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


OBJECTIVE
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.
Klamer
Daniel
D
Department of Pharmacology, The Sahlgrenska Academy, Göteborg University, PO Box 431, 405-30, Goteborg, Sweden.
Pålsson
Erik
E
Revesz
Aron
A
Engel
Jörgen A
JA
Svensson
Lennart
L
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006185:Habituation, Psychophysiologic / Q000187:drug effects*; D006213:Hallucinogens / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D010622:Phencyclidine / Q000494:pharmacology; D013216:Reflex, Startle / Q000187:drug effects*
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D010622:Phencyclidine; D006220:Haloperidol; D003913:Dextroamphetamine; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine