The latent inhibition model of schizophrenia: Further validation using the atypical neuroleptic, clozapine

      This paper is only available as a PDF. To read, Please Download here.
      Latent inhibition (LI) refers to retarded conditioning to a stimulus that has been repeatedly presented without reinforcement. LI is impaired in schizophrenic patients and in rats treated with amphetamine. Neuroleptic drugs produce two effects in this test paradigm: antagonism of amphetamine-induced disruption of LI, and enhancement of LI when administered on their own. The present experiments tested the effects of the atypical neuroleptic, clozapine, on LI. The experiments used a conditioned emotional response procedure in rats licking for water, consisting of three stages: preexposure, in which the to-be-conditioned stimulus (tone) was repeatedly presented without reinforcement; conditioning, in which the preexposed stimulus was paired with reinforcement (foot shock); and test, in which LI was indexed by animals' degree of suppression of licking during tone presentation. In experiments 1 and 2, the effects of 5.0 and 10.0 mg/kg clozapine on LI were assessed following 20 or 10 tone preexposures, respectively. Experiments 3 and 4 used 40 preexposures and investigated antagonism of amphetamine-induced disruption of LI by 5.0 and 10.0 mg/kg clozapine, respectively. The results demonstrated that clozapine possesses a neuroleptic profile in the LI model, namely, it facilitates the development of LI and antagonizes amphetamine-induced disruption of LI.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Barbee JG
        • Mancuso D
        • Freed CR
        • et al.
        Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia.
        Am J Psychiatry. 1992; 149: 506-510
        • Baruch I
        • Hemsley D
        • Gray JA
        Differential performance of acute and chronic schizophrenics in a latent inhibition task.
        J Nerv Ment Dis. 1988; 176: 598-606
        • Brier A
        • Buchanan RW
        • Kirkpatrick B
        • et al.
        Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia.
        Am J Psychiatry. 1994; 151: 20-26
        • Bruhwyler J
        • Chleide E
        • Mercier M
        Clozapine—An atypical neuroleptic.
        Neurosci Biobehav Rev. 1990; 14: 357-363
        • Carpenter Jr, WT
        • Heinrichs DW
        • Alphs LD
        Treatment of negative symptoms.
        Schizophr Bull. 1985; 11: 440-452
        • Carpenter Jr, WT
        • Heinrichs DW
        • Wagman AMI
        Deficit and nondeficit forms of schizophrenia: The concept.
        Am J Psychiatry. 1988; 145: 578-583
        • Cassaday HJ
        • Hodges H
        • Gray JA
        The effects of ritanserin, RU 24969 and 8-OH-DPAT on latent inhibition in the rat.
        J Psychopharmacol. 1993; 77: 63-77
        • Chen J
        • Paredes W
        • Gardner EL
        Serotonin denervation enhances responsiveness of presynaptic dopamine efflux to acute clozapine in nucleus accumbens but not in caudateputamen.
        Brain Res. 1992; 582: 173-179
        • Chiodo LA
        • Bunney SB
        Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons.
        J Neurosci. 1985; 5: 2539-2544
        • Christison GW
        • Atwater GE
        • Dunn LA
        • Kilts CD
        Haloperidol enhancement of latent inhibition: Relation to therapeutic action?.
        Biol Psychiatry. 1988; 23: 746-749
        • Coward DM
        • Imperato A
        • Urwyler S
        • White TG
        Biochemical and behavioural properties of clozapine.
        Psychopharmacology. 1989; 99: S6-S12
        • Duinkerke SJ
        • Botter PA
        • Jansen AAI
        • et al.
        Ritanserin, a selective 5-HT2/1C antagonist, and negative symptoms in schizophrenia: A placebo-controlled double-blind trial.
        Br J Psychiatry. 1993; 163: 451-455
        • Dunn LA
        • Atwater GE
        • Kilts CD
        Effects of antipsychotic drugs on latent inhibition—Sensitivity and specificity of an animal behavioral model of clinical drug action.
        Psychopharmacology. 1993; 112: 315-323
        • Farde L
        • Nordstrom AL
        PET analysis indicates atypical central dopamine receptor occupancy in clozapine-treated patients.
        Br J Psychiatry. 1992; 160: 30-33
        • Farde L
        • Wiesel FA
        • Nordstrom AL
        • Sedvall G
        D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics.
        Psychopharmacology. 1989; 99: S28-S31
        • Feldon J
        • Weiner I
        Long-term attentional deficit in nonhandled males: Possible involvement of the dopaminergic system.
        Psychopharmacology. 1988; 95: 231-236
        • Feldon J
        • Weiner I
        Abolition of the acquisition but not the expression of latent inhibition by chlordiazepoxide in rats.
        Pharmacol Biochem Behav. 1989; 32: 123-127
        • Feldon J
        • Weiner I
        The latent inhibition model of schizophrenic attention disorder: Haloperidol and sulpiride enhance rats' ability to ignore irrelevant stimuli.
        Biol Psychiatry. 1991; 29: 635-646
        • Gerlach J
        New antipsychotics: Classification, efficacy, and adverse effects.
        Schizophr Bull. 1991; 17: 289-309
        • Gerlach J
        • Casey DE
        Drug treatment of schizophrenia: Myths and realities.
        Curr Opin Psychiatry. 1994; 7: 65-70
        • Gray JA
        • Feldon J
        • Rawlins JNP
        • Hemsley DR
        • Smith AD
        The neuropsychology of schizophrenia.
        Behav Brain Sci. 1991; 14: 1-84
        • Gray JA
        • Joseph MH
        • Hemsley DR
        • et al.
        The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: Implications for schizophrenia.
        Behav Brain Res. 1995; 71: 19-31
        • Gray NS
        • Hemsley DR
        • Gray JA
        Abolition of latent inhibition in acute, but not chronic, schizophrenics.
        Neurol Psychiat Brain Res. 1992; 1: 83-89
        • Gray NS
        • Pickering AD
        • Hemsley DR
        • Dawling S
        • Gray JA
        Abolition of latent inhibition by a single 5 mg dose of d-amphetamine in man.
        Psychopharmacology. 1992; 107: 425430
        • Jackson DM
        • Mohell N
        • Bengtsson A
        • Malmberg A
        What are atypical neuroleptics and how do they work?.
        in: Brunello N Mendlewicz J Racagni G New Generation of Antipsychotic Drugs: Novel Mechanisms of Action. Karger, Amsterdam1993: 27-38
        • Jann MW
        Pharmacotherapy. 1991; 11: 179-195
        • Kane J
        • Honigfeld G
        • Singer J
        • Meltzer H
        Clozapine for the treatment-resistant schizophrenic—A double-blind comparison with chlorpromazine.
        Arch Gen Psychiatry. 1988; 45: 789796
        • Kane JM
        • Freeman HL
        Towards more effective antipsychotic treatment.
        Br J Psychiatry. 1994; 165: 22-31
        • Kane JM
        • Marder SR
        Psychopharmacologic treatment of schizophrenia.
        Schizophr Bull. 1993; 19: 287-302
        • Kerwin RW
        The new atypical antipsychotics.
        Br J Psychiatry. 1994; 164: 141-148
        • Killcross AS
        • Robbins TW
        Differential effects of intraaccumbens and systemic amphetamine on latent inhibition using an on-baseline, within-subject conditioned suppression paradigm.
        Psychopharmacology. 1993; 110: 479-489
        • Killcross AS
        • Dickinson A
        • Robbins TW
        Effects of the neuroleptic alpha-flupenthixol on latent inhibition in aversively- and appetitively-motivated paradigms—Evidence for dopamine-reinforcer interactions.
        Psychopharmacology. 1994; 115: 196-205
        • Leonard BE
        Serotonin receptors—Where are they going?.
        Int Clin Psychopharmacol. 1994; 9: 7-17
        • Louwerens JW
        • Buddingh JA
        • Zijlstra S
        • et al.
        Dopamine (D2)-receptor occupancy in clozapine-treated patients as measured by positron emission tomography using 18FESP.
        in: Brunello N Mendlewicz J Racagni G New Generation of Antipsychotic Drugs: Novel Mechanisms of Action. Karger, Basel1993: 130-135
        • Lubow RE
        Latent inhibition.
        Psychol Bull. 1973; 79: 398-407
        • Lubow RE
        Latent Inhibition and Conditioned Attention Theory.
        Cambridge University Press, Basel1989
        • Lubow RE
        • Gewirtz JC
        Latent inhibition in humans: Data, theory, and implications for schizophrenia.
        Psychol Bull. 1995; 117: 87-103
        • Lubow RE
        • Weiner I
        • Schnur P
        Conditioned attention theory.
        in: Bower GH The Psychology of Learning and Motivation. vol 15. Academic Press, Cambridge, England1981: 1-49
        • Mackintosh NJ
        A theory of attention: Variations in the associability of stimuli with reinforcement.
        Psychol Rev. 1975; 82: 276-298
        • Mackintosh NJ
        Conditioning and Associative Learning.
        Oxford University Press, New York1983
        • Meltzer HY
        Clinical studies on the mechanism of action of clozapine: The dopamine-serotonin hypothesis of schizophrenia.
        Psychopharmacology. 1989; 99: S18-S27
        • Meltzer HY
        The mechanism of action of novel antipsychotic drugs.
        Schizophr Bull. 1991; 17: 263-287
        • Meltzer HY
        • Bastani B
        • Ramirez L
        • Matsubara S
        Clozapine—New research on efficacy and mechanism of action.
        Eur Arch Psychiatr Neurol Sci. 1989; 238: 332-339
        • Meltzer HY
        • Matsubara S
        • Lee JC
        The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs.
        Psychopharmacol Bull. 1989; 25: 390392
        • Moore JW
        • Stickney KJ
        Formation of attentional-associative networks in real time: Role of the hippocampus and implications for conditioning.
        Physiol Psychology. 1980; 8: 207-217
        • Moran PM
        • Moser PC
        MDL 73,1 47EF, a 5-HT[3] antagonist, facilitates latent inhibition in the rat.
        Pharmacol Biochem Behav. 1992; 42: 519-522
        • Mortimer AM
        Newer and older antipsychotics: A comparative review of appropriate use.
        CNS Drugs. 1994; 2: 381-396
        • Nutt DJ
        Specific anatomy, non-specific drugs: The present state of schizophrenia.
        J Psychopharmacol. 1990; 4: 171-175
        • Peters SL
        • Joseph MH
        Haloperidol potentiation of latent inhibition in rats: Evidence for a critical role at conditioning rather than pre-exposure.
        Behav Pharmacol. 1993; 4: 183-186
        • Reyntjens A
        • Gelders YG
        • Hoppenbrouwers MLJA
        • et al.
        Thymostenic effects of ritanserin (R 55667) a centrally acting serotonin-S2 receptor blocker.
        Drug Develop Res. 1986; 8: 205-211
        • Schmajuk NA
        • Moore JW
        Real-time attentional models for classical conditioning and the hippocampus.
        Physiol Psychol. 1985; 13: 278-290
        • Seeman P
        Dopamine receptor sequences—Therapeutic levels of neuroleptics occupy D2-receptors, clozapine occupies D4.
        Neuropsychopharmacology. 1992; 7: 261-284
        • Solomon PR
        • Crider A
        • Winkelman JW
        • Turi A
        • Kamer RM
        • Kaplan LJ
        Disrupted latent inhibition in the rat with chronic amphetamine or haloperidol-induced supersensitivity: Relationship to schizophrenic attention disorder.
        Biol Psychiatry. 1981; 16: 519-537
        • Tandon R
        • Kane JM
        Neuropharmacologic basis for clozapine's unique profile.
        Arch Gen Psychiatry. 1993; 50: 158-159
        • Tandon R
        • Goldman R
        • DeQuardo JR
        • Goldman M
        • Perez M
        • Jibson M
        Positive and negative symptoms covary during clozapine treatment in schizophrenia.
        J Psychiat Res. 1993; 27: 341-347
        • van Tol HH
        • Bunzow JR
        • Guan HC
        • et al.
        Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine.
        Nature. 1991; 350: 610-614
        • Warburton EC
        • Joseph MH
        • Feldon J
        • Weiner I
        • Gray JA
        Antagonism of amphetamine-induced disruption of LI in rats by haloperidol and ondansetron: Implications for a possible antipsychotic action of ondansetron.
        Psychopharmacology. 1994; 114: 657-664
        • Weiner I
        Neural substrates of latent inhibition: The switching model.
        Psychol Bull. 1990; 108: 442-461
        • Weiner I
        • Feldon J
        Facilitation of latent inhibition by haloperidol.
        Psychopharmacology. 1987; 91: 248-253
        • Weiner I
        • Feldon J
        The latent inhibition model of schizophrenic attention disorder and of antipsychotic drug action: Comment on Dunn, Atwater and Kilts.
        Psychopharmacology. 1994; 116 (Psychopharmacology, 1993, 112: 315–323): 379-380
        • Weiner I
        • Lubow RE
        • Feldon J
        Chronic amphetamine and latent inhibition.
        Behav Brain Res. 1981; 2: 285-286
        • Weiner I
        • Lubow RE
        • Feldon J
        Abolition of the expression but not the acquisition of latent inhibition by chronic amphetamine in rats.
        Psychopharmacology. 1984; 83: 194-199
        • Weiner I
        • Feldon J
        • Katz Y
        Facilitation of the expression but not the acquisition of latent inhibition by haloperidol in rats.
        Pharmacol Biochem Behav. 1987; 26: 241-246
        • Weiner I
        • Lubow RE
        • Feldon J
        Disruption of latent inhibition by acute administration of low doses of amphetamine.
        Pharmacol Biochem Behav. 1988; 30: 871-878
        • Weiner I
        • Kidron R
        • Tarrasch R
        • Arnt J
        • Feldon J
        The effects of the new antipsychotic, sertindole, on latent inhibition in rats.
        Behav Pharmacol. 1994; 5: 119-124
        • Wiley JL
        • Compton AD
        • Porter JH
        Effects of four antipsychotics on punished responding in rats.
        Pharmacol Biochem Behav. 1993; 45: 263-267