pharmacologica et Toxicologica · doi:10.1111/j.1600-0773.1963.tb01730.x · Cited by 2,156 · see citing works
Grace, A. A. (1991) · Neuroscience · doi:10.1016/0306-4522(91)90196-u · Cited by 1,831 · see citing works
Self-citationLaruelle, M., Abi-Dargham, A., van Dyck, C. H., Gil, R., D'Souza, C. D., Erdos, J., McCance, E., Rosenblatt, W., Fingado, C., Zoghbi, S. S., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.17.9235 · Cited by 1,291 · see citing works
Kapur, S., & Seeman, P. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.3.360 · Cited by 1,140 · see citing works
Floresco, S. B., West, A. R., Ash, B., Moore, H., & Grace, A. A. (2003) · Nature Neuroscience · doi:10.1038/nn1103 · Cited by 1,106 · see citing works
Self-citationCarlsson, M. L., & Carlsson, A. (1990) · Trends in Neurosciences · doi:10.1016/0166-2236(90)90108-m · Cited by 1,086 · see citing works
Increased baseline occupancy of D <sub>2</sub> receptors by dopamine in schizophrenia
Abi-Dargham, A., Rodenhiser, J., Printz, D., Zea-Ponce, Y., Gil, R., Kegeles, L. S., Weiss, R., Cooper, T. B., Mann, J. J., Van Heertum, R. L., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.14.8104 · Cited by 1,020 · see citing works
Grace, A. A., & Bunney, B. S. (1983) · Neuroscience · doi:10.1016/0306-4522(83)90135-5 · Cited by 937 · see citing works
Self-citationThe control of firing pattern in nigral dopamine neurons: single spike firing
Grace, A., & Bunney, B. (1984) · Journal of Neuroscience · doi:10.1523/jneurosci.04-11-02866.1984 · Cited by 862 · see citing works
Self-citationIncreased dopamine transmission in schizophrenia: relationship to illness phases.
Laruelle, M., Abi-Dargham, A., Gil, R. B., Kegeles, L., & Innis, R. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00067-0 · Cited by 744 · see citing works
Brain receptors for antipsychotic drugs and dopamine: direct binding assays.
Seeman, P. M., Chau-Wong, M., Tedesco, J., & Wong, K. (1975) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.72.11.4376 · Cited by 702 · see citing works
Chiodo, L. A., & Bunney, B. (1983) · Journal of Neuroscience · doi:10.1523/jneurosci.03-08-01607.1983 · Cited by 680 · see citing works
Differential Effects of Classical and Atypical Antipsychotic Drugs on A9 and A10 Dopamine Neurons
White, F. J., & Wang, R. Y. (1983) · Science · doi:10.1126/science.6136093 · Cited by 590 · see citing works
The Hippocampal Formation in Schizophrenia
Tamminga, C. A., Stan, A. D., & Wagner, A. D. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2010.09081187 · Cited by 583 · see citing works
Impaired recruitment of the hippocampus during conscious recollection in schizophrenia
Heckers, S., Rauch, S., Goff, D., Savage, C., Schacter, D., Fischman, A., & Alpert, N. (1998) · Nature Neuroscience · doi:10.1038/1137 · Cited by 570 · see citing works
Acute and chronic haloperidol treatment: Comparison of effects on nigral dopaminergic cell activity
Bunney, B. S., & Grace, A. A. (1978) · Life Sciences · doi:10.1016/0024-3205(78)90471-x · Cited by 553 · see citing works
Self-citationSignificance of Neuroleptic Dose and Plasma Level in the Pharmacological Treatment of Psychoses
Baldessarini, R. J. (1988) · Archives of General Psychiatry · doi:10.1001/archpsyc.1988.01800250095013 · Cited by 545 · see citing works
Gating of information flow within the limbic system and the pathophysiology of schizophrenia.
Grace, A. (2000) · Brain research. Brain research reviews · doi:10.1016/s0165-0173(99)00049-1 · Cited by 532 · see citing works
Self-citationLodge, D., & Grace, A. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2847-07.2007 · Cited by 475 · see citing works
Self-citationMECHANISM OF THE ANTIPSYCHOTIC EFFECT IN THE TREATMENT OF ACUTE SCHIZOPHRENIA
Johnstone, E., Frith, C., Crow, T. J., Carney, M. W. P., & Price, J. (1978) · The Lancet · doi:10.1016/s0140-6736(78)90193-9 · Cited by 460 · see citing works
Seeman, P. (1992) · PubMed · Cited by 441 · see citing works
Delayed-Onset Hypothesis of Antipsychotic Action: A Hypothesis Tested and Rejected
Agid, O., Kapur, S., Arenovich, T., & Zipursky, R. B. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.12.1228 · Cited by 408 · see citing works
Kapur, S., & Remington, G. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01251-3 · Cited by 390 · see citing works
Do we still believe in the dopamine hypothesis? New data bring new evidence.
Abi-Dargham, A. (2004) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145704004110 · Cited by 373 · see citing works
Moore, H. M., Jentsch, J. D., Ghajarnia, M., Geyer, M. A., & Grace, A. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.01.003 · Cited by 359 · see citing works
Self-citationGrace, A. A., & Bunney, B. S. (1986) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)24386-5 · Cited by 315 · see citing works
Self-citationProvocation of Schizophrenic Symptoms by Intravenous Administration of Methylphenidate
Janowsky, D. S. (1973) · Archives of General Psychiatry · doi:10.1001/archpsyc.1973.01750320023004 · Cited by 310 · see citing works
Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs
Grace, A. A., Bunney, B. S., Moore, H. M., & Todd, C. L. (1997) · Trends in Neurosciences · doi:10.1016/s0166-2236(96)10064-3 · Cited by 284 · see citing works
Self-citationLodge, D. J., & Grace, A. A. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300963 · Cited by 280 · see citing works
Self-citationProbing the human hippocampus using rCBF: Contrasts in schizophrenia
Medoff, D. R., Holcomb, H. H., Lahti, A. C., & Tamminga, C. A. (2001) · Hippocampus · doi:10.1002/hipo.1070 · Cited by 257 · see citing works
Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat
White, F. J., & Wang, R. Y. (1983) · Life Sciences · doi:10.1016/0024-3205(83)90929-3 · Cited by 212 · see citing works
Valenti, O., Lodge, D. J., & Grace, A. A. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5310-10.2011 · Cited by 173 · see citing works
Self-citationArnt, J. (1995) · European Journal of Pharmacology · doi:10.1016/0014-2999(95)00292-s · Cited by 143 · see citing works
Cognitive function in schizophrenia
Weinberger, D. R., & Gallhofer, B. (1997) · International Clinical Psychopharmacology · doi:10.1097/00004850-199709004-00006 · Cited by 139 · see citing works
Chronic Cold Stress Reduces the Spontaneous Activity of Ventral Tegmental Dopamine Neurons
Moore, H. M. (2001) · Neuropsychopharmacology · doi:10.1016/s0893-133x(00)00188-3 · Cited by 130 · see citing works
Abi-Dargham, A., Kegeles, L. S., Zea-Ponce, Y., Mawlawi, O., Martinez, D., Mitropoulou, V., O'Flynn, K., Koenigsberg, H. W., Van Heertum, R., Cooper, T., et al. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.01.018 · Cited by 128 · see citing works
Lodge, D. J., & Grace, A. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1582-08.2008 · Cited by 127 · see citing works
Self-citationHand, T. H., Hu, X., & Wang, R. Y. (1987) · Brain Research · doi:10.1016/0006-8993(87)90207-1 · Cited by 108 · see citing works
Striatal Nitric Oxide Signaling Regulates the Neuronal Activity of Midbrain Dopamine Neurons In Vivo
West, A. R., & Grace, A. A. (2000) · Journal of Neurophysiology · doi:10.1152/jn.2000.83.4.1796 · Cited by 103 · see citing works
Self-citationGrace, A. A. (2010) · Neurotoxicity Research · doi:10.1007/s12640-010-9154-6 · Cited by 96 · see citing works
Self-citationSkarsfeldt, T. (1992) · Synapse · doi:10.1002/syn.890100105 · Cited by 86 · see citing works
SPECT study of visual fixation in schizophrenia and comparison subjects
Malaspina, D., Storer, S., Furman, V., Esser, P. D., PRINTZ, D. J., Berman, A., Lignelli, A., Gorman, J. M., & Heertum, R. V. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00306-0 · Cited by 68 · see citing works
Nyberg, S., Nordström, A., Halldin, C., et al. (1995) · International Clinical Psychopharmacology · doi:10.1097/00004850-199509000-00011 · Cited by 67 · see citing works
Sertindole, a new neuroleptic with extreme selectivity on A10 versus A9 dopamine neurones in the rat
Skarsfeldt, T., & Perregaard, J. (1990) · European Journal of Pharmacology · doi:10.1016/0014-2999(90)90067-g · Cited by 58 · see citing works
Hollerman, J. R., Abercrombie, E. D., & Grace, A. A. (1992) · Neuroscience · doi:10.1016/0306-4522(92)90168-2 · Cited by 53 · see citing works
Self-citationLodge, D. J., & Grace, A. A. (2011) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711000113 · Cited by 52 · see citing works
Self-citationGinovart, N., Wilson, A., Houle, S., & Kapur, S. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.02.019 · Cited by 44 · see citing works
Valenti, O., & Grace, A. A. (2009) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145709990599 · Cited by 44 · see citing works
Self-citationEmerging role of sertindole in the management of schizophrenia
Rodefer, J. S., & Cincotta (2010) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s7602 · Cited by 16 · see citing works
Jiang, L. H., Tsai, M., & Wang, R. Y. (1988) · Life Sciences · doi:10.1016/0024-3205(88)90239-1 · Cited by 16 · see citing works
Watanabe, M., & Hagino, Y. (1999) · European Journal of Pharmacology · doi:10.1016/s0014-2999(98)00936-4 · Cited by 12 · see citing works
Absence of acquired tolerance to neuroleptics in schizophrenic patients
Palmstierna, T., & Wistedt, B. (1987) · American Journal of Psychiatry · doi:10.1176/ajp.144.8.1084 · Cited by 7 · see citing works
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Research works printed but not linked: 3
- Cifelli P Lakoski JM Grace AA 2009 Pilocarpine-induced temporal lobe epilepsy in rats is associated with increased dopamine neuron activity Society for Neuroscience Annual Meeting PMC3694768 21745437
- Kinon BJ Chen L Stauffer VL Sniadecki J Ascher-Svanum H Kollack-Walker S Jacob J Kapur S 2010 Early onset of antipsychotic action in schizophrenia: evaluating the possibility of shorter acute efficacy trials J Clin Psychopharmacol 30 286 289 20473064
- Murray RM Dean K Murray RM Kendler KS McGuffin P Wesseley S Castle DJ 2008 Schizophrenia and related disorders Essential Psychiatry 4 284 319 Cambridge Cambridge University Press
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Heckers, S., & Konradi, C. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2014.09.041 · Cited by 277 · see citing works
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Chouinard, G., Samaha, A.-N., Chouinard, V.-A., Peretti, C.-S., Kanahara, N., Takase, M., & Iyo, M. (2017) · Psychotherapy and Psychosomatics · doi:10.1159/000477313 · Cited by 270 · see citing works
Dopaminergic basis of salience dysregulation in psychosis
Winton-Brown, T. T., Fusar-Poli, P., Ungless, M. A., & Howes, O. D. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2013.11.003 · Cited by 231 · see citing works
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Bloomfield, M. A., McCutcheon, R. A., Kempton, M., Freeman, T. P., & Howes, O. (2019) · eLife · doi:10.7554/elife.46797 · Cited by 112 · see citing works
“Acute and repeated stress activates the entire dopamine system projecting to much of the striatum (Valenti et al., 2011), in particular the associative (dorsal) striatum where object salience is important, whereas in chronic stress-induced depression (Holly and Miczek, 2016), the blunting occurs primarily in the neuro…”
BackgroundInfluentialJauhar, S., Veronese, M., Nour, M. M., Rogdaki, M., Hathway, P., Natesan, S., Turkheimer, F., Stone, J., Egerton, A., McGuire, P., et al. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.07.003 · Cited by 75 · see citing works
Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test
Addy, N. A., Nunes, E. J., & Wickham, R. J. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.04.002 · Cited by 42 · see citing works
Moreines, J. L., Owrutsky, Z. L., Gagnon, K. G., & Grace, A. A. (2017) · Translational Psychiatry · doi:10.1038/s41398-017-0039-9 · Cited by 17 · see citing works
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Yu, N., Tucker, K. R., Levitan, E. S., Shepard, P. D., & Canavier, C. C. (2014) · Progress in Molecular Biology and Translational Science · doi:10.1016/b978-0-12-397897-4.00011-5 · Cited by 17 · see citing works
- Authors
- Valenti, O., Cifelli, P., Gill, K. M., & Grace, A. A.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Grace, Anthony A.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-08-24
- Volume
- 31
- Issue
- 34
- Pages
- 12330-12338
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3167216
- OpenAlex
- W2029409685
- Cited by
- 124
- References
- 52
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 7 · 2023: 9 · 2022: 11 · 2021: 3 · 2020: 12 · 2019: 10 · 2018: 7 · 2017: 10 · 2016: 5 · 2015: 6 · 2014: 16 · 2013: 5 · 2012: 11
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion)
- Funders
- Eli Lilly and Company
- University of Pittsburgh
- Fondazione Ri.Med
- H. Lundbeck A/S
- National Institutes of Health (2r01mh057440-26a1)
- U.S. Public Health Service (MH57440)
- National Institute of Mental Health (MH-57440, R01-MH057440, R37MH057440)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- antipsychotic drugs, depolarization block, dopaminergic neurons, schizophrenia, methylazoxymethanol acetate, ventral tegmental area, haloperidol, sertindole, dopamine D2 receptor antagonists, apomorphine, hyperdopaminergic state, spontaneous neuronal activity, drug tolerance
- MeSH terms
- Action Potentials, Animals, Animals, Newborn, Disease Models, Animal, Dopamine, Female, Male, Methylazoxymethanol Acetate, Neural Inhibition, Neurons, Neurotoxins, Reaction Time, Schizophrenia, Antipsychotic Agents, Cell Polarity, Rats, Sprague-Dawley, Ventral Tegmental Area, Rats, Inhibitory Postsynaptic Potentials
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