Psychopharmacology

, Volume 206, Issue 1, pp 39–49

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

Original Investigation

Abstract

Rationale

Second-generation antipsychotics have some beneficial effect on cognition. Recent studies, furthermore, indicate differential effects of second-generation antipsychotics on impairment in executive cognitive function.

Objective

We evaluated the effect of the second-generation antipsychotic drug, sertindole, on extracellular levels of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in the rat medial prefrontal cortex (mPFC). Risperidone was studied for comparison. Moreover, selective serotonin 5-HT2A, 5-HT2C, and 5-HT6 receptor antagonists were used, given alone and in combination with the preferential DA D2 receptor antagonist, haloperidol, to further clarify the action of the two drugs.

Materials and methods

Rats were treated acutely with vehicle or drugs, and extracellular levels of neurotransmitters were assessed by microdialysis in freely moving animals.

Results

Sertindole and risperidone significantly increased extracellular levels of DA. Haloperidol; the 5-HT2A receptor antagonist, M100907; the 5-HT2C receptor antagonist, SB242084; and the 5-HT6 receptor antagonist, GSK-742457, induced minor increases in levels of DA, but the three latter compounds raised the DA levels notably in combination with haloperidol. Sertindole and risperidone significantly increased the extracellular levels of ACh but only sertindole raised the extracellular levels of Glu. The selective 5-HT6 receptor antagonist, SB-271046, significantly increased the extracellular levels of Glu.

Conclusion

Sertindole and risperidone markedly increased extracellular levels of DA in mPFC. The built-in 5-HT2A/5-HT2C/D2 receptor antagonism of the two drugs might be involved in this action. Both drugs increased the extracellular levels of ACh but only sertindole enhanced Glu levels. The high affinity of sertindole for the 5-HT6 receptor compared to risperidone may differentiate sertindole from risperidone.

Keywords

Schizophrenia Sertindole Risperidone Haloperidol Dopamine Acetylcholine Glutamate Rat medial prefrontal cortex Antipsychotic Microdialysis 

References

  1. Abdul-Monim Z, Neill JC, Reynolds GP (2007) Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat. J Psychopharmacol 21:198–205PubMedCrossRefGoogle Scholar
  2. Abi-Dargham A, Moore H (2003) Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. Neuroscientist 9:404–416PubMedCrossRefGoogle Scholar
  3. Adams BW, Moghaddam B (2001) Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex. Biol Psychiatry 50:750–757PubMedCrossRefGoogle Scholar
  4. Ago Y, Nakamura S, Baba A, Matsuda T (2005) Sulpiride in combination with fluvoxamine increases in vivo dopamine release selectively in rat prefrontal cortex. Neuropsychopharmacology 30:43–51PubMedCrossRefGoogle Scholar
  5. Arai AC, Kessler M (2007) Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior. Curr Drug Targets 8:583–602PubMedCrossRefGoogle Scholar
  6. Arnt J, Skarsfeldt T (1998) Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18:63–101PubMedCrossRefGoogle Scholar
  7. Arvanov VL, Wang RY (1999) Clozapine, but not haloperidol, prevents the functional hyperactivity of N-methyl-d-aspartate receptors in rat cortical neurons induced by subchronic administration of phencyclidine. J Pharmacol Exp Ther 289:1000–1006PubMedGoogle Scholar
  8. Assie MB, Ravailhe V, Faucillon V, Newman-Tancredi A (2005) Contrasting contribution of 5-hydroxytryptamine 1A receptor activation to neurochemical profile of novel antipsychotics: frontocortical dopamine and hippocampal serotonin release in rat brain. J Pharmacol Exp Ther 315:265–272PubMedCrossRefGoogle Scholar
  9. Azorin JM, Strub N, Loft H (2006) A double-blind, controlled study of sertindole versus risperidone in the treatment of moderate-to-severe schizophrenia. Int Clin Psychopharmacol 21:49–56PubMedCrossRefGoogle Scholar
  10. Benveniste H (2009) Glutamate, microdialysis, and cerebral ischemia: lost in translation? Anesthesiology 110:422–425PubMedGoogle Scholar
  11. Bogen IL, Risa O, Haug KH, Sonnewald U, Fonnum F, Walaas SI (2008) Distinct changes in neuronal and astrocytic amino acid neurotransmitter metabolism in mice with reduced numbers of synaptic vesicles. J Neurochem (in press)Google Scholar
  12. Bortolozzi A, az-Mataix L, Scorza MC, Celada P, Artigas F (2005) The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem 95:1597–1607PubMedCrossRefGoogle Scholar
  13. Bortolozzi A, Az-Mataix L, Toth M, Celada P, Artigas F (2007) In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain. Psychopharmacology (Berl) 191:745–758CrossRefGoogle Scholar
  14. Brooks JM, Sarter M, Bruno JP (2007) D2-like receptors in nucleus accumbens negatively modulate acetylcholine release in prefrontal cortex. Neuropharmacology 53:455–463PubMedCrossRefGoogle Scholar
  15. Bubar MJ, Cunningham KA (2007) Distribution of serotonin 5-HT2C receptors in the ventral tegmental area. Neuroscience 146:286–297PubMedCrossRefGoogle Scholar
  16. Cochran SM, Kennedy M, McKerchar CE, Steward LJ, Pratt JA, Morris BJ (2003) Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. Neuropsychopharmacology 28:265–275PubMedCrossRefGoogle Scholar
  17. 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 409:187–209PubMedCrossRefGoogle Scholar
  18. Dawson LA, Nguyen HQ, Li P (2000) In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate. Br J Pharmacol 130:23–26PubMedCrossRefGoogle Scholar
  19. Dawson LA, Nguyen HQ, Li P (2001) The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology 25:662–668PubMedCrossRefGoogle Scholar
  20. Devoto P, Flore G, Pira L, Longu G, Gessa GL (2004) Alpha2-adrenoceptor mediated co-release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex. J Neurochem 88:1003–1009PubMedGoogle Scholar
  21. 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
  22. Dijk SN, Francis PT, Stratmann GC, Bowen DM (1995a) NMDA-induced glutamate and aspartate release from rat cortical pyramidal neurones: evidence for modulation by a 5-HT1A antagonist. Br J Pharmacol 115:1169–1174Google Scholar
  23. Dijk SN, Francis PT, Stratmann GC, Bowen DM (1995b) Cholinomimetics increase glutamate outflow via an action on the corticostriatal pathway: implications for Alzheimer's disease. J Neurochem 65:2165–2169Google Scholar
  24. Dohmen C, Kumura E, Rosner G, Heiss WD, Graf R (2005) Extracellular correlates of glutamate toxicity in short-term cerebral ischemia and reperfusion: a direct in vivo comparison between white and gray matter. Brain Res 1037:43–51PubMedCrossRefGoogle Scholar
  25. Enomoto T, Noda Y, Nabeshima T (2007) Phencyclidine and genetic animal models of schizophrenia developed in relation to the glutamate hypothesis. Methods Find Exp Clin Pharmacol 29:291–301PubMedCrossRefGoogle Scholar
  26. Fonnum F (1984) Glutamate: a neurotransmitter in mammalian brain. J Neurochem 42:1–11PubMedCrossRefGoogle Scholar
  27. Frantz K, Harte M, Ungerstedt U, O'Connor WT (2002) A dual probe characterization of dialysate amino acid levels in the medial prefrontal cortex and ventral tegmental area of the awake freely moving rat. J Neurosci Methods 119:109–119PubMedCrossRefGoogle Scholar
  28. 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 36:205–221PubMedCrossRefGoogle Scholar
  29. Goetghebeur P, Dias R (2009) Comparison of haloperidol, risperidone, sertindole, and modafinil to reverse an attentional set-shifting impairment following subchronic PCP administration in the rat-a back translational study. Psychopharmacology (Berl) 202:287–293CrossRefGoogle Scholar
  30. Gray JA, Roth BL (2007) Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr Bull 33:1100–1119PubMedCrossRefGoogle Scholar
  31. Grayson B, Idris NF, Neill JC (2007) Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. Behav Brain Res 184:31–38PubMedCrossRefGoogle Scholar
  32. Hajszan T, Leranth C, Roth RH (2006) Subchronic phencyclidine treatment decreases the number of dendritic spine synapses in the rat prefrontal cortex. Biol Psychiatry 60:639–644PubMedCrossRefGoogle Scholar
  33. Herrera-Marschitz M, You ZB, Goiny M, Meana JJ, Silveira R, Godukhin OV, Chen Y, Espinoza S, Pettersson E, Loidl CF, Lubec G, Andersson K, Nylander I, Terenius L, Ungerstedt U (1996) On the origin of extracellular glutamate levels monitored in the basal ganglia of the rat by in vivo microdialysis. J Neurochem 66:1726–1735PubMedCrossRefGoogle Scholar
  34. Hirst WD, Stean TO, Rogers DC, Sunter D, Pugh P, Moss SF, Bromidge SM, Riley G, Smith DR, Bartlett S, Heidbreder CA, Atkins AR, Lacroix LP, Dawson LA, Foley AG, Regan CM, Upton N (2006) SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models. Eur J Pharmacol 553:109–119PubMedCrossRefGoogle Scholar
  35. Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O'Laughlin IA, Meltzer HY (2001) 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 76:1521–1531PubMedCrossRefGoogle Scholar
  36. Ichikawa J, Dai J, Meltzer HY (2002a) 5-HT(1A) and 5-HT(2A) receptors minimally contribute to clozapine-induced acetylcholine release in rat medial prefrontal cortex. Brain Res 939:34–42Google Scholar
  37. Ichikawa J, Dai J, O'Laughlin IA, Fowler WL, Meltzer HY (2002b) Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum. Neuropsychopharmacology 26:325–339CrossRefGoogle Scholar
  38. Ichikawa J, Li Z, Dai J, Meltzer HY (2002c) Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT1A receptor agonism. Brain Res 956:349–357CrossRefGoogle Scholar
  39. Jakab RL, Goldman-Rakic PS (2000) Segregation of serotonin 5-HT2A and 5-HT3 receptors in inhibitory circuits of the primate cerebral cortex. J Comp Neurol 417:337–348PubMedCrossRefGoogle Scholar
  40. Javitt DC (2007) Glutamate and schizophrenia: phencyclidine, N-methyl-d-aspartate receptors, and dopamine–glutamate interactions. Int Rev Neurobiol 78:69–108PubMedCrossRefGoogle Scholar
  41. Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225PubMedCrossRefGoogle Scholar
  42. Krivoy A, Fischel T, Weizman A (2008) The possible involvement of metabotropic glutamate receptors in schizophrenia. Eur Neuropsychopharmacol 18:395–405PubMedCrossRefGoogle Scholar
  43. 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 288:774–781PubMedGoogle Scholar
  44. Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (2004) 5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex. Synapse 51:158–164PubMedCrossRefGoogle Scholar
  45. Lammel S, Hetzel A, Hackel O, Jones I, Liss B, Roeper J (2008) Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57:760–773PubMedCrossRefGoogle Scholar
  46. Leysen J (2000) Receptor profile of antipsychotics. In: Ellenbroek BA, Cools AR (eds) Atypical antipsychotics. Birkhäuser, Basel, Switzerland, pp 57–81Google Scholar
  47. Li Z, Ichikawa J, Huang M, Prus AJ, Dai J, Meltzer HY (2005) ACP-103, a 5-HT2A/2C inverse agonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Psychopharmacology (Berl) 183:144–153CrossRefGoogle Scholar
  48. Li Z, Huang M, Prus AJ, Dai J, Meltzer HY (2007) 5-HT6 receptor antagonist SB-399885 potentiates haloperidol and risperidone-induced dopamine efflux in the medial prefrontal cortex or hippocampus. Brain Res 1134:70–78PubMedCrossRefGoogle Scholar
  49. Liegeois JF, Ichikawa J, Meltzer HY (2002) 5-HT(2A) receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner. Brain Res 947:157–165PubMedCrossRefGoogle Scholar
  50. Lopez-Gil X, Babot Z, Margos-Bosch M, Sunol C, Artigas F, Adell A (2007) Clozapine and haloperidol differently suppress the MK-801-increased glutamatergic and serotonergic transmission in the medial prefrontal cortex of the rat. Neuropsychopharmacology 32:2087–2097PubMedCrossRefGoogle Scholar
  51. 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 320:486–496PubMedCrossRefGoogle Scholar
  52. Meltzer HY, McGurk SR (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25:233–255PubMedGoogle Scholar
  53. Moor E, Schirm E, Jacso J, Westerink BH (1998) Effects of neostigmine and atropine on basal and handling-induced acetylcholine output from ventral hippocampus. Neuroscience 82:819–825PubMedCrossRefGoogle Scholar
  54. Noda Y, Kamei H, Mamiya T, Furukawa H, Nabeshima T (2000) Repeated phencyclidine treatment induces negative symptom-like behavior in forced swimming test in mice: imbalance of prefrontal serotonergic and dopaminergic functions. Neuropsychopharmacology 23:375–387PubMedCrossRefGoogle Scholar
  55. O'Grada C, Dinan T (2007) Executive function in schizophrenia: what impact do antipsychotics have? Hum Psychopharmacol 22:397–406PubMedCrossRefGoogle Scholar
  56. 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
  57. Parikh V, Man K, Decker MW, Sarter M (2008) Glutamatergic contributions to nicotinic acetylcholine receptor agonist-evoked cholinergic transients in the prefrontal cortex. J Neurosci 28:3769–3780PubMedCrossRefGoogle Scholar
  58. Paxinos G, Watson C (1998) The rat brain in sterotaxic coordinates. Academic, San DiegoGoogle Scholar
  59. Pozzi L, Acconcia S, Ceglia I, Invernizzi RW, Samanin R (2002) Stimulation of 5-hydroxytryptamine (5-HT(2C)) receptors in the ventrotegmental area inhibits stress-induced but not basal dopamine release in the rat prefrontal cortex. J Neurochem 82:93–100PubMedCrossRefGoogle Scholar
  60. Pratt JA, Winchester C, Egerton A, Cochran SM, Morris BJ (2008) Modelling prefrontal cortex deficits in schizophrenia: implications for treatment. Br J Pharmacol 153(Suppl 1):S465–S470PubMedCrossRefGoogle Scholar
  61. Remington G, Kapur S (2000) Atypical antipsychotics: are some more atypical than others? Psychopharmacology (Berl) 148:3–15CrossRefGoogle Scholar
  62. Riemer C, Borroni E, Levet-Trafit B, Martin JR, Poli S, Porter RH, Bos M (2003) Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl) phenylamine, a potent and selective 5-HT6 receptor antagonist. J Med Chem 46:1273–1276PubMedCrossRefGoogle Scholar
  63. 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-HT(6) receptor antagonist: comparison among antipsychotics. Neuropsychopharmacology 33:2657–2666PubMedCrossRefGoogle Scholar
  64. Routledge C, Bromidge SM, Moss SF, Price GW, Hirst W, Newman H, Riley G, Gager T, Stean T, Upton N, Clarke SE, Brown AM, Middlemiss DN (2000) Characterization of SB-271046: a potent, selective and orally active 5-HT(6) receptor antagonist. Br J Pharmacol 130:1606–1612PubMedCrossRefGoogle Scholar
  65. 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 273:273–279PubMedCrossRefGoogle Scholar
  66. Schousboe A, Waagepetersen HS (2006) Glial modulation of GABAergic and glutamatergic neurotransmission. Curr Top Med Chem 6:929–934PubMedCrossRefGoogle Scholar
  67. Shirazi-Southall S, Rodriguez DE, Nomikos GG (2002) Effects of typical and atypical antipsychotics and receptor selective compounds on acetylcholine efflux in the hippocampus of the rat. Neuropsychopharmacology 26:583–594PubMedCrossRefGoogle Scholar
  68. Stone JM, Morrison PD, Pilowsky LS (2007) Glutamate and dopamine dysregulation in schizophrenia—a synthesis and selective review. J Psychopharmacol 21:440–452PubMedCrossRefGoogle Scholar
  69. Talbot PS, Laruelle M (2002) The role of in vivo molecular imaging with PET and SPECT in the elucidation of psychiatric drug action and new drug development. Eur Neuropsychopharmacol 12:503–511PubMedCrossRefGoogle Scholar
  70. Tan HY, Callicott JH, Weinberger DR (2007) Dysfunctional and compensatory prefrontal cortical systems, genes and the pathogenesis of schizophrenia. Cereb Cortex 17(Suppl 1):i171–i181PubMedCrossRefGoogle Scholar
  71. Upton N, Chuang TT, Hunter AJ, Virley DJ (2008) 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics 5:458–469PubMedCrossRefGoogle Scholar
  72. van der Zeyden M, Oldenziel WH, Rea K, Cremers TI, Westerink BH (2008) Microdialysis of GABA and glutamate: analysis, interpretation and comparison with microsensors. Pharmacol Biochem Behav 90:135–147PubMedCrossRefGoogle Scholar
  73. Westerink BH, De Vries JB (1989) On the mechanism of neuroleptic induced increase in striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals. Neurosci Lett 99:197–202PubMedCrossRefGoogle Scholar
  74. Wood MD, Scott C, Clarke K, Cato KJ, Patel N, Heath J, Worby A, Gordon L, Campbell L, Riley G, Davies CH, Gribble A, Jones DN (2006) Pharmacological profile of antipsychotics at monoamine receptors: atypicality beyond 5-HT2A receptor blockade. CNS Neurol Disord Drug Targets 5:445–452PubMedCrossRefGoogle Scholar
  75. Zuo DY, Zhang YH, Cao Y, Wu CF, Tanaka M, Wu YL (2006) Effect of acute and chronic MK-801 administration on extracellular glutamate and ascorbic acid release in the prefrontal cortex of freely moving mice on line with open-field behavior. Life Sci 78:2172–2178PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of NeurophysiologyDiscovery Pharmacology ResearchValbyDenmark
  2. 2.Lundbeck Research DKValbyDenmark

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