Psychopharmacology

, Volume 202, Issue 1–3, pp 315–328 | Cite as

Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors

  • Taku Nagai
  • Rina Murai
  • Kanae Matsui
  • Hiroyuki Kamei
  • Yukihiro Noda
  • Hiroshi Furukawa
  • Toshitaka Nabeshima
Original Investigation

Abstract

Rationale

Cognitive deficits, including memory impairment, are regarded as a core feature of schizophrenia. Aripiprazole, an atypical antipsychotic drug, has been shown to improve disruption of prepulse inhibition and social interaction in an animal model of schizophrenia induced by phencyclidine (PCP); however, the effects of aripiprazole on recognition memory remain to be investigated.

Objectives

In this study, we examined the effect of aripiprazole on cognitive impairment in mice treated with PCP repeatedly.

Materials and methods

Mice were repeatedly administered PCP at a dose of 10mg/kg for 14days, and their cognitive function was assessed using a novel-object recognition task. We investigated the therapeutic effects of aripiprazole (0.01–1.0mg/kg) and haloperidol (0.3 and 1.0mg/kg) on cognitive impairment in mice treated with PCP repeatedly.

Results

Single (1.0mg/kg) and repeated (0.03 and 0.1mg/kg, for 7days) treatment with aripiprazole ameliorated PCP-induced impairment of recognition memory, although single treatment significantly decreased the total exploration time during the training session. In contrast, both single and repeated treatment with haloperidol (0.3 and 1.0mg/kg) failed to attenuate PCP-induced cognitive impairment. The ameliorating effect of aripiprazole on recognition memory in PCP-treated mice was blocked by co-treatment with a dopamine D1 receptor antagonist, SCH23390, and a serotonin 5-HT1A receptor antagonist, WAY100635; however, co-treatment with a D2 receptor antagonist raclopride had no effect on the ameliorating effect of aripiprazole.

Conclusions

These results suggest that the ameliorative effect of aripiprazole on PCP-induced memory impairment is associated with dopamine D1 and serotonin 5-HT1A receptors.

Keywords

Aripiprazole Dopamine D1 receptor Memory Phencyclidine Serotonin 5-HT1A receptor 

Supplementary material

213_2008_1240_MOESM1_ESM.doc (54 kb)
ESM Supplemental Fig. 1Effect of single administrations of aripiprazole on PCP-induced cognitive impairment in novel object recognition. Eight days after withdrawal from repeated PCP (10 mg/kg, s.c., for 14 days) treatment, mice were subjected to the novel-object recognition test. Objects A and B were used in the training. Object B was replaced by object C in the retention session. Aripiprazole (0.01–1.0 mg/kg, p.o.) or vehicle (0.1% CMC) was administered 1 h before the training session. A paired comparisons test for each group comparing the time spent on objects in the training session (a) and retention session (b). Values indicate the mean ± S.E. (n = 8–16). **p < 0.01 compared with object A. (DOC 54.0 KB)

References

  1. Aggleton JP, Brown MW (1999) Episodic memory, amnesia, and the hippocampal–anterior thalamic axis. Behav Brain Sci 22:425–444PubMedGoogle Scholar
  2. Allen RM, Young SJ (1978) Phencyclidine-induced psychosis. Am J Psychiatry 135:1081–1084PubMedGoogle Scholar
  3. Bakshi VP, Swerdlow NR, Geyer MA (1994) Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. J Pharmacol Exp Ther 271:787–794PubMedGoogle Scholar
  4. Bantick RA, Deakin JF, Grasby PM (2001) The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics. J Psychopharmacol 15:37–46PubMedCrossRefGoogle Scholar
  5. Bortolozzi A, Díaz-Mataix L, Toth M, Celada P, Artigas F (2007) In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain. Psychopharmacology 191:745–758PubMedCrossRefGoogle Scholar
  6. Bruins Slot LA, Kleven MS, Newman-Tancredi A (2005) Effects of novel antipsychotics with mixed D2 antagonist/5-HT1A agonist properties on PCP-induced social interaction deficits in the rat. Neuropharmacology 49:996–1006PubMedCrossRefGoogle Scholar
  7. Burnet PW, Eastwood SL, Harrison PJ (1996) 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 15:442–455PubMedCrossRefGoogle Scholar
  8. Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB (2002) Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302:381–389PubMedCrossRefGoogle Scholar
  9. DeLeon A, Patel NC, Crismon ML (2004) Aripiprazole: a comprehensive review of its pharmacology, clinical efficacy, and tolerability. Clin Ther 26:649–666PubMedCrossRefGoogle Scholar
  10. Dias R, Robbins TW, Roberts AC (1996a) Dissociation in prefrontal cortex of affective and attentional shifts. Nature 380:69–72PubMedCrossRefGoogle Scholar
  11. Dias R, Robbins TW, Roberts AC (1996b) Primate analogue of the Wisconsin card sorting test: Effects of excitotoxic lesions of the prefrontal cortex in the marmoset. Behav Neurosci 110:872–886PubMedCrossRefGoogle Scholar
  12. Díaz-Mataix L, Scorza MC, Bortolozzi A, Toth M, Celada P, Artigas F (2005) Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action. J Neurosci 25:10831–10843PubMedCrossRefGoogle Scholar
  13. Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res 31:47–59PubMedCrossRefGoogle Scholar
  14. Enomoto T, Noda Y, Mouri A, Shin EJ, Wang D, Murai R, Hotta K, Furukawa H, Nitta A, Kim HC, Nabeshima T (2005) Long-lasting impairment of associative learning is correlated with a dysfunction of N-methyl-d-aspartate-extracellular signaling-regulated kinase signaling in mice after withdrawal from repeated administration of phencyclidine. Mol Pharmacol 68:1765–1774PubMedGoogle Scholar
  15. Fejgin K, Safonov S, Pålsson E, Wass C, Engel JA, Svensson L, Klamer D (2007) The atypical antipsychotic, aripiprazole, blocks phencyclidine-induced disruption of prepulse inhibition in mice. Psychopharmacology 191:377–385PubMedCrossRefGoogle Scholar
  16. 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
  17. Green B (2004) Focus on aripiprazole. Curr Med Res Opin 20:207–213PubMedCrossRefGoogle Scholar
  18. Gurevich EV, Joyce JN (1997) Alterations in the cortical serotonergic system in schizophrenia: a postmortem study. Biol Psychiatry 42:529–545PubMedCrossRefGoogle Scholar
  19. Hagiwara H, Fujita Y, Ishima T, Kunitachi S, Shirayama Y, Iyo M, Hashimoto K (2008) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone: role of serotonin 5-HT1A receptors. Eur Neuropsychopharmacol 18:448–454PubMedCrossRefGoogle Scholar
  20. Hashimoto K, Fujita Y, Shimizu E, Iyo M (2005) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of clozapine, but not haloperidol. Eur J Pharmacol 519:114–117PubMedCrossRefGoogle Scholar
  21. Hirose T, Kikuchi T (2005) Aripiprazole, a novel antipsychotic agent: dopamine D2 receptor partial agonist. J Med Invest 52:284–290PubMedCrossRefGoogle Scholar
  22. Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY (2001) 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 76:1521–1531PubMedCrossRefGoogle Scholar
  23. Inoue T, Domae M, Yamada K, Furukawa T (1996) Effects of the novel antipsychotic agent 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro -2(1H)-quinolinone (OPC-14597) on prolactin release from the rat anterior pituitary gland. J Pharmacol Exp Ther 277:137–143PubMedGoogle Scholar
  24. Ito M, Nagai T, Mizoguchi H, Fukakusa A, Nakanishi Y, Kamei H, Nabeshima T, Takuma K, Yamada K (2007a) Possible involvement of protease-activated receptor-1 in the regulation of morphine-induced dopamine release and hyperlocomotion by the tissue plasminogen activator-plasmin system. J Neurochem 101:1392–1399PubMedCrossRefGoogle Scholar
  25. Ito Y, Takuma K, Mizoguchi H, Nagai T, Yamada K (2007b) A novel azaindolizinone derivative ZSET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) improves methamphetamine-induced impairment of recognition memory in mice by activating extracellular signal-regulated kinase 1/2. J Pharmacol Exp Ther 320:819–827PubMedCrossRefGoogle Scholar
  26. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308PubMedGoogle Scholar
  27. Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA (2002) The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol 441:137–140PubMedCrossRefGoogle Scholar
  28. Joyce JN, Shane A, Lexow N, Winokur A, Casanova MF, Kleinman JE (1993) Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenia. Neuropsychopharmacol 8:315–336Google Scholar
  29. Kamei H, Nagai T, Nakano H, Togan Y, Takayanagi M, Takahashi K, Kobayashi K, Yoshida S, Maeda K, Takuma K, Nabeshima T, Yamada K (2006) Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice. Biol Psychiatry 59:75–84PubMedCrossRefGoogle Scholar
  30. Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000) Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157:514–520PubMedCrossRefGoogle Scholar
  31. 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, CATIE InvestigatorsNeurocognitive Working Group (2007) Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 64:633–647PubMedCrossRefGoogle Scholar
  32. Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, Morita S (1995) 7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther 274:329–336PubMedGoogle Scholar
  33. Lerner SE, Burns RS (1986) Legal issues associated with PCP abuse-the role of the forensic expert. NIDA Res Monogr 64:229–236PubMedGoogle Scholar
  34. Li Z, Ichikawa J, Dai J, Meltzer HY (2004) Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain. Eur J Pharmacol 493:75–83PubMedCrossRefGoogle Scholar
  35. Lopez-Figueroa AL, Norton CS, Lopez-Figueroa MO, Armellini-Dodel D, Burke S, Akil H, Lopez JF, Watson SJ (2004) Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry 55:225–233PubMedCrossRefGoogle Scholar
  36. Maddox VH, Godefroi EF, Parcell RF (1965) The synthesis of phencyclidine and other 1-arylcyclohexylamines. J Med Chem 56:230–235CrossRefGoogle Scholar
  37. McQuade RD, Burris KD, Jordan S, Tottori K, Kurahashi N, Kikuchi T (2002) Aripiprazole: a dopamine–serotonin system stabilizer. Int Neuropsychopharmacol 5(Suppl. 1):S176Google Scholar
  38. Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacol 21:106S–115SGoogle Scholar
  39. Mishara AL, Goldberg TE (2004) A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol Psychiatry 55:1013–1022PubMedCrossRefGoogle Scholar
  40. Mouri A, Noda Y, Enomoto T, Nabeshima T (2007a) Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment. Neurochem Int 51:173–184PubMedCrossRefGoogle Scholar
  41. Mouri A, Noda Y, Noda A, Nakamura T, Tokura T, Yura Y, Nitta A, Furukawa H, Nabeshima T (2007b) Involvement of a dysfunctional dopamine-D1/N-methyl-d-aspartate-NR1 and Ca2+/calmodulin-dependent protein kinase II pathway in the impairment of latent learning in a model of schizophrenia induced by phencyclidine. Mol Pharmacol 71:1598–1609PubMedCrossRefGoogle Scholar
  42. Murai R, Noda Y, Matsui K, Kamei H, Mouri A, Matsuba K, Nitta A, Furukawa H, Nabeshima T (2007) Hypofunctional glutamatergic neurotransmission in the prefrontal cortex is involved in the emotional deficit induced by repeated treatment with phencyclidine in mice: implications for abnormalities of glutamate release and NMDA-CaMKII signaling. Behav Brain Res 180:152–160PubMedCrossRefGoogle Scholar
  43. Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y, Nabeshima T (2003) Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 17:50–52PubMedGoogle Scholar
  44. Nagai T, Takuma K, Kamei H, Ito Y, Nakamichi N, Ibi D, Nakanishi Y, Murai M, Mizoguchi H, Nabeshima T, Yamada K (2007) Dopamine D1 receptors regulate protein synthesis-dependent long-term recognition memory via extracellular signal-regulated kinase 1/2 in the prefrontal cortex. Learn Mem 14:117–125PubMedCrossRefGoogle Scholar
  45. Newcomer JW (2005) Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 19(Suppl 1):1–93PubMedGoogle Scholar
  46. Newman-Tancredi A, Verriele L, Touzard M, Millan MJ (2001) Efficacy of antipsychotic agents at human 5-HT1A receptors determined by [3H]WAY100,635 binding affinity ratios: relationship to efficacy for G-protein activation. Eur J Pharmacol 428:177–184PubMedCrossRefGoogle Scholar
  47. Noda Y, Yamada K, Furukawa H, Nabeshima T (1995) Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia. Br J Pharmacol 116:2531–2537PubMedGoogle Scholar
  48. Noda Y, Mamiya T, Furukawa H, Nabeshima T (1997) Effects of antidepressants on phencyclidine-induced enhancement of immobility in a forced swimming test in mice. Eur J Pharmacol 324:135–140PubMedCrossRefGoogle Scholar
  49. 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
  50. Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK (2004) Identification of separable cognitive factors in schizophrenia. Schizophr Res 72:29–39PubMedCrossRefGoogle Scholar
  51. Pearlson GD (2000) Neurobiology of schizophrenia. Ann Neurol 48:556–566PubMedCrossRefGoogle Scholar
  52. Qiao H, Noda Y, Kamei H, Nagai T, Furukawa H, Miura H, Kayukawa Y, Ohta T, Nabeshima T (2001) Clozapine, but not haloperidol, reverses social behavior deficit in mice during withdrawal from chronic phencyclidine treatment. Neuroreport 12:11–15PubMedCrossRefGoogle Scholar
  53. Rainey Jr JM, Crowder MK (1975) Prolonged psychosis attributed to phencyclidine: report of three cases. Am J Psychiatry 132:1076–1078Google Scholar
  54. Rivas-Vasquez RA (2003) Aripiprazole: a novel antipsychotic with dopamine-stabilising properties. Prof Psychol: Res Prac 34:108–111CrossRefGoogle Scholar
  55. Rollema H, Lu Y, Schmidt AW, Sprouse JS, Zorn SH (2000) 5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Biol Psychiatry 48:229–237PubMedCrossRefGoogle Scholar
  56. Rössler W, Salize HJ, van Os J, Riecher-Rössler A (2005) Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol 15:399–409PubMedCrossRefGoogle Scholar
  57. Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950PubMedCrossRefGoogle Scholar
  58. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R (2003) Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 28:1400–1411PubMedCrossRefGoogle Scholar
  59. Shimokawa Y, Akiyama H, Kashiyama E, Koga T, Miyamoto G (2005) High performance liquid chromatographic methods for the determination of aripiprazole with ultraviolet detection in rat plasma and brain: application to the pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 821:8–14PubMedCrossRefGoogle Scholar
  60. Sprouse JS, Reynolds LS, Braselton JP, Rollema H, Zorn SH (1999) Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation. Neuropsychopharmacol 21:622–631CrossRefGoogle Scholar
  61. Stark AD, Jordan S, Allers KA, Bertekap RL, Chen R, Mistry Kannan T, Molski TF, Yocca FD, Sharp T, Kikuchi T, Burris KD (2007) Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT 2A receptors: functional receptor-binding and in vivo electrophysiological studies. Psychopharmacology 190:373–382PubMedCrossRefGoogle Scholar
  62. Sumiyoshi T, Matsui M, Nohara S, Yamashita I, Kurachi M, Sumiyoshi C, Jayathilake K, Meltzer HY (2001a) Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am J Psychiatry 158:1722–1725PubMedCrossRefGoogle Scholar
  63. Sumiyoshi T, Matsui M, Yamashita I, Nohara S, Kurachi M, Uehara T, Sumiyoshi S, Sumiyoshi C, Meltzer HY (2001b) The effect of tandospirone, a serotonin-1A agonist, on memory function in schizophrenia. Biol Psychiatry 49:861–868PubMedCrossRefGoogle Scholar
  64. Tamminga CA (2002) Partial dopamine agonists in the treatment of psychosis. J Neural Transm 109:411–420PubMedCrossRefGoogle Scholar
  65. Tamminga CA (2006) The neurobiology of cognition in schizophrenia. J Clin Psychiatry 67:9–13PubMedCrossRefGoogle Scholar
  66. Tan HY, Callicott JH, Weinberger DR (2007) Dysfunctional and compensatory prefrontal cortical systems, genes and the pathogenesis of schizophrenia. Cereb Cortex 17:i171–i181PubMedCrossRefGoogle Scholar
  67. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ (1999) Genetic enhancement of learning and memory in mice. Nature 401:63–69PubMedCrossRefGoogle Scholar
  68. Vincent SL, Khan Y, Benes FM (1995) Cellular colocalization of dopamine D1 and D2 receptors in rat medial prefrontal cortex. Synapse 19:112–120PubMedCrossRefGoogle Scholar
  69. Woodward ND, Purdon SE, Meltzer HY, Zald DH (2005) A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol 8:457–472PubMedCrossRefGoogle Scholar
  70. Zocchi A, Fabbri D, Heidbreder CA (2005) Aripiprazole increases dopamine but not noradrenaline and serotonin levels in the mouse prefrontal cortex. Neurosci Lett 387:157–161PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Taku Nagai
    • 1
  • Rina Murai
    • 2
  • Kanae Matsui
    • 3
  • Hiroyuki Kamei
    • 3
  • Yukihiro Noda
    • 4
  • Hiroshi Furukawa
    • 5
  • Toshitaka Nabeshima
    • 1
    • 2
  1. 1.Department of Neuropsychopharmacology and Hospital PharmacyNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Department of Chemical Pharmacology, Graduate School of Pharmaceutical SciencesMeijo UniversityNagoyaJapan
  3. 3.Department of Health-Care Pharmacy, Graduate School of Pharmaceutical SciencesMeijo UniversityNagoyaJapan
  4. 4.Division of Clinical Science in Clinical Pharmacy Practice, Graduate School of Pharmaceutical SciencesMeijo UniversityNagoyaJapan
  5. 5.Department of Medical Chemistry, Graduate School of Pharmaceutical SciencesMeijo UniversityNagoyaJapan

Personalised recommendations