Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms

RationaleA deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and d-amphetamine (d-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP.ObjectivesThe first aim of the present study was to investigate if PCP, MK-801 and d-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, l-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation.ResultsPCP (4 mg/kg), MK-801 (0.4 mg/kg) and d-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, l-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and d-AMP, but not that of MK-801.ConclusionsThe finding that PCP, MK-801 and d-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.

[1]  M. Geyer,et al.  Deficits in prepulse inhibition and habituation in never-medicated, first-episode schizophrenia , 2003, Biological Psychiatry.

[2]  G. Berríos,et al.  The early development of Kraepelin's ideas on classification: a conceptual history , 1988, Psychological Medicine.

[3]  L. Petrinovich,et al.  Habituation to territorial song in the White-crowned sparrow (Zonotrichia leucophrys). , 1973, Behavioral biology.

[4]  Braff Dl,et al.  Acute and chronic LSD effects on rat startle: data supporting an LSD--rat model of schizophrenia. , 1980 .

[5]  R. Rothman,et al.  PCP site 2: a high affinity MK-801-insensitive phencyclidine binding site. , 1994, Neurotoxicology and teratology.

[6]  M. Geyer,et al.  Acute and chronic LSD effects on rat startle: data supporting an LSD--rat model of schizophrenia. , 1980, Biological psychiatry.

[7]  N. Swerdlow,et al.  Central dopamine hyperactivity in rats mimics abnormal acoustic startle response in schizophrenics , 1986, Biological Psychiatry.

[8]  L. Kokkinidis.  Sensitization to amphetamine and tolerance to cocaine and phencyclidine stimulation in mice , 1986, Pharmacology Biochemistry and Behavior.

[9]  D. Segal,et al.  Increased startle responding in rats treated with phencyclidine. , 1984, Neurobehavioral toxicology and teratology.

[10]  H. Hoffman,et al.  Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system processes sensory input. , 1980, Psychological review.

[11]  N. Swerdlow,et al.  Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. , 1994, The Journal of pharmacology and experimental therapeutics.

[12]  D. Jackson,et al.  Nitric oxide synthase inhibition blocks phencyclidine-induced behavioural effects on prepulse inhibition and locomotor activity in the rat , 1997, Psychopharmacology.

[13]  M. Koch,et al.  The neurobiology of startle , 1999, Progress in Neurobiology.

[14]  M. Koch,et al.  Substance P is involved in the sensitization of the acoustic startle response by footshocks in rats , 1994, Behavioural Brain Research.

[15]  R. Idzerda,et al.  Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Charpie,et al.  Nitric oxide regulation of ADP-ribosylation of G proteins in hypertension. , 1995, Medical hypotheses.

[17]  A Carlsson,et al.  Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. , 2001, Annual review of pharmacology and toxicology.

[18]  P. Greengard,et al.  Diverse Psychotomimetics Act Through a Common Signaling Pathway , 2003, Science.

[19]  D. Levy,et al.  Smooth pursuit eye movements, attention, and schizophrenia. , 1976, Archives of general psychiatry.

[20]  Effects of phencyclidine (PCP) and (+)MK-801 on sensorimotor gating in CD-1 mice. , 1998, Progress in neuro-psychopharmacology & biological psychiatry.

[21]  P. Huang,et al.  Genetic analysis of NOS isoforms using nNOS and eNOS knockout animals. , 1998, Progress in brain research.

[22]  P. Goldman-Rakic,et al.  Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling. , 2003, Trends in pharmacological sciences.

[23]  C. Grillon,et al.  Startle gating deficits occur across prepulse intensities in schizophrenic patients , 1992, Biological Psychiatry.

[24]  H. Schulman,et al.  An ADP-ribosyltransferase as a potential target for nitric oxide action in hippocampal long-term potentiation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[25]  JaneR . Taylor,et al.  Activation of cAMP-Dependent Protein Kinase A in Prefrontal Cortex Impairs Working Memory Performance , 1999, The Journal of Neuroscience.

[26]  N. Swerdlow,et al.  Discrepant Findings of Clozapine Effects on Prepulse Inhibition of Startle: Is It the Route or the Rat? , 1998, Neuropsychopharmacology.

[27]  W. Simonds.  G protein regulation of adenylate cyclase. , 1999, Trends in pharmacological sciences.

[28]  Chris Muly.  Signal transduction abnormalities in schizophrenia: the cAMP system. , 2002, Psychopharmacology bulletin.

[29]  Daniel R Weinberger,et al.  To Model a Psychiatric Disorder in Animals: Schizophrenia As a Reality Test , 2000, Neuropsychopharmacology.

[30]  J. Stamford,et al.  Effects of dizocilpine (MK 801) on noradrenaline, serotonin and dopamine release and uptake , 2000, Neuroreport.

[31]  K. Rice,et al.  The psychotomimetic drug phencyclidine labels two high affinity binding sites in guinea pig brain: evidence for N-methyl-D-aspartate-coupled and dopamine reuptake carrier-associated phencyclidine binding sites. , 1989, Molecular pharmacology.

[32]  C. Ledent,et al.  Reduced startle habituation and prepulse inhibition in mice lacking the adenosine A2A receptor , 2003, Behavioural Brain Research.

[33]  J. Wiley.  Nitric Oxide Synthase Inhibitors Attenuate Phencyclidine-Induced Disruption of Prepulse Inhibition , 1998, Neuropsychopharmacology.

[34]  Christian Grillon,et al.  Gating and habituation of the startle reflex in schizophrenic patients. , 1992 .

[35]  E. Daneluzzo,et al.  Startle reflex habituation in functional psychoses: A controlled study , 1992, Neuroscience Letters.

[36]  M. Geyer,et al.  Habituation of the Blink reflex in normals and schizophrenic patients. , 1982, Psychophysiology.

[37]  N. Andreasen.  A unitary model of schizophrenia: Bleuler's "fragmented phrene" as schizencephaly. , 1999, Archives of general psychiatry.

[38]  D. Jackson,et al.  The neuronal selective nitric oxide inhibitor AR-R 17477, blocks some effects of phencyclidine, while having no observable behavioural effects when given alone. , 1999, Pharmacology & toxicology.

[39]  Michael Davis,et al.  Effects of d- and l-amphetamine on habituation and sensitization of the acoustic startle response in rats , 1975, Psychopharmacologia.

[40]  D. Javitt,et al.  Phencyclidine (PCP)-induced deficits of prepulse inhibition in monkeys , 2001, Neuroreport.

[41]  Michael Davis,et al.  Neurochemical modulation of sensory-motor reactivity: Acoustic and tactile startle reflexes , 1980, Neuroscience & Biobehavioral Reviews.

[42]  M. Davis,et al.  A primary acoustic startle circuit: lesion and stimulation studies , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[43]  Michael Davis,et al.  Involvement of cyclic AMP at the level of the nucleus reticularis pontis caudalis in the acoustic startle response , 1995, Brain Research.

[44]  M. Decker,et al.  Effects of phencyclidne (PCP) and (+)MK-801 on sensorimotor gating in CD-1 mice , 1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[45]  M. Geyer,et al.  Startle habituation and sensorimotor gating in schizophrenia and related animal models. , 1987, Schizophrenia bulletin.

[46]  Paul Greengard,et al.  DARPP-32: Regulator of the Efficacy of Dopaminergic Neurotransmission , 1998 .

[47]  N. Swerdlow,et al.  Seroquel restores sensorimotor gating in phencyclidine-treated rats. , 1996, The Journal of pharmacology and experimental therapeutics.

[48]  Mark Ellisman,et al.  Direct modulation of calmodulin targets by the neuronal calcium sensor NCS-1. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[49]  M. Geyer,et al.  Prestimulus effects on human startle reflex in normals and schizophrenics. , 1978, Psychophysiology.

[50]  M. Low,et al.  Differential Effects of Direct and Indirect Dopamine Agonists on Prepulse Inhibition: A Study in D1 and D2 Receptor Knock-Out Mice , 2002, The Journal of Neuroscience.

[51]  P. Groves,et al.  Habituation: a dual-process theory. , 1970, Psychological review.

[52]  Jörgen A. Engel,et al.  The nitric oxide synthase inhibitor. L-NAME, blocks certain phencyclidine-induced but not amphetamine-induced effects on behaviour and brain biochemistry in the rat , 1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[53]  S. Kapur,et al.  NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia , 2002, Molecular Psychiatry.

[54]  H. Schnitzler,et al.  Synaptic plasticity in the acoustic startle pathway: the neuronal basis for short‐term habituation? , 2002, The European journal of neuroscience.

[55]  P. Goldman-Rakic.  Working memory dysfunction in schizophrenia. , 1994, The Journal of neuropsychiatry and clinical neurosciences.

[56]  D. Jackson,et al.  Prepulse inhibition of acoustic startle, a measure of sensorimotor gating: Effects of antipsychotics and other agents in rats , 1995, Pharmacology Biochemistry and Behavior.

[57]  K H Nuechterlein,et al.  Information‐processing abnormalities as neuropsychological vulnerability indicators for schizophrenia , 1994, Acta psychiatrica Scandinavica. Supplementum.

[58]  Glutamate antagonists in the reticular formation reduce the acoustic startle response. , 1993, Neuroreport.

[59]  D. Braff.  Information processing and attention dysfunctions in schizophrenia. , 1993, Schizophrenia bulletin.

[60]  Torben Mackeprang,et al.  Effects of antipsychotics on prepulse inhibition of the startle response in drug-naïve schizophrenic patients , 2002, Biological Psychiatry.

[61]  D. Jackson,et al.  The atypical antipsychotic, remoxipride, blocks phencyclidine-induced disruption of prepulse inhibition in the rat , 1994, Psychopharmacology.