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

Journal article
Authors Daniel Klamer
Erik Pålsson
Aron Revesz
Jörgen Engel
Lennart Svensson
Published in Psychopharmacology (Berl)
Volume 176
Issue 3-4
Pages 440-50
Publication year 2004
Published at Institute of Physiology and Pharmacology, Dept of Pharmacology
Pages 440-50
Language en
Links www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Animals, Antipsychotic Agents/pharmacology, Central Nervous System Stimulants/pharmacology, Dextroamphetamine/pharmacology, Dizocilpine Maleate/pharmacology, Dopamine/*physiology, Dose-Response Relationship, Drug, Enzyme Inhibitors/pharmacology, Excitatory Amino Acid Antagonists/pharmacology, Habituation, Psychophysiologic/*drug effects, Hallucinogens/*pharmacology, Haloperidol/pharmacology, Male, Mice, NG-Nitroarginine Methyl Ester/pharmacology, Nerve Tissue Proteins/antagonists & inhibitors, Nitric Oxide/*physiology, Nitric Oxide Synthase/antagonists & inhibitors, Nitric Oxide Synthase Type I, Phencyclidine/pharmacology, Startle Reaction/*drug effects
Subject categories Physiology

Abstract

RATIONALE: A 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. OBJECTIVES: The 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. RESULTS: PCP (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. CONCLUSIONS: The 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.

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