Selective interaction of nitric oxide synthase inhibition with phencyclidine: behavioural and NMDA receptor binding studies in the rat.
The psychotomimetic drugs, phencyclidine (PCP) and MK-801, are non-competitive antagonists of the N-methyl-d-aspartate (NMDA) receptor and used as pharmacological tools to mimic a possible NMDA receptor hypofunction in schizophrenia. These drugs were tested in two behavioural paradigms in the present study: prepulse inhibition (PPI) of acoustic startle and locomotor activity (LMA) in an open field. Recent studies show that several behavioural and biochemical effects of PCP are blocked by nitric oxide synthase (NOS) inhibition. Hence, it is likely that some effects of PCP are mediated via an increase in NO production, an assumption not in accordance with the NMDA receptor antagonistic effect of PCP. Experiments were conducted in rats to further elucidate the involvement of NO-dependent mechanisms in the effects of PCP and MK-801, and how these effects may involve the NMDA receptor. The NOS inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) (10 mg/kg) normalised the disruptive effect of PCP (2 mg/kg) on PPI and the stimulatory effect of PCP (4 mg/kg) on LMA. In contrast to these observations, the deficit in PPI induced by MK-801 (0.1 mg/kg) was not affected by L-NAME (10, 20 or 40 mg/kg). MK-801 (0.15 mg/kg)-induced hyperlocomotion was not affected by L-NAME (10 mg/kg), but attenuated by L-NAME (40 mg/kg). Furthermore, receptor binding studies aimed at investigating the influence of L-NAME on the binding of PCP to the MK-801-sensitive NMDA receptor binding site failed to show such an influence. These results suggest that the NO-sensitive effects of PCP are not sufficiently explained by its antagonistic effect at the NMDA receptor channel complex.
Klamer
Daniel
D
Department of Pharmacology, The Sahlgrenska Academy at Göteborg University, Göteborg University, P.O. Box 431, SE 40530 Göteborg, Sweden.
Zhang
Jianhua
J
Engel
Jörgen A
JA
Svensson
Lennart
L
D000161:Acoustic Stimulation; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects*
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; D010622:Phencyclidine; D019331:NG-Nitroarginine Methyl Ester