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Psychopharmacology

, Volume 184, Issue 2, pp 190–200 | Cite as

Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function

  • Gary E. Duncan
  • Sheryl S. Moy
  • Jeffery A. Lieberman
  • Beverly H. Koller
Original Investigation

Abstract

Rationale

Reduced N-methyl d-aspartate (NMDA) receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor. These mice show increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle.

Objectives

The present study tested the hypothesis that these altered acoustic startle responses in the NR1 hypomorphic (NR1−/−) mice would be affected by antipsychotic drug treatment.

Methods

Mice were injected with drugs 30 min before assessment of acoustic startle responses with and without prepulse stimuli.

Results

Haloperidol (0.5 or 1.0 mg/kg) did not reduce the increased startle reactivity in the NR1−/− mice, but did increase PPI in both the mutant and wild type mice. Clozapine (3 mg/kg) and quetiapine (20 mg/kg) reduced startle magnitude and increased PPI in both the wild type and mutant mice. The antidepressant drug imipramine (10 and 20 mg/kg) had minimal effects on startle amplitude in NR1−/− or wild type mice. However, for the 20-mg/kg dose of imipramine, a significant increase in PPI was observed in the wild type animals, but not in the mutant mice.

Conclusions

The results demonstrate that PPI can be increased in a mouse model of chronic NMDA receptor hypofunction by typical and atypical antipsychotic drugs. The similar effects of typical and atypical antipsychotic drugs to increase PPI in the wild type and mutant mice indicates that the assessment of behavior of the NR1 hypomorphic mice in the PPI paradigm offers no advantage over the wild type controls for identifying new clozapine-like drugs.

Keywords

Acoustic startle Antipsychotic NMDA receptor Mouse model Prepulse inhibition Schizophrenia 

Notes

Acknowledgements

This research was supported by MH063398, the UNC Neurodevelopmental Disorders Research Center (HD03110), the UNC Silvio O. Conte Center for the Neuroscience of Mental Disorders (MH064065), and was given a grant from the Investigator Sponsored Studies Program of AstraZeneca.

References

  1. Acri JB, Morse DE, Popke EJ, Grunberg NE (1994) Nicotine increases sensory gating measured as inhibition of the acoustic startle reflex in rats. Psychopharmacology 114:369–374CrossRefPubMedGoogle Scholar
  2. Angrist B, Rotrosen J, Gershon S (1980) Responses to apomorphine, amphetamine, and neuroleptics in schizophrenic subjects. Psychopharmacology 67:31–38CrossRefPubMedGoogle Scholar
  3. Arvanov VL, Liang X, Schwartz J, Grossman S, Wang RY (1997) Clozapine and haloperidol modulate N-methyl-d-aspartate- and non-N-methyl-d-aspartate receptor-mediated neurotransmission in rat prefrontal cortical neurons in vitro. J Pharmacol Exp Ther 283:226–234PubMedGoogle Scholar
  4. 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
  5. Bai F, Li X, Clay M, Lindstrom T, Skolnick P (2001) Intra- and interstrain differences in models of "behavioral despair". Pharmacol Biochem Behav 70:187–192CrossRefPubMedGoogle Scholar
  6. Bakshi VP, Geyer MA (1995) Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. Psychopharmacology 122:198–201CrossRefPubMedGoogle Scholar
  7. 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
  8. Ballard TM, Pauly-Evers M, Higgins GA, Ouagazzal AM, Mutel V, Borroni E, Kemp JA, Bluethmann H, Kew JNC (2002) Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity. J Neurosci 22:6713–6723PubMedGoogle Scholar
  9. Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology 156:234–258CrossRefPubMedGoogle Scholar
  10. Brody SA, Conquet F, Geyer MA (2003) Disruption of prepulse inhibition in mice lacking mGluR1. Eur J Neurosci 18:3361–3366CrossRefPubMedGoogle Scholar
  11. Brody SA, Conquet F, Geyer MA (2004) Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice. Psychopharmacology 172:187–195CrossRefPubMedGoogle Scholar
  12. Cohen BD, Rosenbaum G, Luby ED, Gottlieb JS (1962) Comparison of phencyclidine hydrochloride (sernyl) with other drugs: simulation of schizophrenic performance with phencyclidine hydrochloride (sernyl) lysergic acid diethylamide (LSD-25), and amobarbital (Amytal) sodium, II — symbolic and sequential thinking. Arch Gen Psychiatry 6:79–85Google Scholar
  13. Corbett R, Camacho F, Woods AT, Kerman LL, Fishkin RJ, Brooks K, Dunn RW (1995) Antipsychotic agents antagonize non-competitive N-methyl-d-aspartate antagonist-induced behaviors. Psychopharmacology 120:67–74CrossRefPubMedGoogle Scholar
  14. David DJP, Renard CE, Jolliet P, Hascoet M, Bourin M (2003) Antidepressant-like effects in various mice strains in the forced swimming test. Psychopharmacology 166:373–382PubMedGoogle Scholar
  15. Duncan GE, Leipzig JN, Mailman RB, Lieberman JA (1998) Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation. Brain Res 812:65–75CrossRefPubMedGoogle Scholar
  16. Duncan GE, Miyamoto S, Gu HB, Lieberman JA, Koller BH, Snouwaert JN (2002) Alterations in regional brain metabolism in genetic and pharmacological models of reduced NMDA receptor function. Brain Res 951:166–176CrossRefPubMedGoogle Scholar
  17. Duncan GE, Miyamoto S, Leipzig JN, Lieberman JA (2000) Comparison of the effects of clozapine, risperidone, and olanzapine on ketamine-induced alterations in regional brain metabolism. J Pharmacol Exp Ther 293:8–14PubMedGoogle Scholar
  18. Duncan GE, Moy SS, Perez A, Eddy DM, Zinzow WM, Lieberman JA, Snouwaert JN, Koller BH (2004) Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res 153:507–519CrossRefPubMedGoogle Scholar
  19. Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology 156:117–154CrossRefPubMedGoogle Scholar
  20. Goff DC, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld DA, Hayden DL, McCarley R, Coyle JT (1999) A placebo-controlled trial of d-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 56:21–27CrossRefPubMedGoogle Scholar
  21. Goff DC, Tsai G, Manoach DS, Coyle JT (1995) Dose-finding trial of d-cycloserine added to neuroleptics for negative symptoms in schizophrenia. Am J Psychiatry 152:1213–1215PubMedGoogle Scholar
  22. Heresco-Levy U, Ermilov M, Shimoni J, Shapira B, Silipo G, Javitt DC (2002) Placebo-controlled trial of d-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. Am J Psychiatry 159:480–482CrossRefPubMedGoogle Scholar
  23. Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Horowitz A, Kelly D (1996) Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry 169:610–617PubMedCrossRefGoogle Scholar
  24. Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M (1999) Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 56:29–36CrossRefPubMedGoogle Scholar
  25. Javitt DC, Zylberman I, Zukin SR, Heresco-Levy U, Lindenmayer JP (1994) Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 151:1234–1236PubMedGoogle Scholar
  26. Keith VA, Mansbach RS, Geyer MA (1991) Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle. Biol Psychiatry 30:557–566CrossRefPubMedGoogle Scholar
  27. 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
  28. Lahti AC, Holcomb HH, Medoff DR, Tamminga CA (1995a) Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport 6:869–872PubMedCrossRefGoogle Scholar
  29. Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995b) Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19CrossRefPubMedGoogle Scholar
  30. Lahti AC, Weiler MA, Tamara MB, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467CrossRefPubMedGoogle Scholar
  31. Leeson PD, Iversen LL (1994) The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. J Med Chem 37:4053–4067CrossRefPubMedGoogle Scholar
  32. Lieberman JA, Kane JM, Alvir JAJ (1987) Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology 91:415–433CrossRefPubMedGoogle Scholar
  33. Lipina T, Labrie V, Weiner I, Roder J (2005) Modulators of the glycine site on NMDA receptors, d-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. Psychopharmacology 179:54–67CrossRefPubMedGoogle Scholar
  34. Luby ED, Cohen BD, Rosenbaum G, Gottilieb JS, Kelley R (1959) Study of a new schizophrenomimetic drug-sernyl. Arch Neurol Psych 81:363–369Google Scholar
  35. 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 17:141–150CrossRefPubMedGoogle Scholar
  36. Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier A (1996) NMDA receptor function and human cognition — the effects of ketamine in healthy volunteers. Neuropsychopharmacology 14:301–307CrossRefPubMedGoogle Scholar
  37. Mansbach RS, Carver J, Zorn SH (2001) Blockade of drug-induced deficits in prepulse inhibition of acoustic startle by ziprasidone. Pharmacol Biochem Behav 69:535–542CrossRefPubMedGoogle Scholar
  38. McCaughran J, Mahjubi E, Decena E, Hitzemann R (1997) Genetics, haloperidol induced catalepsy and haloperidol-induced changes in acoustic startle and prepulse inhibition. Psychopharmacology 134:131–139CrossRefPubMedGoogle Scholar
  39. Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T (2001) Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor epsilon 1 subunit. J Neurosci 21:750–757PubMedGoogle Scholar
  40. Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98:427–436CrossRefPubMedGoogle Scholar
  41. Olivier B, Leahy C, Mullen T, Paylor R, Groppi VE, Sarnyai Z, Brunner D (2001) The DBA/2J strain and prepulse inhibition of startle: a model system to test antipsychotics? Psychopharmacology 156:284–290CrossRefPubMedGoogle Scholar
  42. Ouagazzal AM, Jenck F, Moreau JL (2001) Drug-induced potentiation of prepulse inhibition of acoustic startle reflex in mice: a model for detecting antipsychotic activity? Psychopharmacology 156:273–283CrossRefPubMedGoogle Scholar
  43. Paylor R, Crawley JN (1997) Inbred strain differences in prepulse inhibition of the mouse startle response. Psychopharmacology 132:169–180CrossRefPubMedGoogle Scholar
  44. Schreiber R, Dalmus M, De Vry J (2002) Effects of alpha(4)/beta(2)- and alpha(7)-nicotine acetylcholine receptor agonists on prepulse inhibition of the acoustic startle response in rats and mice. Psychopharmacology 159:248–257CrossRefPubMedGoogle Scholar
  45. Simon VM, Parra A, Minarro J, Arenas MC, Vinader-Caerols C, Aguilar MA (2000) Predicting how equipotent doses of chlorpromazine, haloperidol, sulpiride, raclopride and clozapine reduce locomotor activity in mice. Eur Neuropsychopharmacol 10:159–164CrossRefPubMedGoogle Scholar
  46. Swerdlow NR, Bakshi V, Waikar M, Taaid N, Geyer MA (1998) Seroquel, clozapine and chlorpromazine restore sensorimotor gating in ketamine-treated rats. Psychopharmacologia 140:75–80CrossRefGoogle Scholar
  47. Swerdlow NR, Bakshi VP, Geyer MA (1996) Seroquel restores sensorimotor gating in phencyclidine-treated rats. J Pharmacol Exp Ther 279:1290–1299PubMedGoogle Scholar
  48. Tada M, Shirakawa K, Matsuoka N, Mutoh S (2004) Combined treatment of quetiapine with haloperidol in animal models of antipsychotic effect and extrapyramidal side effects: comparison with risperidone and chlorpromazine. Psychopharmacology 176:94–100CrossRefPubMedGoogle Scholar
  49. Tsai G, Pinchen Y, Chung L-C, Lange N, Coyle JT (1998) d-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 44:1081–1089CrossRefPubMedGoogle Scholar
  50. Zhang W, Bymaster FP (1999) The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D-1, D-2, D-3, 5HT(2A) and muscarinic receptors. Psychopharmacology 141:267–278CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Gary E. Duncan
    • 1
  • Sheryl S. Moy
    • 1
  • Jeffery A. Lieberman
    • 1
  • Beverly H. Koller
    • 2
  1. 1.Department of Psychiatry, CB# 7090University of North Carolina School of MedicineChapel HillUSA
  2. 2.Department of GeneticsUniversity of North Carolina School of MedicineChapel HillUSA

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