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Clozapine, SCH 23390 and α-flupenthixol but not haloperidol attenuate acute phencyclidine-induced disruption of conditional discrimination performance

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Abstract

Rationale

Forebrain dopamine (DA) manipulation has recently been shown to selectively disrupt a conditional discrimination task whose design parameters approximate tasks repeatedly shown to be impaired in schizophrenia.

Objective

To investigate the reversal potential of the D1/D2 receptor antagonist α-flupenthixol, the selective D1 antagonist SCH 23390, the typical antipsychotic haloperidol and the atypical antipsychotic clozapine on acute phencyclidine (PCP)-induced disruption of a conditional discrimination task dependent on the ability to use task-setting cues that inform goal-directed performance.

Materials and methods

Rats learned a conditional discrimination task where reinforcement was contingent on an appropriate lever press during a specific auditory stimulus.

Results

PCP disrupted task performance at 1.5 mg/kg, attenuated correct lever pressing at 2.5 mg/kg and abolished overall responding at 5 mg/kg (experiment 1). Pavlovian-instrumental transfer task results (experiment 2) showed that 1.5 and 2.5 mg/kg PCP had no disruptive effects on basic sensory, motor or motivational processes; however, such deficits were evident in 5-mg/kg-treated animals. PCP (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pretreatment with clozapine, SCH 23390 and α-flupenthixol; however, pretreatment with haloperidol did not attenuate task disruption.

Conclusion

The predictive validity of the conditional discrimination model is enhanced as the selective task disruption by the preeminent psychotomimetic PCP is reversed by clozapine (known to ameliorate cognitive deficits in schizophrenia) and the role of DA D1 receptors as mediators of tasks that require conditional relationships is discussed.

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References

  • Adler CM, Goldberg TE, Malhotra AK, Pickar D, Breier A (1998) Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers. Biol Psychiatry 43:811–816

    Article  PubMed  CAS  Google Scholar 

  • Barch DM, Carter CS, Braver TS, Sabb FW, MacDonald A 3rd, Noll DC, Cohen JD (2001) Selective deficits in prefrontal cortex function in medication-naïve patients with schizophrenia. Arch Gen Psychiatry 58:280–288

    Article  PubMed  CAS  Google Scholar 

  • Cohen JD, Servan-Schreiber D (1992) Context, cortex, and dopamine: a connectionist approach to behavior and biology in schizophrenia. Psychol Rev 99:45–77

    Article  PubMed  CAS  Google Scholar 

  • Cohen RM, Semple WE, Gross M, Mordahl TE, Holcomb HH, Dowling MS, Pickar D (1988) The effect of neuroleptics on dysfunction in the prefrontal substrate of sustained attention in schizophrenia. Life Sci 43:1141–1150

    Article  PubMed  CAS  Google Scholar 

  • Cohen JD, Servan-Schreiber D, Steingard S (1995) Schizophrenic deficits in the processing of context: a test of neural network simulations of cognitive functioning in schizophrenia. Schizophr Res 15:113

    Article  Google Scholar 

  • Cornblatt BA, Lenzenweger MF, Erlenmeyer-Kimling L (1989) A continuous performance test, identical pairs version II: contrasting attentional profiles in schizophrenic and depressed patients. Psychiatry Res 29:65–85

    Article  PubMed  CAS  Google Scholar 

  • Dunn MJ, Killcross AS (2006a) Differential attenuation of d-amphetamine-induced disruption of conditional discrimination performance by dopamine and serotonin antagonists. Psychopharmacology 188:183–192

    Article  CAS  Google Scholar 

  • Dunn MJ, Killcross AS (2006b) Clozapine but not haloperidol treatment reverses sub-chronic phencyclidine-induced disruption of conditional discrimination performance. Behav Brain Res 175:271–277

    Article  CAS  Google Scholar 

  • Dunn MJ, Futter D, Bonardi C, Killcross AS (2005) Attenuation of d-amphetamine-induced disruption of conditional discrimination performance by α-flupenthixol. Psychopharmacology 177:296–306

    Article  PubMed  CAS  Google Scholar 

  • George D, Jenkins T, Killcross AS (2002) Interactions of the prefrontal cortex and nucleus accumbens dopaminergic systems in conditional discrimination learning in rats. Society for Neuroscience, Washington, DC, Program No. 941.13

    Google Scholar 

  • Goldman-Rakic PC (1999) The relevance of the dopamine-D1 receptor in the cognitive symptoms of schizophrenia. Neuropsychopharmacology 21:170–180

    Article  Google Scholar 

  • 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 20:1208–1215

    PubMed  CAS  Google Scholar 

  • Hagger C, Buckley P, Kenny JT, Friedman L, Ubogy D, Meltzer H (1993) Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biol Psychiatry 34:702–712

    Article  PubMed  CAS  Google Scholar 

  • Heidbreder CA, Foxton R, Cilia J, Hughes ZA, Shah AJ, Atkins A, Hunter AJ, Hagan JJ, Jones DNC (2001) Increased responsiveness of dopamine to atypical, but not typical antipsychotics in the medial prefrontal cortex of rats reared in isolation. Psychopharmacology 156:338–351

    Article  PubMed  CAS  Google Scholar 

  • Hertel P, Mathe JM, Nomikos GG, Iurlo M, Mathe AA, Svensson TH (1996) Effects of D-amphetamine and phencyclidine on behavior and extracellular concentrations of neurotensin and dopamine in the ventral striatum and the medial prefrontal cortex of the rat. Behav Brain Res 72:103–114

    Article  Google Scholar 

  • Hoehn-Saric R, McLeod DR, Glowa JR (1991) The effects of NMDA receptor blockade on the acquisition of a conditioned emotional response. Biol Psychiatry 30:170–176

    Article  PubMed  CAS  Google Scholar 

  • Hondo H, Yonezawa Y, Nakahara T, Nakamura K, Hirano M, Uchimura H, Tashiro N (1994) Effects of phencyclidine on dopamine release in the rat prefrontal cortex: an in vivo microdialysis study. Brain Res 633:337–342

    Article  PubMed  CAS  Google Scholar 

  • Idris NF, Repeto P, Neill JC, Large CH (2005) Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and d-amphetamine in the rat. Psychopharmacology 179:336–348

    Article  PubMed  CAS  Google Scholar 

  • Ital T, Keskiner A, Kiremitci N, Holden JMC (1967) Effect of phencyclidine in chronic schizophrenics. Can Psychiatr Assoc J 12:209–212

    Google Scholar 

  • Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308

    PubMed  CAS  Google Scholar 

  • Javitt DC, Shelley A-M, Silipo G, Lieberman JA (2000) Deficits in auditory and visual context-dependent processing in schizophrenia: defining the pattern. Arch Gen Psychiatry 57:1131–1137

    Article  PubMed  CAS  Google Scholar 

  • Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225

    Article  PubMed  CAS  Google Scholar 

  • Jentsch JD, Elsorth JD, Redmond DE Jr, Roth RH (1997a) Phencyclidine increases forebrain monoamine metabolism in rats and monkeys: modulation by the isomers of HA966. J Neurosci 17:1769–1775

    PubMed  CAS  Google Scholar 

  • Jentsch JD, Tran A, Le D, Youngren KD, Roth RH (1997b) Sub-chronic phencyclidine administration reduces mesoprefrontal dopamine utilisation and impairs prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacology 17:92–99

    Article  PubMed  CAS  Google Scholar 

  • Keefe RS (2000) Working memory dysfunction and its relevance to schizophrenia. In: Sharma T, Harvey P (eds) Cognition in schizophrenia: impairments, importance and treatment strategies. Oxford University Press, New York

    Google Scholar 

  • Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, Cooper TB, Carlsson A, Laruelle M (2000) Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry 48:627–640

    Article  PubMed  CAS  Google Scholar 

  • Krystal JH, Laurence PK, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanaesthetic effects of the non-competitive NMDA antagonist, ketamine, in humans. Arch Gen Psychiatry 51:199–214

    PubMed  CAS  Google Scholar 

  • Krystal JH, Bennett A, Abi-Saab D, Belger A, Karper LP, D’Souza C, Lipschitz D, Abi-Dargham A, Charney DS (2000) Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions. Biol Psychiatry 47:137–143

    Article  PubMed  CAS  Google Scholar 

  • Laruelle M, Abi-Dargham, A van Dyck CH et al (1996) Single photon emission computerised tomography imaging of amphetamine-induced dopamine release in drug free schizophrenic subjects. Proc Natl Acad Sci USA 93:9235–9240

    Article  PubMed  CAS  Google Scholar 

  • Malhotra AK, Pinals DA, Weisenfeld N, Pickar D, Breier A (1996) NMDA receptor function and schizophrenia: studies with ketamine. Biol Psychiatry 39:586

    Article  Google Scholar 

  • 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 17:141–150

    Article  PubMed  CAS  Google Scholar 

  • McCullough LD, Salamone JD (1992) Increases in extracellular dopamine levels and locomotor activity after direct infusion of phencyclidine into the nucleus accumbens. Brain Res 577:1–9

    Article  PubMed  CAS  Google Scholar 

  • Moerschbaecher JM, Thompson DM (1980) Effects of phencyclidine, pentobarbital, and d-amphetamine on the acquisition and performance of conditional discriminations in monkeys. Pharmacol Biochem Behav 13:887–894

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam B, Roth RH, Bunney BS (1990) Characterization of dopamine release in the rat medial prefrontal cortex as assessed by in vivo microdialysis: comparison to the striatum. Neuroscience 36:669–676

    Article  PubMed  CAS  Google Scholar 

  • 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 17:2921–2927

    PubMed  CAS  Google Scholar 

  • Nakahara T, Kuroki T, Hashimoto K, Hondo H, Tsutsumi T, Motomura K, Ueki H, Hirano M, Uchimura H (2000) Effect of atypical antipsychotics on phencyclidine-induced expression of arc in the rat brain. Neuroreport 11:551–555

    Article  PubMed  CAS  Google Scholar 

  • Pallares MA, Nadal RA, Silvestre JS, Ferre NS (1995) Effects of ketamine, a non-competitive NMDA antagonist, on the acquisition of the lever-press response in rats. Physiol Behav 57:389–392

    Article  PubMed  CAS  Google Scholar 

  • Porrino LJ, Lucignani G, Dow-Edwards D, Sokoloff L (1984) Correlation of dose-dependent effects of acute amphetamine administration on behaviour and local cerebral metabolism in rats. Brain Res 307:311–320

    Article  PubMed  CAS  Google Scholar 

  • Rao TS, Kim HS, Lehmann J, Martin LL, Wood PL (1989) Differential effects of phencyclidine (PCP) and ketamine on mesocortical and mesostriatal dopamine release. Life Sci 45:1065–1072

    Article  PubMed  CAS  Google Scholar 

  • Robbins TW, Sahakian BJ (1983) Behavioural effects of psychomotor stimulant drugs: clinical and neuropsychological implications. In: Creese I (ed) Stimulants: neurochemical, behavioural and clinical perspectives. Raven, New York, pp 301–338

    Google Scholar 

  • Sarter M (1990) Retrieval of well-learned prepositional rules: insensitive to changes in activity of individual neurotransmitter systems? Psychobiology 18:451–459

    Google Scholar 

  • Sedvall GC, Karlsson P (1999) Pharmacological manipulation of D1-dopamine receptor function in schizophrenia. Neuropsychopharmacology 21:181–188

    Article  Google Scholar 

  • Steinpreis RE (1996) The behavioural and neurochemical effects of phencyclidine in humans and animals: some implications for modelling psychosis. Behav Brain Res 74:45–55

    Article  CAS  Google Scholar 

  • Steinpreis RE, Salamone JD (1993) The role of nucleus accumbens dopamine in the neurochemical and behavioural effects of PCP: a microdialysis and behavioral study. Brain Res 612:263–270

    Article  PubMed  CAS  Google Scholar 

  • Stratta P, Daneluzzo E, Bustini M, Prosperini P, Rossi A (2000) Processing of context information in schizophrenia: relation to clinical symptoms and WCST performance. Schizophr Res 44:57–67

    Article  PubMed  CAS  Google Scholar 

  • Tanii Y, Nishikawa T, Umino A, Takahashi K (1990) Phencyclidine increases extracellular dopamine metabolites in rat medial frontal cortex as measured by in vivo dialysis. Neurosci Lett 112:318–323

    Article  Google Scholar 

  • Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC (2000) Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry 57:1139–1147

    Article  PubMed  CAS  Google Scholar 

  • Verma A, Moghaddam B (1996) NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine. J Neurosci 16:373–379

    PubMed  CAS  Google Scholar 

  • Wang RY, Liang X (1998) M100907 and clozapine, but not haloperidol or raclopride, prevent phencyclidine-induced blockade of NMDA responses in pyramidal neurons of the rat medial prefrontal cortex slice. Neuropsychopharmacology 19:74–85

    Article  PubMed  CAS  Google Scholar 

  • Weinberger DR, Lipska BK (1995) Cortical maldevelopment, antipsychotic drugs, and schizophrenia: a search for common ground. Schizophr Res 16:87–110

    Article  PubMed  CAS  Google Scholar 

  • Willmore CB, Bespalov AY, Beardsley PM (2001) Competitive and non-competitive NMDA antagonist effects in rats trained to discriminate lever-press counts. Pharmacol Biochem Behav 69:493–502

    Article  PubMed  CAS  Google Scholar 

  • Youngren KD, Moghaddam B, Bunney BS, Roth RH (1994) Preferential activation of dopamine overflow in prefrontal cortex produced by chronic clozapine treatment. Neurosci Lett 165:41–44

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Health and Social Sciences (Psychology), University of Wales Institute Cardiff (UWIC), Llandaff Campus, Western Avenue, Cardiff, CF5 2SG, UK

    Michael J. Dunn

  2. School of Psychology, Cardiff University, P.O. Box, Park Place, Cardiff, CF10 3YG, UK

    Simon Killcross

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  1. Michael J. Dunn
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Correspondence to Michael J. Dunn.

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Dunn, M.J., Killcross, S. Clozapine, SCH 23390 and α-flupenthixol but not haloperidol attenuate acute phencyclidine-induced disruption of conditional discrimination performance. Psychopharmacology 190, 403–414 (2007). https://doi.org/10.1007/s00213-006-0605-y

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  • DOI: https://doi.org/10.1007/s00213-006-0605-y

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