Abstract
Latent inhibition (LI), i.e., retarded conditioning to a stimulus following its nonreinforced preexposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Typical and atypical antipsychotic drugs (APD's) potentiate LI, but to date the model has not dissociated between them. This study demonstrates such a dissociation using haloperidol (0.1 mg/kg), clozapine (5 mg/kg), and ritanserin (0.6 mg/kg) administered in preexposure and/or conditioning. Under conditions which did not yield LI in vehicle controls (40 preexposures and five conditioning trials), both haloperidol and clozapine, but not ritanserin, led to LI when administered in conditioning. Under conditions which led to LI in vehicle controls (40 preexposures and two conditioning trials), clozapine and ritanserin, but not haloperidol, abolished LI when administered in preexposure. It is suggested that LI potentiation via conditioning detects the “typical” action of APD's whereas LI disruption via preexposure detects the “atypical” action of APD's.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Arnt J . (1995): Differential effects of classical and newer antipsychotics on the hypermotility induced by two dose levels of d-amphetamine. Eur J Pharmacol 283: 55–62
Arnt J, Skarsfeldt T . (1998): Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18: 63–101
Asin KE, Wirtshafter D, Kent EW . (1980): The effects of electrolytic median raphe lesions on two measures of latent inhibition. Behav Neural Biol 28: 408–417
Awouters F, Niemegeers CJE, Megens AA, Meert TF, Janssen PAJ . (1988): Pharmacological profile of ritanserin: A very specific central serotonin S2 antagonist. Drug Dev Res 15: 61–73
Baldessarini RJ, Frankenburg FR . (1991): Clozapine. A novel antipsychotic agent. N Engl J Med 11: 746–754
Baruch I, Hemsley D, Gray JA . (1988): Differential performance of acute and chronic schizophrenics in a latent inhibition task. J Nerv Mental Dis 176: 598–606
Bakshi VP, Geyer MA . (1995): Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. Psychopharmacology 122: 198–201
Blin O, Azorin JM, Bouhours P . (1996): Antipsychotic and anxiolytic properties of risperidone, haloperidol, and methotrimeprazine in schizophrenic patients. J Clin Psychopharmacol 16: 38–44
Brunello N, Masotto C, Steardo L, Markstein R, Racagni G . (1995): New insights into the biology of schizophrenia through the mechanism of action of clozapine. Neuropsychopharmacology 13: 177–213
Cassaday HF, Hodges H, Gray JA . (1993a): The effects of ritanserin, RU 24969 and 8-OH-DPAT on latent inhibition in the rat. Psychopharmacology 7: 63–71
Cassaday HJ, Mitchell SN, Williams JH, Gray JA . (1993b): 5,7-Dihydroxytryptamine lesions in the fornix-fimbria attenuate latent inhibition. Behav Neural Biol 59: 194–207
Christison GW, Atwater GE, Dunn LA, Kilts CD . (1988): Haloperidol enhancement of latent inhibition: Relation to therapeutic action? Biol Psychiatry 23: 746–749
Duinkerke SJ, Botter PA, Jansen AAI, Vandongen PAM, Vanhaaften AJ, Boom AJ, Vanlaarhoven JHM, Busard HLSM . (1993): Ritanserin, a selective 5-HT(2/1C) antagonist, and negative symptoms in schizophrenia—a placebo-controlled double-blind trial. Br J Psychiatry 163: 451–455
Dunn LA, Atwater GE, Kilts CD . (1993): Effects of antipsychotic drugs on latent inhibition—sensitivity and specificity of an animal behavioral model of clinical drug action. Psychopharmacology 112: 315–323
Dunn LA, Scibilia RJ . (1996): Reaction time and pupil response measures show reduced latent inhibition in chronic schizophrenia. Soc Neurosci 22: 239
Feldon J, Weiner I . (1991): The latent inhibition model of schizophrenic attention disorder: Haloperidol and sulpiride enhance rats’ ability to ignore irrelevant stimuli. Biol Psychiatry 29: 635–646
Fiorella D, Helsley S, Rabin RA, Winter JC . (1995): The interactions of typical and atypical antipsychotics with the (-)2,5,-dimethoxy-4-methamphetamine (DOM) discriminative stimulus. Neuropharmacology 34: 1297–1303
Gelders YG, Bussche GV, Reyntjens A, Janssen PAJ . (1986): Serotonin-S2 blockers in the treatment of chronic schizophrenia. Clin Neuropharmacol 9: 325–327
Gosselin G, Oberling P, Di Scala G . (1996): Antagonism of amphetamine-induced disruption of latent inhibition by the atypical antipsychotic olanzapine in rats. Behav Pharmacol 7: 820–826
Gray NS, Hemsley DR, Gray JA . (1992a): Abolition of latent inhibition in acute, but not chronic, schizophrenics. Neurol Psychiatry Brain Res 1: 83–89
Gray NS, Pickering AD, Hemsley DR, Dawling S, Gray JA . (1992b): Abolition of latent inhibition by a single low dose of amphetamine in man. Psychopharmacology 107: 425–430
Gray NS, Pilowsky LS, Gray JA, Kerwin RW . (1995): Latent inhibition in drug naive schizophrenics: Relationship to duration of illness and dopamine D2 binding using SPET. Schizophr Res 17: 95–107
Hitchcock JM, Lister S, Fischer TR, Wettstein JG . (1997): Disruption of latent inhibition in the rat by the 5-HT2 agonist DOI: effects of MDL 100,907, clozapine, risperidon and haloperidol. Behav Brain Res 88: 43–49
Killcross AS, Dickinson A, Robbins TW . (1994a): Amphetamine-induced disruptions of latent inhibition are reinforcer mediated: Implications for animal models of schizophrenic attentional dysfunction. Psychopharmacology 115: 185–195
Killcross AS, Dickinson A, Robbins TW . (1994b): Effects of the neuroleptic alpha-flupenthixol on latent inhibition in aversively- and appetitively-motivated paradigms: Evidence for dopamine-reinforcer interactions. Psychopharmacology 115: 196–205
Kinon BJ, Lieberman JA . (1996): Mechanisms of action of atypical antipsychotic drugs: A critical analysis. Psychopharmacology 124: 2–34
Leysen JE, Janssen PM, Schotte A, Luyten WH, Megens AA . (1993): Interaction of antipsychotic drugs with neurotransmitter receptor sites in-vitro and in-vivo in relation to pharmacological and clinical effects - role of 5HT2 receptors. Psychopharmacology 112: S40–S54
Lorden JF, Rickert EJ, Berry DW . (1983): Forebrain monoamines and associative learning. I. Latent inhibition and conditioned inhibition. Behav Brain Res 9: 181–199
Meltzer HY . (1989): Clinical studies on the mechanism of action of clozapine: The dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology 99: S18–S27
Meltzer HY, Nash JF . (1991): Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43: 587–604
Moran PM, Fischer TR, Hitchcock JM, Moser PC . (1996): Effects of clozapine on latent inhibition in the rat. Behav Pharmacol 7: 42–48
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: 2531–2537
Nordstrom AL, Farde L, Halldin C . (1993): High 5-HT(2) receptor occupancy in clozapine treated patients demonstrated by PET. Psychopharmacology 110: 365–367
Peters SL, Joseph MH . (1993): Haloperidol potentiation of latent inhibition in rats: Evidence for a critical role at conditioning rather than pre-exposure. Behav Pharmacol 4: 183–186
Reyntjens A, Gelders YG, Hoppenbrouwers M-LJA, Vanden Bussche G . (1986): Thymostenic effects of ritanserin (R 55 667), a centrally acting serotonin-S2 receptor blocker. Drug Dev Res 8: 205–211
Ruob C, Weiner I, Feldon J . (1998): Haloperidol-induced potentiation of latent inhibition: Interaction with parameters of conditioning. Behav Pharmacol 9: 245–253
Sams-Dodd F . (1996): Phencyclidine-induced stereotyped behaviour and social isolation in rats: A possible animal model of schizophrenia. Behav Pharmacol 7: 3–23
Sams-Dodd F . (1997): Effect of novel antipsychotic drugs on phencyclidine-induced stereotyped behaviour and social isolation in the rat social interaction test. Behav Pharmacol 8: 196–215
Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE . (1996): Risperidone compared with new and reference antipsychotic drugs: In vitro and in vivo receptor binding. Psychopharmacology 124: 57–73
Seeger TF, Seymour PA, Schmidt AW, Zorn SH, Schulz DW, Lebel LA, Mclean S, Guanowsky V, Howard HR, Lowe JA, Heym J . (1995): Ziprasidone (CP-88,059): A new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther 275: 101–113
Shadach E, Feldon J, Weiner I . (1999): Clozapine-induced potentiation of latent inhibition is due to its action in the conditioning stage: Implications for the mechanism of action of antipsychotic drugs. Intl J Neuropsychopharmacol 2: 283–291
Solomon P, Nichols GL, Kiernan JM, Kamer RS, Kaplan LJ . (1980): Differential effects of lesions in medial and dorsal raphe of the rat: Latent inhibition and septo-hippocampal serotonin levels. J Compar and Physiol Psychol 94: 145–154
Solomon PR, Crider A, Winkelman JW, Turi A, Kamer RM, Kaplan LJ . (1981): Disrupted latent inhibition in the rat with chronic amphetamine or haloperidol-induced supersensitivity: Relationship to schizophrenic attention disorder. Biol Psychiatry 16: 519–537
Solomon PR, Kiney CA, Scott DR . (1978): Disruption of latent inhibition following systematic administration of parachlorophenylalanine (PCPA). Physiol Behav 20: 265–271
Swerdlow NR, Bakshi V, Geyer MA . (1996a): Seroquel restores sensorimotor gating in phencyclidine-treated rats. J Pharmacol Exp Ther 279: 1290–1299
Swerdlow NR, Braff DL, Hartston H, Perry W, Geyer MA . (1996b): Latent inhibition in schizophrenia. Schizophr Res 20: 91–103
Thornton JC, Dawe S, Lee C, Capstick C, Corr PJ, Cotter P, Frangou S, Gray NS, Russell MA, Gray JA . (1996): Effects of nicotine and amphetamine on latent inhibition in human subjects. Psychopharmacology 127: 164–173
Trimble KM, Bell R, King DJ . (1997): Enhancement of latent inhibition in the rat by the atypical antipsychotic agent remoxipride. Pharmacol Biochem Behav 56: 809–816
Trimble KM, Bell R, King DJ . (1998): Enhancement of latent inhibition in the rat at a high dose of clozapine. J Psychopharmacol 12: 215–219
Vaitl D, Lipp V . (1997): Latent inhibition and autonomic responses: A psycholophysiological approach. Behav Brain Res 88: 85–94
Warburton EC, Joseph MH, Feldon J, Weiner I, Gray JA . (1994): Antagonism of amphetamine-induced disruption of latent inhibition in rats by haloperdiol and ondansetron—implications for a possible antipsychotic action of ondansetron. Psychopharmacology 114: 657–664
Weiner I . (1990): Neural substrates of latent inhibition: The switching model. Psychol Bull 108: 442–461
Weiner I, Feldon J . (1987): Facilitation of latent inhibition by haloperidol in rats. Psychopharmacology 91: 248–253
Weiner I, Feldon J . (1997): The switching model of latent inhibition: An update of neural substrates. Behav Brain Res 88: 11–25
Weiner I, Lubow RE, Feldon J . (1981): Chronic amphetamine and latent inhibition. Behav Brain Res 2: 285–286
Weiner I, Lubow RE, Feldon J . (1984): Abolition of the expression but not the acquisition of latent inhibition by chronic amphetamine in rats. Psychopharmacology 83: 194–199
Weiner I, Feldon J, Katz Y . (1987): Facilitation of the expression but not the acquisition of latent inhibition by haloperidol in rats. Pharmacol Biochem Behav 26: 241–246
Weiner I, Lubow RE, Feldon J . (1988): Disruption of latent inhibition by acute administration of low doses of amphetamine. Pharmacol Biochem Behav 30: 871–878
Weiner I, Shadach E, Barkai R, Feldon J . (1997): Haloperidol- and clozapine-induced enhancement of latent inhibition with extended conditioning: Implications for the mechanism of action of neuroleptic drugs. Neuropsychopharmacology 16: 42–50
Weiner I, Shadach E, Tarrasch R, Kidron R, Feldon J . (1996): The latent inhibition model of schizophrenia: Further validation using the atypical neuroleptic, clozapine. Biol Psychiatry 40: 834–843
Weisel FA, Nordstrom AL, Farde L, Eriksson B . (1994): An open clinical and biochemical study of ritanserin in acute patients with schizophrenia. Psychopharmacology 114: 31–38
Williams JH, Wellman NA, Geaney DP, Feldon J, Rawlins JN, Cowen PJ . (1996): Anti-psychotic drug effects in a model of schizophrenic attentional disorder: A randomised trial of the effects of haloperidol on latent inhibition in healthy people. Biol Psychiatry 40: 1135–1143
Williams JH, Wellman NA, Geaney DP, Feldon J, Cowen PJ, Rawlins JNP . (1997): Haloperidol enhances latent inhibition in visual tasks in healthy people. Psychopharmacology 133: 262–268
Williams JH, Wellman NA, Geaney DP, Cowen PJ, Feldon J, Rawlins JN . (1998): Reduced latent inhibition in people with schizophrenia: An effect of psychosis or of its treatment. Br J Psychiatry 172: 243–249
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Shadach, E., Gaisler, I., Schiller, D. et al. The Latent Inhibition Model Dissociates between Clozapine, Haloperidol, and Ritanserin. Neuropsychopharmacol 23, 151–161 (2000). https://doi.org/10.1016/S0893-133X(00)00096-8
Received:
Revised:
Accepted:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(00)00096-8
Keywords
This article is cited by
-
Effects of aripiprazole and clozapine on the treatment of glycolytic carbon in PC12 cells
Journal of Neural Transmission (2012)
-
Neuroprotection of paliperidone on SH-SY5Y cells against β-amyloid peptide25-35, N-methyl-4-phenylpyridinium ion, and hydrogen peroxide-induced cell death
Psychopharmacology (2011)
-
A new model of the disrupted latent inhibition in C57BL/6J mice after bupropion treatment
Psychopharmacology (2010)
-
Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia
Neuropsychopharmacology (2009)
-
Haloperidol and risperidone have specific effects on altered pain sensitivity in the ketamine model of schizophrenia
Psychopharmacology (2009)
