Advertisement

Psychopharmacology

, Volume 179, Issue 2, pp 336–348 | Cite as

Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and d-amphetamine in the rat

  • N. F. Idris
  • P. Repeto
  • J. C. NeillEmail author
  • C. H. Large
Original Investigation

Abstract

Rationale

Phencyclidine (PCP), a glutamate/N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to induce a range of symptoms similar to those of patients with schizophrenia, while d-amphetamine induces predominantly positive symptoms. Previous studies in our laboratory have shown that PCP can selectively impair the performance of an operant reversal-learning task in the rat. Furthermore, we found that the novel antipsychotic ziprasidone, but not the classical antipsychotic haloperidol, could prevent the PCP-induced deficit.

Objectives

The aim of the present study was to validate the model further using the atypical antipsychotic clozapine and then to investigate the effects of lamotrigine, a broad-spectrum anticonvulsant that is known to reduce glutamate release in vitro and is able to prevent ketamine-induced psychotic symptoms in healthy human volunteers. A further aim was to compare effects of PCP and d-amphetamine in the test and investigate the effects of the typical antipsychotic haloperidol against the latter.

Methods

Female hooded-Lister rats were food deprived and trained to respond for food in a reversal-learning paradigm.

Results

PCP at 1.5 mg/kg and 2.0 mg/kg and d-amphetamine at 0.5 mg/kg significantly and selectively impaired performance in the reversal phase of the task. The cognitive deficit induced by 1.5 mg/kg PCP was attenuated by prior administration of lamotrigine (20 mg/kg and 30 mg/kg) or clozapine (5 mg/kg), but not haloperidol (0.05 mg/kg). In direct contrast, haloperidol (0.05 mg/kg), but not lamotrigine (25 mg/kg) or clozapine (5 mg/kg), prevented a similar cognitive impairment produced by d-amphetamine (0.5 mg/kg).

Conclusions

Our findings provide further data to support the use of PCP-induced disruption of reversal learning in rodents to investigate novel antipsychotic drugs. The results also provide evidence for different mechanisms of PCP and d-amphetamine-induced disruption of performance in the test, and their different sensitivities to typical and atypical antipsychotic drugs.

Keywords

Phencyclidine d-Amphetamine Reversal learning Cognitive deficit Schizophrenia Lamotrigine Clozapine Haloperidol 

Notes

Acknowledgements

The authors would like to thank Ben Grayson for technical assistance and Graham Pearson and Darren Brown for construction of the skinner boxes.

Some of these results were presented to the British Pharmacological Society in January 2003.

References

  1. Abdul-Monim Z, Reynolds GP, Neill JC (2003) The atypical antipsychotic ziprasidone, but not haloperidol, improves PCP-induced cognitive deficits in a reversal learning task in the rat. J Psychopharmacology 17(1):57–66CrossRefGoogle Scholar
  2. Adams B, Moghaddam M (1998) Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine. J Neurosci 18:5545–5554Google Scholar
  3. Addington J, Addington D, Gasbarre L (2001) Neurocognitive and social functioning in schizophrenia and other diagnoses. Schizophr Res 48(2–3):367–368CrossRefGoogle Scholar
  4. Alessandri B, Battig K, Welzl H (1989) Effects of ketamine on tunnel maze and water maze performance in the rat. Behav Neural Biol 52:194–212CrossRefGoogle Scholar
  5. Anand A, Charney D, Oren D, Berman R, Hu X, Cappiello A, Krystal J (2000) Attenuation of the neuropsychiatric effects of ketamine with lamotrigine. Arch Gen Psychiatry 57:270–276CrossRefPubMedGoogle Scholar
  6. Andersen MP, Pouzet B (2001) Effects of acute versus chronic treatment with typical or atypical antipsychotics on d-amphetamine-induced sensorimotor gating deficits in rats. Psychopharmacology (Berl) 156(2–3):291–304CrossRefGoogle Scholar
  7. Bakshi VP, Swerdlow NR, Geyer MA (1994) Clozapine antagonizes PCP-induced deficits in sensorimotor gating of the startle response. J Pharmacol Exp Ther 271:787–794PubMedGoogle Scholar
  8. Barnes TR, McEvedy CJ, Nelson HE (1996) Management of treatment resistant schizophrenia unresponsive to clozapine. Br J Psychiatry Suppl 31:31–40Google Scholar
  9. Bensadoun JC, Brooks SP, Dunnett SB (2004) Free operant and discrete trial performance of mice in the nine-hole box apparatus: validation using amphetamine and scopolamine. Psychopharmacology 174:396–405CrossRefGoogle Scholar
  10. Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, Kunz M, Chakos M, Cooper TB, Horowitz TL, Lieberman JA (2001) Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol on treatment-resistant patients with schizophrenia and schizoaffective disorder. Eur Neuropsychopharmacol 11(3):S256CrossRefGoogle Scholar
  11. Braff DL, Stone C, Callaway E, Geyer MA, Glick ID, Bali L (1978) Pre-stimulus effects on human startle reflex in normals and schizophrenics. J Psychophysiol 15:339–343Google Scholar
  12. Braff DL, Grillon C, Geyer MA (1992) Gating and habituation of the startle reflex in schizophrenia patients. Arch Gen Psychiatry 49:206–215PubMedGoogle Scholar
  13. Brody SA, Geyer MA, Large CH (2003) Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse inhibition in mice. Psychopharmacology 169:240–246CrossRefPubMedGoogle Scholar
  14. Calabresi P, Centonze D, Marfia GA, Pisani A, Bernardi G (1999) An in vitro electrophysiological study of the effects of phenytoin, lamotrigine and gabapentin on striatal neurons. Br J Psychiatry 126:689–696Google Scholar
  15. Corbett R, Camacho R, Woods AT, Kerman LL, Fishkin RJ, Brooks K, Dunn RW (1995) Antipsychotic agents antagonise non-competitive NMDA antagonist-induced behaviours. Psychopharmacology 120:67–74Google Scholar
  16. Cuesta MJ, Peralta V, Zarzuela A (2001) Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: a longitudinal study. Schizophr Res 48(1):17–28CrossRefGoogle Scholar
  17. Cunningham MO, Jones RSG (2000) The anticonvulsant lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro. Neuropharmacology 39:2139–2146CrossRefGoogle Scholar
  18. Deicken RF, Merrin EL, Floyd TC, Weiner MW (1995) Correlation between left frontal phospholipids and Wisconsin Card Sort Test performance in schizophrenia. Schizophr Res 14:177–181CrossRefGoogle Scholar
  19. Dias R, Robbins TW, Roberts AC (1997) Dissociable forms of inhibitory control within prefrontal cortex with an analog of the Wisconsin Card Sort Test: restriction to novel situations and independence from “on-line” processing. J Neurosci 17:9285–9297Google Scholar
  20. Duncan GE, Zorn S, Lieberman JA (1999) Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Mol Psychiatry 4:418–428CrossRefGoogle Scholar
  21. Dursun S, McIntosh D, Milliken H (1999) Clozapine plus lamotrigine in treatment-resistant schizophrenia. Arch Gen Psychiatry 56:950CrossRefGoogle Scholar
  22. Evins A, Amico E, Shih V, Goff D (1997) Clozapine treatment increases serum glutamate and aspartate compared to conventional neuroleptics. J Neural Transm 104:761–766Google Scholar
  23. Geyer MA, Segal DS, Greenberg BD (1984): Increased startle responding in rats treated with phencyclidine. Neurobehav Toxicol Teratol 6:1–4Google Scholar
  24. Goff DC, Hennen J, Tsai G, Evins AE, Yurgelun-Todd D, Renshaw P (2002) Modulation of brain and serum glutamatergic concentrations following a switch from conventional neuroleptics to clozapine. Biol Psychiatry 51:493–497CrossRefGoogle Scholar
  25. Goldberg TE, Gold JM (1995) Neurocognitive deficits in schizophrenia. In: Hirsch SR, Weinberger DR (eds) Schizophrenia. Blackwell, London, pp 146–162Google Scholar
  26. Hassel B, Tauboll E, Gjerstad L (2001) Chronic lamotrigine treatment increases rat hippocampal GABA shunt activity and elevates cerebral taurine levels. Epilepsy Res 43:153–163CrossRefGoogle Scholar
  27. Jentsch JD (2003) Pre-clinical models of cognitive dysfunction in schizophrenia: new avenues to addressing unmet needs. Clin Neurosci Res 3:303–313CrossRefGoogle Scholar
  28. Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20(3):201–225CrossRefGoogle Scholar
  29. Jentsch JD, Taylor JR (2001) Impaired inhibition of conditioned responses produced by subchronic administration of phencyclidine to rats. Neuropsychopharmacology 24:66–74CrossRefGoogle Scholar
  30. Jentsch JD, Anh Tran, Dung Lee, Youngren, KD, Roth RH (1997) Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilisation and impairs prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacology 17(2):92–99CrossRefGoogle Scholar
  31. Jones GH, Marsden CA, Robbins TW (1991) Behavioral rigidity and rule-learning deficits following isolation-rearing in the rat: neurochemical correlates. Behav Brain Res 43:35–50Google Scholar
  32. Jorgensen HA (2002) Drug treatment of schizophrenia. Tidsskr Nor Laegeforen 122(22):2206–2209Google Scholar
  33. Kapur S, Zipursky RB, Remington G (1999) Clinical and theoretical implications of 5HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 156:286–293Google Scholar
  34. Ketter TA, Manji HK, Post RM (2003) Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. J Clin Psychopharmacol 23:484–495CrossRefGoogle Scholar
  35. 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) 169:215–233CrossRefGoogle Scholar
  36. Kuzniecky R, Ho S, Pan J, Martin R, Gilliam F, Faught E, Hetherington H (2002) Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults. Neurology 58:368–372Google Scholar
  37. Langosch JM, Zhou X-Y, Frick A, Grunze H, Walden J (2000) Effects of lamotrigine on field potentials and long-term potentiation in guinea pig slices. Epilepsia 41:1102–1106Google Scholar
  38. Leysen JE, Luyten WH, Lesage AS, Heylen L, Vanhoenacker P, Haegeman G, Schotte A, Lemmens P, Lewi P (1997) Neurotransmitter receptor profiles of antipsychotics, relations to clinical properties. Biol Psychiatry 42:55SCrossRefGoogle Scholar
  39. Lerner V, Libov I, Kotler M, Strous RD (2004) Combination of “atypical” antipsychotic medication in the management of treatment-resistant schizophrenia and schizoaffective disorder. Prog Neuropsychopharmacol Biol Psychiatry 28(1):89–98CrossRefGoogle Scholar
  40. Lingamaneni R, Hemmings HC Jr (1999) Effects of anticonvulsants on veratridine- and KCl-evoked glutamate release from rat cortical synaptosomes. Neurosci Lett 276:127–130Google Scholar
  41. Linn GS, Negi SS, Gerum SV, Javitt DC (2000) Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys Psychopharmacology (Berl) 169(3–4):234–239CrossRefGoogle Scholar
  42. Lipska BK, Weinberger DR (2000) To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23(3):223–239PubMedGoogle Scholar
  43. Liu G, Yarov-Yarovoy V, Nobbs M, Clare JJ, Scheuer T, Catterall WA (2003) Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels. Neuropharmacology 44:413–422CrossRefGoogle Scholar
  44. Mackintosh NJ, Little L (1969): Selective attention and response strategies as factors in serial reversal learning. Can J Psychol 23:335–346Google Scholar
  45. Mansbach RS, Carver J, Zorn SH (2001) Blockade of drug-induced deficits in prepulse inhibition of acoustic startle by ziprasidone. Pharmacol Biochem Behav 69(3–4):535–542CrossRefPubMedGoogle Scholar
  46. Martinez ZA, Oostwegel J, Geyer MA, Ellison GD, Swerdlow NR (2000) “Early” and “Late” effects of sustained haloperidol on apomorphine- and phencyclidine-induced sensorimotor gating deficits. Neuropsychopharmacology 23:517–527CrossRefGoogle Scholar
  47. Mason SB, Domeney AM, Costall B, Naylor RJ (1992) Effect of antagonists on amphetamine induced reversal learning impairments in the marmoset. J Psychopharmacol 269:A68Google Scholar
  48. Messenheimer JA (1995) Lamotrigine. Epilepsia 36:S87–S94Google Scholar
  49. 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
  50. Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007Google Scholar
  51. Olney JW, Newcomer JW, Farber NB (1999) NMDA receptor hypofunction model of schizophrenia. J Psych Res 33:523–533CrossRefGoogle Scholar
  52. Reynolds GP, Abdul-Monim Z, Neill JC, Zhang ZJ (2004) Calcium binding protein markers of GABA deficits in schizophrenia—post mortem studies and animal models. Neurotoxicity 6(1):1–6Google Scholar
  53. Ridley RM, Baker HF, Frith CD, Dowdy J, Crow TJ (1988) Stereotyped responding on a two-choice guessing task by marmosets and humans treated with amphetamine. Psychopharmacology (Berlin) 95:560–564Google Scholar
  54. Sams-Dodd FF (1996) Phencyclidine-induced stereotyped behavior and social isolation in rats: a possible animal model of schizophrenia. Behav Pharmacol 7(1):3–23PubMedGoogle Scholar
  55. Smith AG, Neill JC, Costall B (1999) The dopamine D3/D2 receptor agonist 7-OH-DPAT induces cognitive impairment in the common marmoset. Pharmacol Biochem Behav 63(2):201–211CrossRefGoogle Scholar
  56. Steinpreis RE (1996) The behavioral and neurochemical effects of phencyclidine in humans and animals: some implications for modeling psychosis. Behav Brain Res 74:45–55Google Scholar
  57. Sturgeon RD, Fessler RG, Meltzer HY (1979) Behavioral rating scales for assessing phencyclidine-induced locomotor activity, stereotyped behavior and ataxia in rats. Eur J Pharmacol 59:169–179CrossRefGoogle Scholar
  58. Tiihonen J, Hallikainen T, Ryynanen O-P, Repo-Tiihonen E, Kotilainen I, Eronen M, Toivonen P, Wahlbeck K, Putkonen A (2003) Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biol Psychiatry 54:1241–1248CrossRefGoogle Scholar
  59. Toren P, Laor N, Weizman A (1998) Use of atypical neuroleptics in child and adolescent psychiatry. Clin Psychiatry 59(12):644–656Google Scholar
  60. Van den Bos R, Cools AR (1989) The involvement of the nucleus accumbens in the ability of rats to switch to cue-directed behaviours. Life Sci 44:1697–1704CrossRefGoogle Scholar
  61. Verma A, Moghaddam B (1996) NMDA receptor antagonists impair prefrontal cortical function as assessed via spatial delayed alternation performance in rats: modulation by dopamine. J Neurosci 16:373–379Google Scholar
  62. Waldmeier PC, Martin P, Stocklin K, Portet C, Schmutz M (1996) Effect of carbamazepine, oxcarbamazepine and lamotrigine on the increase in extracellular glutamate elicited by veratridine in rat cortex and striatum Nauyn-Schmeid. Arch Pharmacol 354:164–172CrossRefGoogle Scholar
  63. Wang S-J, Huang C-C, Hsu K-S, Tsai J-J, Gean P-W (1996) Presynaptic inhibition of excitatory neurotransmission by lamotrigine in rat amygdalar neurons. Synapse 24:248–255Google Scholar
  64. Weiner I (2003) The “two-headed” latent inhibition model of schizophrenia: modelling positive and negative symptoms and their treatment. Psychopharmacology 169:257–297CrossRefGoogle Scholar
  65. Weiner I, Feldon J, Ben-Shahar O (1986) Simultaneous brightness discrimination and reversal: the effects of amphetamine administration in the two stages. Pharmacol Biochem Behav 25:939–942CrossRefGoogle Scholar
  66. Xie X, Lancaster B, Peakman T, Garthwaite J (1995) Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIa Na+channels and with native Na+channels in rat hippocampal neurons. Pflugers Arch Eur J Physiol 430:437–446CrossRefGoogle Scholar
  67. Xie X, Hagan RM (1998) Cellular and molecular actions of lamotrigine: possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 38:119–130Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • N. F. Idris
    • 1
  • P. Repeto
    • 2
  • J. C. Neill
    • 1
    Email author
  • C. H. Large
    • 2
  1. 1.The School of PharmacyThe University of BradfordBradfordUK
  2. 2.Department of Neuropharmacology, Psychiatry CEDDGlaxosmithkline S.p.A.VeronaItaly

Personalised recommendations