Nitric oxide synthase inhibition attenuates phencyclidine-induced disruption of cognitive flexibility.
Schizophrenia encompasses, amongst other symptoms, a heavy load of cognitive dysfunctionality. Using the psychotomimetic agent, phencyclidine (PCP), we have previously found that PCP-induced disruptions of cognitive function in translational rodent models of schizophrenia are dependent on nitric oxide (NO) production. In the present study, male Sprague-Dawley rats were subjected to a Morris water maze task designed to assess cognitive flexibility (i.e. the ability to cope with an increasingly demanding cognitive task) by means of a "constant reversal learning paradigm". Experiments were conducted to evaluate the effects of the NO synthase inhibitor, L-NAME (10 mg/kg), on PCP-induced (2 mg/kg) impairments. Control animals significantly improved their learning over the first 3 consecutive days, whereas PCP-treated animals failed to show any significant learning. Pretreatment with L-NAME normalized the PCP-induced disruption of learning to control levels. These findings suggest that PCP-induced disruptions of cognitive flexibility (i.e. ability to modify behaviour according to an increasingly demanding cognitive task) are dependent upon NO production. These observations, together with accumulated clinical findings, suggest that the NO system is a potential treatment target for cognitive dysfunctions in schizophrenia.
Wass
Caroline
C
Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. caroline.wass@pharm.gu.se
Svensson
Lennart
L
Fejgin
Kim
K
Pålsson
Erik
E
Archer
Trevor
T
Engel
Jörgen A
JA
Klamer
Daniel
D
D000818:Animals; D003071:Cognition / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects; D013550:Swimming
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010622:Phencyclidine; D019331:NG-Nitroarginine Methyl Ester