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Antagonism at serotonin 5-HT2A receptors modulates functional activity of frontohippocampal circuit

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Abstract

Rationale

Several second-generation antipsychotics are characterised by a significant antagonistic effect at serotonin 5-HT2A receptors (5-HT2AR), a feature that has been associated with lower incidence of extra-pyramidal symptoms and a putative amelioration of positive and negative symptoms experienced by schizophrenic patients. However, the neurofunctional substrate of 5-HT2A antagonism and its exact contribution to the complex pharmacological profile of these drugs remain to be elucidated.

Objectives

Here, we used pharmacological magnetic resonance imaging to map the modulatory effects of the selective 5-HT2AR antagonist Ml00907 on the spatiotemporal patterns of brain activity elicited by acute phencyclidine (PCP) challenge in the rat. PCP is a non-competitive NMDA receptor antagonist that induces dysregulation of corticolimbic glutamatergic neurotransmission and produces cognitive impairment and psychotic-like symptoms reminiscent of those observed in schizophrenia.

Results

Pre-administration of M100907 produced focal and region-dependent attenuation of PCP-induced response in frontoseptohippocampal areas. As early studies highlighted a permissive role of 5-HT2AR on frontal dopamine release, the role of post-synaptic dopamine D1 receptors on PCP-induced response was examined by using the potent antagonist SCH23390. Interestingly, SCH23390 did not affect PCP’s response in any of the regions examined. This finding rules out a significant contribution of dopamine in the functional changes mapped and, indirectly, the inhibitory effect of M100907, in favour of a glutamatergic origin.

Conclusions

Our data expand recent evidence suggesting a key role of 5-HT2AR in modulating glutamate-mediated cognitive performance in the prefrontal cortex and highlight the whole frontoseptohippocampal circuit as a key functional substrate of 5-HT2AR antagonism in normal and disease states.

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References

  • Adams BW, Moghaddam B (2001) Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex. Biol Psychiatry 50:750–757

    PubMed  Google Scholar 

  • Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 156:1646–1649

    PubMed  Google Scholar 

  • Aghajanian GK, Marek GJ (1997) Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36:589–599

    PubMed  Google Scholar 

  • Aghajanian GK, Marek GJ (2000) Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Rev 31:302–312

    PubMed  Google Scholar 

  • Allen RM, Young SJ (1978) Phencyclidine-induced psychosis. Am J Psychiatry 135:1081–1084

    PubMed  Google Scholar 

  • Alreja M (1996) Excitatory actions of serotonin on GABAergic neurons of the medial septum and diagonal band of Broca. Synapse 22:15–27

    PubMed  Google Scholar 

  • Andersen PH, Gronvald FC, Hohlweg R, Hansen LB, Guddal E, Braestrup C, Nielsen EB (1992) NNC-112, NNC-687 and NNC-756, new selective and highly potent dopamine D1 receptor antagonists. Eur J Pharmacol 219:45–52

    PubMed  Google Scholar 

  • Carli M, Baviera M, Invernizzi RW, Balducci C (2005) Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 31:757–767

    Google Scholar 

  • Cartmell J, Monn JA, Schoepp DD (1999) The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther 291:161–170

    PubMed  Google Scholar 

  • Ceglia I, Carli M, Baviera M, Renoldi G, Calcagno E, Invernizzi RW (2004) The 5-HT2A receptor antagonist M100, 907 prevents extracellular glutamate rising in response to NMDA receptor blockade in the mPFC. J Neurochem 91:189–199

    PubMed  Google Scholar 

  • Choi JK, Chen YI, Hamel E, Jenkins BG (2006) Brain hemodynamic changes mediated by dopamine receptors: role of the cerebral microvasculature in dopamine-mediated neurovascular coupling. NeuroImage 30:700–712

    PubMed  Google Scholar 

  • Cornea-Hebert V, Riad M, Wu C, Singh SK, Descarries L (1999) Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 409:187–209

    PubMed  Google Scholar 

  • Coyle J (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:363–382

    Google Scholar 

  • Davidson RJ, Abercrombie H, Nitschke JB, Putnam K (1999) Regional brain function, emotion and disorders of emotion. Curr Opin Neurobiol 9:228–234

    PubMed  Google Scholar 

  • De Paulis T (2001) M-100907 (Aventis). Curr Opin Investig Drugs 2:123–132

    PubMed  Google Scholar 

  • Deakin JFW, Lees J, McKie S, Hallak JEC, Williams SR, Dursun SM (2008) Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry 65:154–164

    PubMed  Google Scholar 

  • Fletcher PJ, Grottick AJ, Higgins GA (2002) Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 27:576–586

    PubMed  Google Scholar 

  • Friston KJ, Jezzard P, Turner R (1994) Analysis of functional MRI time-series. Hum Brain Mapp 1:153–171

    Google Scholar 

  • Garris PA, Ciolkowski EL, Pastore P, Wightman RM (1994) Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain. J Neurosci 14:6084–6093

    PubMed  Google Scholar 

  • Geyer MA, Vollenweider FX (2008) Serotonin research: contributions to understanding psychoses. Trends Pharmacol Sci 29:445–453

    PubMed  Google Scholar 

  • Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, dhumeau-Auclair A, Nicolas JP, Cistarelli L, Melon C, Millan MJ (2000) Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221

    PubMed  Google Scholar 

  • Gozzi A, Schwarz A, Reese T, Bertani S, Crestan V, Bifone A (2006) Region-specific effects of nicotine on brain activity: a pharmacological MRI study in the drug-naïve rat. Neuropsychopharmacology 31:1690–1703

    PubMed  Google Scholar 

  • Gozzi A, Ceolin L, Schwarz A, Reese T, Bertani S, Bifone A (2007) A multimodality investigation of cerebral haemodynamics and autoregulation in phMRI. Magn Reson Imaging 25:826–833

    PubMed  Google Scholar 

  • Gozzi A, Herdon H, Schwarz A, Bertani S, Crestan V, Turrini G, Bifone A (2008a) Pharmacological stimulation of NMDA receptors via co-agonist site suppresses fMRI response to phencyclidine in the rat. Psychopharmacology 201:273–284

    PubMed  Google Scholar 

  • Gozzi A, Large C, Schwarz A, Bertani S, Crestan V, Bifone A (2008b) Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine. Neuropsychopharmacology 33:1690–1703

    PubMed  Google Scholar 

  • Gozzi A, Schwarz AJ, Reese T, Crestan V, Bifone A (2008c) Drug-anaesthetic interaction in phMRI: the case of the pyschotomimetic agent phencyclidine. Magn Reson Imag 26:999–1006

    Google Scholar 

  • Greene R (2001) Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus 11:569–577

    PubMed  Google Scholar 

  • Habara T, Hamamura T, Miki M, Ohashi K, Kuroda S (2001) M100907, a selective 5-HT(2A) receptor antagonist, attenuates phencyclidine-induced Fos expression in discrete regions of rat brain. Eur J Pharmacol 417:189–194

    PubMed  Google Scholar 

  • Hajos M, Hoffmann WE, Weaver RJ (2003) Regulation of septo-hippocampal activity by 5-hydroxytryptamine2C receptors. J Pharmacol Exp Ther 306:605–615

    PubMed  Google Scholar 

  • Heckers S (2001) Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 11:520–528

    PubMed  Google Scholar 

  • Hennig J, Nauerth A, Friedburg H (1986) RARE imaging: a fast imaging method for clinical MR. Magn Reson Med 3:823–833

    PubMed  Google Scholar 

  • Hietala J, Sepp T, Lappalainen J, Syvlahti E (1992) Quantification of SCH 39166, a novel selective D1 dopamine receptor antagonist, in rat brain and blood. Psychopharmacology 106:455–458

    PubMed  Google Scholar 

  • Higgins GA, Enderlin M, Haman M, Fletcher PJ (2003) The 5-HT2A receptor antagonist M100, 907 attenuates motor and ‘impulsive-type’ behaviours produced by NMDA receptor antagonism. Psychopharmacology 170:309–319

    PubMed  Google Scholar 

  • Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500

    PubMed  Google Scholar 

  • Honey G, Bullmore E (2004) Human pharmacological MRI. Trends Pharmacol Sci 25:366–374

    PubMed  Google Scholar 

  • Hoyer D, Pazos A, Probst A, Palacios JM (1986) Serotonin receptors in the human brain. II. Characterization and autoradiographic localization of 5-HT1C and 5-HT2 recognition sites. Brain Res 376:97–107

    PubMed  Google Scholar 

  • Hutson PH, Barton CL, Jay M, Blurton P, Burkamp F, Clarkson R, Bristow LJ (2000) Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT2C/2B receptor antagonists: neurochemical and behavioural studies. Neuropharmacology 39:2318–2328

    PubMed  Google Scholar 

  • Ichikawa J, Meltzer HY (1999) Relationship between dopaminergic and serotonergic neuronal activity in the frontal cortex and the action of typical and atypical antipsychotic drugs. Eur Arch Psychiatry Clin Neurosci 249:S90–S98

    Google Scholar 

  • Idris NF, Repeto P, Neill JC, Large CH (2005) Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat. Psychopharmacology (Berl) 179:336–348

    Google Scholar 

  • Javitt DC, Balla A, Sershen H, Lajtha A (1999) Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors. Biol Psychiatry 45:668–679

    PubMed  Google Scholar 

  • Jenkins BG, Chen Y-CI, Mandeville JB (2003) Pharmacological magnetic resonance imaging (phMRI). In: van Bruggen N, Roberts T (eds) Biomedical imaging in experimental neuroscience. CRC, New York, pp 155–209

    Google Scholar 

  • Kapur S, Seeman P (2002) NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Mol Psychiatry 7:837–844

    PubMed  Google Scholar 

  • Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PL, McCloskey TC, Johnson MP, McCarty DR, Poirot M, Senyah Y, Siegel BW, Widmaier C (1996) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100, 907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther 277:968–981

    PubMed  Google Scholar 

  • Knauer CS, Campbell JE, Galvan B, Bowman C, Osgood S, Buist S, Buchholz L, Henry B, Wong EHF, Shahid M, Grimwood S (2008) Validation of a rat in vivo [3H]M100907 binding assay to determine a translatable measure of 5-HT2A receptor occupancy. Eur J Pharmacol 591:136–141

    PubMed  Google Scholar 

  • Knutson B, Gibbs S (2007) Linking nucleus accumbens dopamine and blood oxygenation. Psychopharmacology 191:813–822

    PubMed  Google Scholar 

  • Kristiansen LV, Huerta I, Beneyto M, Meador-Woodruff JH (2007) NMDA receptors and schizophrenia. Curr Opin Pharmacol 7:48–55

    PubMed  Google Scholar 

  • Krystal JH, D’Souza DC, Karper LP, Bennett A, Abi-Dargham A, Abi-Saab D, Cassello K, Bowers MB Jr, Vegso S, Heninger GR, Charney DS (1999) Interactive effects of subanesthetic ketamine and haloperidol in healthy humans. Psychopharmacology (Berl) 145:193–204

    Google Scholar 

  • Krystal JH, Anand A, Moghaddam B (2002) Effects of NMDA receptor antagonists: implications for the pathophysiology of schizophrenia. Arch Gen Psychiatry 59:663–664

    PubMed  Google Scholar 

  • Krystal JH, D’Souza DC, Mathalon D, Perry E, Belger A, Hoffman R (2003) NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 169:215–233

    Google Scholar 

  • Kuroki T, Meltzer HY, Ichikawa J (1999) Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharmacol Exp Ther 288:774–781

    PubMed  Google Scholar 

  • Langsjo JW, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Oikonen V, Sipila H, Kurki T, Silvanto M, Scheinin H (2003) Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology 99:614–623

    PubMed  Google Scholar 

  • Large CH (2007) Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? J Psychopharmacol 21:283–301

    PubMed  Google Scholar 

  • Lehmann J, Schneider J, McPherson S, Murphy DE, Bernard P, Tsai C, Bennett DA, Pastor G, Steel DJ, Boehm C (1987) CPP, a selective N-methyl-D-aspartate (NMDA)-type receptor antagonist: characterization in vitro and in vivo. J Pharmacol Exp Ther 240:737–746

    PubMed  Google Scholar 

  • Liddle PF, Lane CJ, Ngan E (2000) Immediate effects of risperidone on cortico-striato-thalamic loops and the hippocampus. Br J Psychiatry 177:402–407

    PubMed  Google Scholar 

  • Linn S, Negi S, Gerum V, Javitt C (2003) Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys. Psychopharmacology V169:234–239

    Google Scholar 

  • Littlewood CL, Jones N, O’Neil MJ, Mitchell SN, Tricklebank M, Williams MS (2006) Mapping the central effects of ketamine in the rat using pharmacological MRI. Psychopharmacology V186:64–81

    Google Scholar 

  • Liu W, Alreja M (1997) Atypical antipsychotics block the excitatory effects of serotonin in septohippocampal neurons in the rat. Neuroscience 79:369–382

    PubMed  Google Scholar 

  • Luttgen M, Ove Ígren S, Br M (2004) Chemical identity of 5-HT2A receptor immunoreactive neurons of the rat septal complex and dorsal hippocampus. Brain Res 1010:156–165

    PubMed  Google Scholar 

  • Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150

    PubMed  Google Scholar 

  • Mandeville JB, Marota JJA, Kosofsky BE, Keltner JR, Weissleder R, Rosen B, Weisskoff R (1998) Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation. Magn Reson Med 39:615–624

    PubMed  Google Scholar 

  • Marder SR (1999) Limitations of dopamine-D2 antagonists and the search for novel antipsychotic strategies. Neuropsychopharmacology 21:S117–S121

    Google Scholar 

  • Marquis KL, Sabb AL, Logue SF, Brennan JA, Piesla MJ, Comery TA, Grauer SM, Ashby CR Jr, Nguyen HQ, Dawson LA, Barrett JE, Stack G, Meltzer HY, Harrison BL, Rosenzweig-Lipson S (2007) WAY-163909 [(7bR, 10aR)-1, 2, 3, 4, 8, 9, 10, 10a-octahydro-7bH-cyclopenta-[b][1, 4]diazepino[6, 7, 1hi]indole]: a novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity. J Pharmacol Exp Ther 320:486–496

    PubMed  Google Scholar 

  • Martin-Ruiz R, Puig MV, Celada P, Shapiro DA, Roth BL, Mengod G, Artigas F (2001) Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci 21:9856–9866

    PubMed  Google Scholar 

  • Medoff DR, Holcomb HH, Lahti AC, Tamminga CA (2001) Probing the human hippocampus using rCBF: contrasts in schizophrenia. Hippocampus 11:543–550

    PubMed  Google Scholar 

  • Meltzer HY (1996) Pre-clinical pharmacology of atypical antipsychotic drugs: a selective review. Br J Psychiatry 168(Suppl 29):23–31

    Google Scholar 

  • Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246

    PubMed  Google Scholar 

  • Meltzer HY, Li Z, Kaneda Y, Ichikawa J (2003) Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:1159–1172

    PubMed  Google Scholar 

  • Meltzer HY, Arvanitis L, Bauer D, Rein W (2004) Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161:975–984

    PubMed  Google Scholar 

  • Mirjana C, Baviera M, Invernizzi RW, Balducci C (2004) The serotonin 5-HT2A receptors antagonist M100907 prevents impairment in attentional performance by NMDA receptor blockade in the rat prefrontal cortex. Neuropsychopharmacology 29:1637–1647

    PubMed  Google Scholar 

  • Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 17:2921–2927

    Google Scholar 

  • Molloy AG, Waddington JL (1984) Dopaminergic behaviour stereospecifically promoted by the D1 agonist R-SK & F 38393 and selectively blocked by the D1 antagonist SCH 23390. Psychopharmacology 82:409–410

    PubMed  Google Scholar 

  • Neisewander JL, Fuchs RA, O’Dell LE, Khroyan TV (1998) Effects of SCH-23390 on dopamine D1 receptor occupancy and locomotion produced by intraaccumbens cocaine infusion. Synapse 30:194–204

    PubMed  Google Scholar 

  • Ngan ETC, Lane CJ, Ruth TJ, Liddle PF (2002) Immediate and delayed effects of risperidone on cerebral metabolism in neuroleptic naive schizophrenic patients: correlations with symptom change. J Neurol Neurosurg Psychiatry 72:106–110

    PubMed  Google Scholar 

  • O’Neill MF, Heron-Maxwell CL, Shaw G (1999) 5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D1 agonist C-APB. Pharmacol Biochem Behav 63:237–243

    PubMed  Google Scholar 

  • Palfreyman MG, Schmidt CJ, Sorensen SM, Dudley MW, Kehne JH, Moser P, Gittos MW, Carr AA (1993) Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function. Psychopharmacology (Berl) 112:S60–S67

    Google Scholar 

  • Parellada E, Catafau AM, Bernardo M, Lomena F, Gonzalez-Monclus E, Setoain J (1994) Prefrontal dysfunction in young acute neuroleptic-naive schizophrenic patients: a resting and activation SPECT study. Psychiatry Res 55:131–139

    PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotactic coordinates. Academic, San Diego

    Google Scholar 

  • Peroutka SJ, U’Prichard DC, Greenberg DA, Snyder SH (1977) Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain. Neuropharmacology 16:549–556

    PubMed  Google Scholar 

  • Piguet P, Galvan M (1994) Transient and long-lasting actions of 5-HT on rat dentate gyrus neurones in vitro. J Physiol 481(Pt 3):629–639

    PubMed  Google Scholar 

  • Poyurovsky M, Koren D, Gonopolsky I, Schneidman M, Fuchs C, Weizman A, Weizman R (2003) Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia patients: an add-on, double-blind placebo-controlled study. Eur Neuropsychopharmacol 13:123–128

    PubMed  Google Scholar 

  • Proksch JW, Gentry WB, Owens SM (2000) The effect of rate of drug administration on the extent and time course of phencyclidine distribution in rat brain, testis, and serum. Drug Metab Dispos 28:742–747

    PubMed  Google Scholar 

  • Robbins TW (2005) Chemistry of the mind: neurochemical modulation of prefrontal cortical function. J Comp Neurol 493:140–146

    PubMed  Google Scholar 

  • Rodefer JS, Nguyen TN, Karlsson JJ, Arnt J (2008) Reversal of subchronic PCP-induced deficits in attentional set shifting in rats by sertindole and a 5-HT6 receptor antagonist: comparison among antipsychotics. Neuropsychopharmacology 33:2657–2666

    PubMed  Google Scholar 

  • Roth BL, Hanizavareh SM, Blum AE (2004) Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology 174:17–24

    PubMed  Google Scholar 

  • Schmidt CJ, Fadayel GM (1995) The selective 5-HT2A receptor antagonist, MDL 100, 907, increases dopamine efflux in the prefrontal cortex of the rat. Eur J Pharmacol 273:273–279

    PubMed  Google Scholar 

  • Schreiber R, Brocco M, de Lefebvre LB, Monneyron S, Millan MJ (1995) A drug discrimination analysis of the actions of novel serotonin1A receptor ligands in the rat using the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin. J Pharmacol Exp Ther 275:822–831

    PubMed  Google Scholar 

  • Schwarz AJ, Reese T, Gozzi A, Bifone A (2003) Functional MRI using intravascular contrast agents: detrending of the relative cerebrovascular (rCBV) time course. Magn Reson Imaging 21:1191–1200

    PubMed  Google Scholar 

  • Schwarz AJ, Zocchi A, Reese T, Gozzi A, Varnier G, Girlanda E, Biscaro B, Bertani S, Crestan V, Heidbreder CA, Bifone A (2004) The relationship between local dopamine changes and phMRI response to acute cocaine challenge in the rat revealed by concurrent in situ microdialysis. In: Book of abstracts: Twelfth Annual Meeting of the International Society of Magnetic Resonance in Medicine 12

  • Schwarz AJ, Danckaert A, Reese T, Gozzi A, Paxinos G, Watson C, Merlo-Pich EV, Bifone A (2006a) A stereotaxic MRI template set for the rat brain with tissue class distribution maps and co-registered anatomical atlas: application to pharmacological MRI. NeuroImage 32:538–550

    PubMed  Google Scholar 

  • Schwarz AJ, Whitcher B, Gozzi A, Reese T, Bifone A (2006b) Study-level wavelet cluster analysis and data-driven signal models in pharmacological MRI. J Neurosci Methods 159:346–360

    PubMed  Google Scholar 

  • Schwarz AJ, Gozzi A, Reese T, Heidbreder CA, Bifone A (2007) Pharmacological modulation of functional connectivity: the correlation structure underlying the phMRI response to d-amphetamine modified by selective dopamine D3receptor antagonist SB277011A. Magn Reson Imag 25:811–820

    Google Scholar 

  • Scott DO, Heath TG (1998) Investigation of the CNS penetration of a potent 5-HT2a receptor antagonist (MDL 100, 907) and an active metabolite (MDL 105, 725) using in vivo microdialysis sampling in the rat. J Pharm Biomed Anal 17:17–25

    PubMed  Google Scholar 

  • Scruggs JL, Patel S, Bubser M, Deutch AY (2000) DOI-induced activation of the cortex: dependence on 5-HT2A heteroceptors on thalamocortical glutamatergic neurons. J Neurosci 20:8846–8852

    PubMed  Google Scholar 

  • Scruggs JL, Schmidt D, Deutch AY (2003) The hallucinogen 1-[2, 5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats. Neurosci Lett 346:137–140

    PubMed  Google Scholar 

  • Seeman P (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47:27–38

    PubMed  Google Scholar 

  • Seeman P, Kapur S (2003) Anesthetics inhibit high-affinity states of dopamine D2 and other G-linked receptors. Synapse 50:35–40

    PubMed  Google Scholar 

  • Shen RY, Andrade R (1998) 5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus. J Pharmacol Exp Ther 285:805–812

    PubMed  Google Scholar 

  • Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnorr L (1995) A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:176–179

    PubMed  Google Scholar 

  • Sorensen SM, Kehne JH, Fadayel GM, Humphreys TM, Ketteler HJ, Sullivan CK, Taylor VL, Schmidt CJ (1993) Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies. J Pharmacol Exp Ther 266:684–691

    PubMed  Google Scholar 

  • Soyka M, Koch W, Möller H, Rüther T, Tatsch K (2005) Hypermetabolic pattern in frontal cortex and other brain regions in unmedicated schizophrenia patients. Eur Arch Psychiatry Clin Neurosci 255:308–312

    PubMed  Google Scholar 

  • Tandon R, Fleischhacker W (2005) Comparative efficacy of antipsychotics in the treatment of schizophrenia: a critical assessment. Schizophr Res 79:145–155

    PubMed  Google Scholar 

  • Varty GB, Bakshi VP, Geyer MA (1999) M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague–Dawley and Wistar rats. Neuropsychopharmacology 20:311–321

    PubMed  Google Scholar 

  • Volkow ND, Brodie JD, Wolf AP, Angrist B, Russell J, Cancro R (1986) Brain metabolism in patients with schizophrenia before and after acute neuroleptic administration. J Neurol Neurosurg Psychiatry 49:1199–1202

    PubMed  Google Scholar 

  • Wadenberg M-L (1992) Antagonism by 8-OH-DPAT, but not ritanserin, of catalepsy induced by SCH 23390 in the rat. J Neural Transm 89:49–59

    Google Scholar 

  • Weissman AD, Dam M, London ED (1987) Alterations in local cerebral glucose utilization induced by phencyclidine. Brain Res 435:29–40

    PubMed  Google Scholar 

  • Whitcher B, Schwarz AJ, Barjat H, Smart SC, Grundy RI, James MF (2005) Wavelet-based cluster analysis: data-driven grouping of voxel time courses with application to perfusion-weighted and pharmacological MRI of the rat brain. Neuroimage 24:281–295

    PubMed  Google Scholar 

  • Winstanley CA, Chudasama Y, Dalley JW, Theobald DEH, Glennon JC, Robbins TW (2003) Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology 167:304–314

    PubMed  Google Scholar 

  • Winter JC, Eckler JR, Rabin RA (2004) Serotonergic/glutamatergic interactions: the effects of mGlu2/3 receptor ligands in rats trained with LSD and PCP as discriminative stimuli. Psychopharmacology (Berl) 172:233–240

    Google Scholar 

  • Wolf ME, Xue CJ (1999) Amphetamine-induced glutamate efflux in the rat ventral tegmental area is prevented by MK-801, SCH 23390, and ibotenic acid lesions of the prefrontal cortex. J Neurochem 73:1529–1538

    PubMed  Google Scholar 

  • Wood MD, Reavill C, Trail B, Wilson A, Stean T, Kennett GA, Lightowler S, Blackburn TP, Thomas D, Gager TL, Riley G, Holland V, Bromidge SM, Forbes IT, Middlemiss DN (2001) SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. Neuropharmacology 41:186–199

    PubMed  Google Scholar 

  • Worsley KJ, Evans AC, Marrett S, Neelin P (1992) A three-dimensional statistical analysis for CBF activation studies in human brain. J Cereb Blood Flow Metab 12:900–918

    PubMed  Google Scholar 

  • Zaharchuk G, Mandeville JB, Bogdanov AA Jr, Weissleder R, Rosen BR, Marota JJ (1999) Cerebrovascular dynamics of autoregulation and hypoperfusion. An MRI study of CBF and changes in total and microvascular cerebral blood volume during hemorrhagic hypotension. Stroke 30:2197–2204

    PubMed  Google Scholar 

  • Zahrt J, Taylor JR, Mathew RG, Arnsten AF (1997) Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance. J Neurosci 17:8528–8535

    PubMed  Google Scholar 

  • Zaniewska M, McCreary AC, Przegalinski E, Filip M (2007) Effects of the serotonin 5-HT2A and 5-HT2C receptor ligands on the discriminative stimulus effects of nicotine in rats. Eur J Pharmacol 571:156–165

    PubMed  Google Scholar 

  • Zhai Y, George CA, Zhai J, Nisenbaum ES, Johnson MP, Nisenbaum LK (2002) Group II metabotropic glutamate receptor modulation of DOI-induced c-fos mRNA and excitatory responses in the cerebral cortex. Neuropsychopharmacology 28:45–52

    Google Scholar 

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Acknowledgements

The author would like to thank Dr. Mauro Corsi for critically reviewing the manuscript.

Disclosure/conflict of interest

The author(s) declare that, except for income received from my primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

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  1. Marcel Clemens

    Present address: Osservatorio Astronomico di Padova, Padova, Italy

Authors and Affiliations

  1. Biology, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy

    Alessandro Gozzi, Marcel Clemens & Angelo Bifone

  2. Laboratory Animal Science, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy

    Valerio Crestan & Giuliano Turrini

  3. Neuroimaging, GSK Neurosciences CEDD, Fleming 4, 37100, Verona, Italy

    Alessandro Gozzi

Authors
  1. Alessandro Gozzi
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  2. Valerio Crestan
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  3. Giuliano Turrini
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  4. Marcel Clemens
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  5. Angelo Bifone
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Corresponding author

Correspondence to Alessandro Gozzi.

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All in vivo studies were conducted in accordance with the Italian laws (DL 116, 1992 Ministero della Sanità, Roma). Animal research protocols were also reviewed and consented to by the GSK animal care committee, in accordance with the guidelines of the Principles of Laboratory Animal Care (NIH publication 86-23, revised 1985).

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Gozzi, A., Crestan, V., Turrini, G. et al. Antagonism at serotonin 5-HT2A receptors modulates functional activity of frontohippocampal circuit. Psychopharmacology 209, 37–50 (2010). https://doi.org/10.1007/s00213-009-1772-4

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  • DOI: https://doi.org/10.1007/s00213-009-1772-4

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