Advertisement

The Hallucinogen DOI Reduces Low-Frequency Oscillations in Rat Prefrontal Cortex: Reversal by Antipsychotic Drugs

  • Pau Celada
    Affiliations
    Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
    Search for articles by this author
  • M. Victoria Puig
    Affiliations
    Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
    Search for articles by this author
  • Llorenç Díaz-Mataix
    Affiliations
    Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
    Search for articles by this author
  • Francesc Artigas
    Correspondence
    Address reprint requests to Francesc Artigas, Ph.D., Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (IDIBAPS), Rosselló, 161, 6th Floor, 08036 Barcelona, Spain
    Affiliations
    Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
    Search for articles by this author

      Background

      Perceptual and psychic alterations and thought disorder are fundamental elements of schizophrenia symptoms, a pathology associated with an abnormal macro- and microcircuitry of several brain areas including the prefrontal cortex (PFC). Alterations in information processing in PFC may partly underlie schizophrenia symptoms.

      Methods

      The 5-HT2A/2C agonist DOI and antipsychotic drugs were administered to anesthetized rats. Single unit and local field potential (LFP) extracellular recordings were made in medial PFC (mPFC). Electrolytic lesions were performed in the thalamic nuclei.

      Results

      DOI markedly disrupts cellular and network activity in rat PFC. DOI altered pyramidal discharge in mPFC (39% excited, 27% inhibited, 34% unaffected; n = 51). In all instances, DOI concurrently reduced low-frequency oscillations (.3–4 Hz; power spectrum: .25 ± .02 and .14 ± .01 μV2 in basal conditions and after 50–300 μg/kg intravenous (IV) DOI, respectively; n = 51). Moreover, DOI disrupted the temporal association between the active phase of LFP and pyramidal discharge. Both effects were reversed by M100907 (5-HT2A receptor antagonist) and were not attenuated by thalamic lesions, supporting an intracortical origin of the effects of DOI. The reduction in low-frequency oscillations induced by DOI was significantly reversed by the antipsychotic drugs haloperidol (.1–.2 mg/kg IV) and clozapine (1 mg/kg IV).

      Conclusions

      DOI disorganizes network activity in PFC, reducing low-frequency oscillations and desynchronizing pyramidal discharge from active phases of LFP. These effects may underlie DOI's psychotomimetic action. The reversal by clozapine and haloperidol indicates that antipsychotic drugs may reduce psychotic symptoms by normalizing an altered PFC function.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Harrison P.J.
        The neuropathology of schizophrenia.
        Brain. 1999; 122: 593-624
        • Selemon L.D.
        • Goldman-Rakic P.S.
        The reduced neuropil hypothesis: a circuit based model of schizophrenia.
        Biol Psychiatry. 1999; 45: 17-25
        • Lewis D.A.
        • Lieberman J.A.
        Catching up on schizophrenia: Natural history and neurobiology.
        Neuron. 2000; 28: 325-334
        • Weinberger D.R.
        • Egan M.F.
        • Bertolino A.
        • Callicott J.H.
        • Mattay V.S.
        • Lipska B.K.
        • et al.
        Prefrontal neurons and the genetics of schizophrenia.
        Biol Psychiatry. 2001; 50: 825-844
        • Lewis D.A.
        • Hashimoto T.
        • Volk D.W.
        Cortical inhibitory neurons and schizophrenia.
        Nat Rev Neurosci. 2005; 6: 312-324
        • Fuster J.M.
        The Prefrontal Cortex.
        Lippincott-Raven, New York1997
        • Miller E.K.
        • Cohen J.D.
        An integrative theory of prefrontal cortex function.
        Annu Rev Neurosci. 2001; 24: 167-202
        • Elvevag B.
        • Goldberg T.E.
        Cognitive impairment in schizophrenia is the core of the disorder.
        Crit Rev Neurobiol. 2000; 14: 1-21
        • Akil M.
        • Edgar C.L.
        • Pierri J.N.
        • Casali S.
        • Lewis D.A.
        Decreased density of tyrosine hydroxylase-immunoreactive axons in the entorhinal cortex of schizophrenic subjects.
        Biol Psychiatry. 2000; 47: 361-370
        • Abi-Dargham A.
        • Mawlawi O.
        • Lombardo I.
        • Gil R.
        • Martinez D.
        • Huang Y.
        • et al.
        Prefrontal dopamine D1 receptors and working memory in schizophrenia.
        J Neurosci. 2002; 22: 3708-3719
        • Carlsson A.
        The current status of the dopamine hypothesis of schizophrenia.
        Neuropsychopharmacology. 1988; 1: 179-186
        • Laruelle M.
        • Abi-Dargham A.
        • van Dyck C.H.
        • Gil R.
        • D'Souza C.D.
        • Erdos J.
        • et al.
        Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.
        Proc Natl Acad Sci U S A. 1996; 93: 9235-9240
        • Egan M.F.
        • Weinberger D.R.
        Neurobiology of schizophrenia.
        Curr Opin Neurobiol. 1997; 7: 701-707
        • Kapur S.
        How antipsychotics become anti-“psychotic”—from dopamine to salience to psychosis.
        Trends Pharmacol Sci. 2004; 8: 402-406
        • Kornetsky C.
        • Markowitz R.
        Animal models of schizophrenia.
        in: Lipton M.A. DiMascio Killam A.K.F. Psychopharmacology: A Generation of Progress. 1978: 583-593
        • Ellenbroek B.A.
        • Cools A.R.
        Animal models with construct validity for schizophrenia.
        Behav Pharmacol. 1990; 1: 469-490
        • Krystal J.H.
        • Karper L.P.
        • Seibyl J.P.
        • Freeman G.K.
        • Delaney R.
        • Bremner J.D.
        • et al.
        Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans.
        Arch Gen Psychiatry. 1994; 51: 199-214
        • Krystal J.H.
        • D'Souza D.C.
        • Mathalon D.
        • Perry E.
        • Belger A.
        • Hoffman R.
        NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: Toward a paradigm shift in medication development.
        Psychopharmacology (Berl). 2003; 169: 215-233
        • Newcomer J.W.
        • Farber N.B.
        • Jevtovic-Todorovic V.
        • Selke G.
        • Melson A.K.
        • Hershey T.
        • et al.
        Ketamine-induced NMDA receptor hypofunction as model of memory impairment and psychosis.
        Neuropsychopharmacology. 1999; 20: 106-118
        • Nichols D.E.
        Hallucinogens.
        Pharmacol Ther. 2004; 101: 131-181
        • Schreiber R.
        • Brocco M.
        • Millan M.J.
        Blockade of the discriminative stimulus effects of DOI by MDL 100907 and the “atypical” antipsychotics, clozapine and risperidone.
        Eur J Pharmacol. 1994; 264: 99-102
        • Martín-Ruiz R.
        • Puig M.V.
        • Celada P.
        • Shapiro D.A.
        • Roth B.L.
        • Mengod G.
        • Artigas F.
        Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism.
        J Neurosci. 2001; 21: 9856-9866
        • Puig M.V.
        • Celada P.
        • Díaz-Mataix L.
        • Artigas F.
        In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5-HT2A receptors: Relationship to thalamocortical afferents.
        Cereb Cortex. 2003; 13: 870-882
        • Aghajanian G.K.
        • Marek G.J.
        Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells.
        Neuropharmacology. 1997; 36: 589-599
        • Aghajanian G.K.
        • Marek G.J.
        Serotonin, via 5-HT2A receptors, increases EPSCs in layer v pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release.
        Brain Res. 1999; 825: 161-171
        • Araneda R.
        • Andrade R.
        5-HT2 and 5-HT1A receptors mediate opposing responses on membrane excitability in rat association cortex.
        Neuroscience. 1991; 40: 399-412
        • Villalobos C.
        • Beique J.C.
        • Gingrich J.A.
        • Andrade R.
        Serotonergic regulation of calcium-activated potassium currents in rodent prefrontal cortex.
        Eur J Neurosci. 2005; 22: 1120-1126
        • Amargós-Bosch M.
        • Bortolozzi A.
        • Puig M.V.
        • Serrats J.
        • Adell A.
        • Celada P.
        • et al.
        Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex.
        Cereb Cortex. 2004; 14: 281-299
        • Puig M.V.
        • Artigas F.
        • Celada P.
        Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: Involvement of serotonin and GABA.
        Cereb Cortex. 2005; 15: 1-14
        • Kargieman L.
        • Santana N.
        • Mengod G.
        • Celada P.
        • Artigas F.
        Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine.
        Proc Natl Acad Sci U S A. 2007; 104: 14843-14848
        • Fuller J.H.
        • Schlag J.D.
        Determination of antidromic excitation by the collision test: problems of interpretation.
        Brain Res. 1976; 112: 283-298
        • Berendse H.W.
        • Groenewegen H.J.
        Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat.
        Neuroscience. 1991; 42: 73-102
        • Van der Werf Y.D.
        • Witter M.P.
        • Groenewegen H.J.
        The intralaminar and midline nuclei of the thalamus.
        Brain Res Rev. 2002; 39: 107-140
        • Laviolette S.R.
        • Lipski W.J.
        • Grace A.A.
        A subpopulation of neurons in the medial prefrontal cortex encodes emotional learning with burst and frequency codes through a dopamine D4 receptor-dependent basolateral amygdala input.
        J Neurosci. 2005; 25: 6066-6075
        • Lambe E.K.
        • Aghajanian G.K.
        Prefrontal cortical network activity: opposite effects of psychedelic hallucinogens and and D1/D5 receptor activation.
        Neuroscience. 2007; 145: 900-910
        • Steriade M.
        • McCormick D.A.
        • Sejnowski T.J.
        Thalamocortical oscillations in the sleeping and aroused brain.
        Science. 1993; 262: 679-685
        • Contreras D.
        • Steriade M.
        Cellular basis of EEG slow rhythms: A study of dynamic corticothalamic relationships.
        J Neurosci. 1995; 15: 604-622
        • Steriade M.
        Grouping of brain rhythms in corticothalamic systems.
        Neuroscience. 2006; 137: 1087-1106
        • Mukovski M.
        • Chauvette S.
        • Timofeev I.
        • Volgushev M.
        Detection of active and silent states in neocortical neurons from the field potential signal during slow-wave sleep.
        Cereb Cortex. 2007; 17: 400-414
        • Sanchez-Vives M.V.
        • McCormick D.A.
        Cellular and network mechanisms of rhythmic recurrent activity in neocortex.
        Nat Neurosci. 2000; 3: 1027-1034
        • Steriade M.
        • Nunez A.
        • Amzica F.
        Intracellular analysis of relations between the slow (<1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram.
        J Neurosci. 1993; 13: 3266-3283
        • Rigas P.
        • Castro-Alamancos M.A.
        Thalamocortical up states: Differential effects of intrinsic and extrinsic cortical inputs on persistent activity.
        J Neurosci. 2007; 27: 4261-4272
        • Groenewegen H.J.
        • Uylings H.B.
        The prefrontal cortex and the integration of sensory, limbic and autonomic information.
        Prog Brain Res. 2000; 126: 3-28
        • Gonzalez-Maeso J.
        • Weisstaub N.V.
        • Zhou M.
        • Chan P.
        • Ivic L.
        • Ang R.
        • et al.
        Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior.
        Neuron. 2007; 53: 439-452
        • Béïque J.C.
        • Imad M.
        • Mladenovic L.
        • Gingrich J.A.
        • Andrade R.
        Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex.
        Proc Natl Acad Sci U S A. 2007; 104: 9870-9875
        • Marek G.J.
        • Wright R.A.
        • Gewitz J.C.
        • Schoepp D.D.
        A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in neocortex.
        Neuroscience. 2001; 105: 379-392
        • Santana N.
        • Bortolozzi A.
        • Serrats J.
        • Mengod G.
        • Artigas F.
        Expression of 5-HT1A and 5-HT2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex.
        Cereb Cortex. 2004; 14: 1100-1109
        • Garratt J.C.
        • Kidd E.J.
        • Wright I.K.
        • Marsden C.A.
        Inhibition of 5-hydroxytryptamine neuronal activity by the 5-HT agonist, DOI.
        Eur J Pharmacol. 1991; 199: 349-355
        • Kuroki T.
        • Meltzer H.Y.
        • Ichikawa J.
        5-HT2A receptor stimulation by DOI, a 5-HT2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens.
        Brain Res. 2003; 972: 216-221
        • Bortolozzi A.
        • Díaz-Mataix L.
        • Scorza M.C.
        • Celada P.
        • Artigas F.
        The activation of 5-HT2A receptors in prefrontal cortex enhances dopaminergic activity.
        J Neurochem. 2005; 95: 1597-1607
        • Schotte A.
        • Janssen P.F.
        • Gommeren W.
        • Luyten W.H.
        • Van Gompel P.
        • Lesage A.S.
        • et al.
        Risperidone compared with new and reference antipsychotic drugs: In vitro and in vivo receptor binding.
        Psychopharmacology. 1996; 124: 57-73
        • Bymaster F.P.
        • Calligaro D.O.
        • Falcone J.F.
        • Marsh R.D.
        • Moore N.A.
        • Tye N.C.
        • et al.
        Radioreceptor binding profile of the atypical antipsychotic olanzapine.
        Neuropsychopharmacology. 1996; 14: 87-96
        • Arnt J.
        • Skarsfeldt T.
        Do novel antipsychotics have similar pharmacological characteristics?.
        Neuropsychopharmacology. 1998; 18: 63-101
        • Schotte A.
        • Janssen P.F.
        • Megens A.A.
        • Leysen J.E.
        Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography.
        Brain Res. 1993; 631: 191-202
        • Diaz-Mataix L.
        • Scorza M.C.
        • Bortolozzi A.
        • Toth M.
        • Celada P.
        • Artigas F.
        Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: Role in atypical antipsychotic action.
        J Neurosci. 2005; 25: 10831-10843
        • Gobert A.
        • Millan M.J.
        Serotonin 5-HT2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats.
        Neuropharmacology. 1999; 38: 315-317
        • Pehek E.A.
        • McFarlane H.G.
        • Maguschak K.
        • Price B.
        • Pluto C.P.
        M100907, a selective 5-HT2A antagonist, attenuates dopamine release in the rat medial prefrontal cortex.
        Brain Res. 2001; 888: 51-59
        • Tseng K.Y.
        • Mallet N.
        • Toreson K.L.
        • Le Moine C.
        • Gonon F.
        • O'Donnell P.
        Excitatory response of prefrontal cortical fast-spiking interneurons to ventral tegmental area stimulation in vivo.
        Synapse. 2006; 59: 412-417
        • Peters Y.
        • Barnhardt N.E.
        • O'Donnell P.
        Prefrontal cortical up states are synchronized with ventral tegmental area activity.
        Synapse. 2004; 52: 143-152
        • Gao M.
        • Liu C.L.
        • Yang S.
        • Jin G.Z.
        • Bunney B.S.
        • Shi W.Z.
        Functional coupling between the prefrontal cortex and dopamine neurons in the ventral tegmental area.
        J Neurosci. 2007; 27: 5414-5421
        • Hajos M.
        Targeting information-processing deficit in schizophrenia: a novel approach to psychotherapeutic drug discovery.
        Trends Pharmacol Sci. 2006; 27: 391-398
        • Kwon J.S.
        • O'Donnell B.F.
        • Wallenstein G.V.
        • Greene R.W.
        • Hirayasu Y.
        • Nestor P.G.
        • et al.
        Gamma frequency-range abnormalities to auditory stimulation in schizophrenia.
        Arch Gen Psychiatry. 1999; 56: 1001-1005
        • Spencer K.M.
        • Nestor P.G.
        • Niznikiewicz M.A.
        • Salisbury D.F.
        • Shenton M.E.
        • McCarley R.W.
        Abnormal neural synchrony in schizophrenia.
        J Neurosci. 2003; 23: 7407-7411
        • Uhlhaas P.J.
        • Linden D.E.
        • Singer W.
        • Haenschel C.
        • Lindner M.
        • Maurer K.
        • Rodriguez E.
        Dysfunctional long-range coordination of neural activity during Gestalt perception in schizophrenia.
        J Neurosci. 2006; 26: 8168-8175
        • Uhlhaas P.J.
        • Singer W.
        Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology.
        Neuron. 2006; 52: 155-168
        • Stickgold R.
        Sleep-dependent memory consolidation.
        Nature. 2005; 437: 1272-1278
        • Stickgold R.
        • Hobson J.A.
        • Fosse R.
        • Fosse M.
        Sleep, learning, and dreams: Off-line memory reprocessing.
        Science. 2001; 294: 1052-1057
        • Marshall L.
        • Helgadottir H.
        • Molle M.
        • Born J.
        Boosting slow oscillations during sleep potentiates memory.
        Nature. 2006; 444: 610-613
        • Keshavan M.S.
        • Reynolds 3rd, C.F.
        • Miewald M.J.
        • Montrose D.M.
        • Sweeney J.A.
        • Vasko Jr, R.C.
        • Kupfer D.J.
        Delta sleep deficits in schizophrenia: evidence from automated analyses of sleep data.
        Arch Gen Psychiatry. 1998; 55: 443-448
        • Hoffmann R.
        • Hendrickse W.
        • Rush A.J.
        • Armitage R.
        Slow-wave activity during non-REM sleep in men with schizophrenia and major depressive disorders.
        Psychiatry Res. 2000; 95: 215-225
        • Sekimoto M.
        • Kato M.
        • Watanabe T.
        • Kajimura N.
        • Takahashi K.
        Reduced frontal asymmetry of delta waves during all-night sleep in schizophrenia.
        Schizophr Bull. 2007; 33: 1307-1311
        • Begic D.
        • Hotujac L.
        • Jokic-Begic N.
        Quantitative EEG in “positive” and “negative” schizophrenia.
        Acta Psychiatr Scand. 2000; 101: 307-311
        • Riba J.
        • Anderer P.
        • Jane F.
        • Saletu B.
        • Barbanoj M.J.
        Effects of the South American psychoactive beverage ayahuasca on regional brain electrical activity in humans: a functional neuroimaging study using low-resolution electromagnetic tomography.
        Neuropsychobiology. 2004; 50: 89-101
        • Goto Y.
        • Grace A.A.
        Alterations in medial prefrontal cortical activity and plasticity in rats with disruption of cortical development.
        Biol Psychiatry. 2006; 60: 1259-1267
        • Scruggs J.L.
        • Patel S.
        • Bubser M.
        • Deutch A.Y.
        DOI-Induced activation of the cortex: dependence on 5-HT2A heteroceptors on thalamocortical glutamatergic neurons.
        J Neurosci. 2000; 20: 8846-8852