, Volume 214, Issue 3, pp 625–637 | Cite as

Sertindole restores attentional performance and suppresses glutamate release induced by the NMDA receptor antagonist CPP

  • Mirjana Carli
  • Eleonora Calcagno
  • Ester Mainini
  • Jorn Arnt
  • Roberto W. Invernizzi
Original Investigation



Blockade of N-methyl-d-aspartic acid (NMDA) receptors in the rat medial prefrontal cortex (mPFC) impairs performance in the five-choice serial reaction time task (5-CSRTT) and increases glutamate (GLU) release. Recent research suggests that excessive GLU release may be critical for attention deficits.


We tested this hypothesis by investigating the effects of the atypical antipsychotics sertindole and clozapine on 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP)-induced performance deficits in the 5-CSRTT and on the CPP-induced GLU release in the mPFC.


The 5-CSRTT, a test of divided and sustained visual attention providing indices of attentional functioning (accuracy of visual discrimination), response control (anticipatory and perseverative responses) and intracortical microdialysis in conscious rats were used to investigate the effects of sertindole and clozapine.


Low doses of sertindole (0.02–0.32 mg/kg) prevented CPP-induced accuracy deficits, anticipatory over-responding and the rise in GLU release. In contrast, doses ranging from 0.6 to 2.5 mg/kg had no effect or even enhanced the effect of CPP on anticipatory responding. Similarly, 2.5 mg/kg sertindole was unable to reverse CPP-induced rise in GLU release. Clozapine (2.5 mg/kg) prevented accuracy deficits and the increase in anticipatory responding and abolished the rise in GLU release induced by CPP.


These findings show that the ameliorating effects of sertindole and clozapine on NMDA receptor dependent attention deficit is associated with suppression in GLU release in the mPFC. This supports the proposal that suppression in GLU release might be a target for the development of novel drugs aimed at counteracting some aspects of cognitive deficits of schizophrenia.


Antipsychotics Cognitive deficits Glutamate Medial prefrontal cortex NMDA receptor -antagonists 



This work was supported by a research grant from H. Lundbeck A/S, Denmark.

Supplementary material

213_2010_2066_MOESM1_ESM.doc (183 kb)
Fig. S1 Effects of sertindole on CPP-induced rise of extracellular 5-HT in the mPFC. Sertindole (S) or vehicle (V) were given orally (arrows) 4 h before the infusion of 100 μM CPP (a) or aCSF (b) through the probe. Horizontal bar indicates the duration of CPP infusion. Experimental groups in a were as follows: V + aCSF (n = 6), V + CPP (n = 6), S0.02 mg/kg + CPP (n = 5), S0.32 mg/kg + CPP (n = 5), S2.5 mg/kg + CPP (n = 6). b V + aCSF the same as in a (dotted line), S0.02 mg/kg + aCSF (n = 5), S0.32 mg/kg + aCSF (n = 5) and S 2.5 mg/kg + aCSF (n = 5). Data are expressed as mean percentages of basal values ± SEM. For the sake of clarity, data from 20 to 220 min were omitted from a. The whole curves are shown in Fig. S1. *P < 0.05 versus basal values (Tukey’s test) (DOC 183 kb)
213_2010_2066_MOESM2_ESM.doc (81 kb)
Fig. S2 Effects of clozapine on CPP-induced rise of extracellular 5-HT in the mPFC. Clozapine (CLOZ) or vehicle (V) were given orally (arrows) 20 min before the infusion of 100 μM CPP or aCSF through the probe. Horizontal bar indicates the duration of CPP or aCSF infusion. Experimental groups were as follows: V + V, V + CPP, CLOZ + CPP, CLOZ + aCSF. Data are expressed as percentages of basal values and are the mean ± SEM of five rats per group. *P < 0.05 versus basal values (Tukey’s test) (DOC 81 kb)


  1. Abdul-Monim Z, Reynolds GP, Neill JC (2006) The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm. Behav Brain Res 169:263–73PubMedCrossRefGoogle Scholar
  2. Arnt J (1992) Sertindole and several antipsychotic drugs differentially inhibit the discriminative stimulus effects of amphetamine, LSD and St 587 in rats. Behav Pharmacol 3:11–18PubMedCrossRefGoogle Scholar
  3. Arnt J, Skarsfeldt T (1998) Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18:63–101PubMedCrossRefGoogle Scholar
  4. Baviera M, Invernizzi RW, Carli M (2008) Haloperidol and clozapine have dissociable effects in a model of attentional performance deficits induced by blockade of NMDA receptors in the mPFC. Psychopharmacology (Berl) 196:269–80CrossRefGoogle Scholar
  5. Benes FM, Berretta S (2001) GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25:1–27PubMedCrossRefGoogle Scholar
  6. Besson M, Belin D, McNamara R, Theobald DE, Castel A, Beckett VL, Crittenden BM, Newman AH, Everitt BJ, Robbins TW, Dalley JW (2010) Dissociable control of impulsivity in rats by dopamine d2/3 receptors in the core and shell subregions of the nucleus accumbens. Neuropsychopharmacology 35:560–569PubMedCrossRefGoogle Scholar
  7. Braff DL (1993) Information processing and attention dysfunctions in schizophrenia. Schizophr Bull 19:233–259PubMedGoogle Scholar
  8. Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D (1997) Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 154:805–811PubMedGoogle Scholar
  9. Calcagno E, Carli M, Baviera M, Invernizzi RW (2009) Endogenous serotonin and serotonin2C receptors are involved in the ability of M100907 to suppress cortical glutamate release induced by NMDA receptor blockade. J Neurochem 108:521–532PubMedCrossRefGoogle Scholar
  10. Calcagno E, Carli M, Invernizzi RW (2006) The 5-HT(1A) receptor agonist 8-OH-DPAT prevents prefrontocortical glutamate and serotonin release in response to blockade of cortical NMDA receptors. J Neurochem 96:853–560PubMedCrossRefGoogle Scholar
  11. Carli M, Baviera M, Invernizzi RW, Balducci C (2006) 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 31:757–767PubMedCrossRefGoogle Scholar
  12. Carli M, Calcagno E, Mainolfi P, Mainini E, Invernizzi RW (2010) Effects of aripiprazole, olanzapine and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex. Psychopharmacology. doi: 10.1007/s00213-010-2065-7
  13. Carli M, Robbins TW, Evenden JL, Everitt BJ (1983) Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380PubMedCrossRefGoogle Scholar
  14. Carli M, Samanin R (2000) The 5-HT1A receptor agonist 8-OH-DPAT reduces rats' accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT1A receptors. Psychopharmacology 149:259–268PubMedCrossRefGoogle Scholar
  15. Ceglia I, Carli M, Baviera M, Renoldi G, Calcagno E, Invernizzi RW (2004) The 5-HT receptor antagonist M100, 907 prevents extracellular glutamate rising in response to NMDA receptor blockade in the mPFC. J Neurochem 91:189–199PubMedCrossRefGoogle Scholar
  16. Chudasama Y, Robbins TW (2006) Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans. Biol Psychol 73:19–38PubMedCrossRefGoogle Scholar
  17. Didriksen M, Kreilgaard M, Arnt J (2006) Sertindole, in contrast to clozapine and olanzapine, does not disrupt water maze performance after acute or chronic treatment. Eur J Pharmacol 542:108–115PubMedCrossRefGoogle Scholar
  18. Didriksen M, Skarsfeldt T, Arnt J (2007) Reversal of PCP-induced learning and memory deficits in the Morris' water maze by sertindole and other antipsychotics. Psychopharmacology (Berl) 193:225–233CrossRefGoogle Scholar
  19. Fattorini G, Melone M, Bragina L, Candiracci C, Cozzi A, Pellegrini Giampietro DE, Torres-Ramos M, Perez-Samartin A, Matute C, Conti F (2008) GLT-1 expression and Glu uptake in rat cerebral cortex are increased by phencyclidine. Glia 56:1320–1327PubMedCrossRefGoogle Scholar
  20. Frith CD (1987) The positive and negative symptoms of schizophrenia reflect impairments in the perception and initiation of action. Psychol Med 17:631–648PubMedCrossRefGoogle Scholar
  21. Gallhofer B, Jaanson P, Mittoux A, Tanghoj P, Lis S, Krieger S (2007) Course of recovery of cognitive impairment in patients with schizophrenia: a randomised double-blind study comparing sertindole and haloperidol. Pharmacopsychiatry 40:275–286PubMedCrossRefGoogle Scholar
  22. Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, Lencz T, Patel RC, Woerner MG, Schooler NR, Kane JM, Robinson DG (2007) Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry 64:1115–1122PubMedCrossRefGoogle Scholar
  23. Gordon JA (2010) Testing the glutamate hypothesis of schizophrenia. Nat Neurosci 13:2–4PubMedCrossRefGoogle Scholar
  24. Gozzi A, Crestan V, Turrini G, Clemens M, Bifone A (2010) Antagonism at serotonin 5-HT(2A) receptors modulates functional activity of frontohippocampal circuit. Psychopharmacology (Berl) 209:37–50CrossRefGoogle Scholar
  25. Gozzi A, Large CH, Schwarz A, Bertani S, Crestan V, Bifone A (2008) Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine. Neuropsychopharmacology 33:1690–1703PubMedCrossRefGoogle Scholar
  26. Granon S, Passetti F, Thomas KL, Dalley JW, Everitt BJ, Robbins TW (2000) Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci 20:1208–1215PubMedGoogle Scholar
  27. Green MF, Marder SR, Glynn SM, McGurk SR, Wirshing WC, Wirshing DA, Liberman RP, Mintz J (2002) The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone. Biol Psychiatry 51:972–978PubMedCrossRefGoogle Scholar
  28. Harrison AA, Everitt BJ, Robbins TW (1997) Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology (Berl) 133:329–342CrossRefGoogle Scholar
  29. Harvey PD, Keefe RS (2001) Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry 158:176–184PubMedCrossRefGoogle Scholar
  30. Higgins GA, Enderlin M, Haman M, Fletcher PJ (2003) The 5-HT(2A) receptor antagonist M100, 907 attenuates motor and 'impulsive-type' behaviours produced by NMDA receptor antagonism. Psychopharmacology (Berl) 170:309–319CrossRefGoogle Scholar
  31. Homayoun H, Jackson ME, Moghaddam B (2005) Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats. J Neurophysiol 93:1989–2001PubMedCrossRefGoogle Scholar
  32. Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500PubMedCrossRefGoogle Scholar
  33. Idris N, Neill J, Grayson B, Bang-Andersen B, Witten LM, Brennum LT, Arnt J (2010) Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT(6) and 5-HT (2A) receptor mechanisms. Psychopharmacology (Berl) 208:23–36CrossRefGoogle Scholar
  34. Jackson ME, Homayoun H, Moghaddam B (2004) NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sci U S A 101:8467–8472PubMedCrossRefGoogle Scholar
  35. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308PubMedGoogle Scholar
  36. Kane JM, Tamminga CA (1997) Sertindole (Serdolect): preclinical and clinical findings of a new atypical antipsychotic. Expert Opin Investig Drugs 6:1729–1741PubMedCrossRefGoogle Scholar
  37. Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA (2007) Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 64:633–647PubMedCrossRefGoogle Scholar
  38. Keefe RS, Seidman LJ, Christensen BK, Hamer RM, Sharma T, Sitskoorn MM, Lewine RR, Yurgelun-Todd DA, Gur RC, Tohen M, Tollefson GD, Sanger TM, Lieberman JA (2004) Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry 161:985–995PubMedCrossRefGoogle Scholar
  39. Keefe RS, Silva SG, Perkins DO, Lieberman JA (1999) The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull 25:201–222PubMedGoogle Scholar
  40. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214PubMedGoogle Scholar
  41. Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995) Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19PubMedCrossRefGoogle Scholar
  42. Lewis DA, Moghaddam B (2006) Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63:1372–1376PubMedCrossRefGoogle Scholar
  43. Lopez-Gil X, Artigas F, Adell A (2009) Role of different monoamine receptors controlling MK-801-induced release of serotonin and glutamate in the medial prefrontal cortex: relevance for antipsychotic action. Int J Neuropsychopharmacol 12:487–499PubMedCrossRefGoogle Scholar
  44. Luby ED, Gottlieb JS, Cohen BD, Rosenbaum G, Domino EF (1962) Model psychoses and schizophrenia. Am J Psychiatry 119:61–67Google Scholar
  45. 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 17:141–150PubMedCrossRefGoogle Scholar
  46. Meltzer HY, McGurk SR (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25:233–255PubMedGoogle Scholar
  47. 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 29:1637–1647PubMedCrossRefGoogle Scholar
  48. 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. J Neurosci 17:2921–2927PubMedGoogle Scholar
  49. Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352PubMedCrossRefGoogle Scholar
  50. Mork A, Witten LM, Arnt J (2007) Differentiating effects of sertindole and risperidone on extracellular levels of neurotransmitters in the frontal cortex of conscious rats. In: Neuroscience So (ed), XXXVII Annual Meeting of the Society of Neuroscience, San Diego, CA, pp 500.13Google Scholar
  51. Mork A, Witten LM, Arnt J (2009) Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved. Psychopharmacology (Berl) 206:39–49CrossRefGoogle Scholar
  52. Olsen CK, Brennum LT, Kreilgaard M (2008) Using pharmacokinetic-pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics. Eur J Pharmacol 584:318–327PubMedCrossRefGoogle Scholar
  53. Passetti F, Chudasama Y, Robbins TW (2002) The frontal cortex of the rat and visual attentional performance: dissociable functions of distinct medial prefrontal subregions. Cereb Cortex 12:1254–1268PubMedCrossRefGoogle Scholar
  54. Passetti F, Levita L, Robbins TW (2003) Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions. Behav Brain Res 138:59–69PubMedCrossRefGoogle Scholar
  55. Paxinos G, Watson C (1986) The Rat Brain in Stereotaxic Coordinates. Academic, San Diego, CAGoogle Scholar
  56. Pezze MA, Dalley JW, Robbins TW (2009) Remediation of attentional dysfunction in rats with lesions of the medial prefrontal cortex by intra-accumbens administration of the dopamine D(2/3) receptor antagonist sulpiride. Psychopharmacology (Berl) 202:307–313CrossRefGoogle Scholar
  57. Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 163:362–380CrossRefGoogle Scholar
  58. Robinson TE, Whishaw IQ (1988) Normalization of extracellular dopamine in striatum following recovery from a partial unilateral 6-OHDA lesion of the substantia nigra: a microdialysis study in freely moving rats. Brain Res 450:209–224PubMedCrossRefGoogle Scholar
  59. 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 33:2657–2666PubMedCrossRefGoogle Scholar
  60. Sanchez C, Arnt J (2000) In-vivo assessment of 5-HT2A and 5-HT2C antagonistic properties of newer antipsychotics. Behav Pharmacol 11:291–298PubMedGoogle Scholar
  61. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 124:57–73CrossRefGoogle Scholar
  62. Suzuki Y, Jodo E, Takeuchi S, Niwa S, Kayama Y (2002) Acute administration of phencyclidine induces tonic activation of medial prefrontal cortex neurons in freely moving rats. Neuroscience 114:769–779PubMedCrossRefGoogle Scholar
  63. Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (1997) Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol 7:25–38PubMedCrossRefGoogle Scholar
  64. Winstanley CA, Chudasama Y, Dalley JW, Theobald DE, 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 (Berl) 167:304–314Google Scholar
  65. Winstanley CA, Dalley JW, Theobald DE, Robbins TW (2004a) Fractionating impulsivity: contrasting effects of central 5-HT depletion on different measures of impulsive behavior. Neuropsychopharmacology 29:1331–1343PubMedCrossRefGoogle Scholar
  66. Winstanley CA, Theobald DE, Dalley JW, Glennon JC, Robbins TW (2004b) 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology (Berl) 176:376–385CrossRefGoogle Scholar
  67. Yonezawa Y, Kuroki T, Kawahara T, Tashiro N, Uchimura H (1998) Involvement of gamma-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex. Eur J Pharmacol 341:45–56PubMedCrossRefGoogle Scholar
  68. Zimbroff DL, Kane JM, Tamminga CA, Daniel DG, Mack RJ, Wozniak PJ, Sebree TB, Wallin BA, Kashkin KB (1997) Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group Am J Psychiatry 154:782–791Google Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Mirjana Carli
    • 1
  • Eleonora Calcagno
    • 1
  • Ester Mainini
    • 1
  • Jorn Arnt
    • 2
  • Roberto W. Invernizzi
    • 1
  1. 1.Istituto di Ricerche Farmacologiche “Mario Negri”Laboratory of Neurochemistry and BehaviorMilanItaly
  2. 2.Lundbeck Research DKCopenhagenDenmark

Personalised recommendations