In Vitro and In Vivo Inhibition of Rat Brain Nitric Oxide Synthase Activity by Phencyclidine

Abstract

Phencyclidine (PCP) is a widely abused psychoactive drug that perturbs many neurotransmitter systems studied to date. Nitric oxide (NO) has been established as a neuronal messenger and its rapid diffusibility across cell membranes makes NO an extensive and versatile messenger in brain development and functioning. The present study was initiated to investigate the effect of PCP on rat brain nitric oxide synthase (NOS) activity both in vitro and in vivo. Brain cytosolic fractions from normal rats were used for in vitro and in vivo studies. The rats were treated with a single dose of PCP (10 mg/kg, intraperitoneally); the brains were removed at 0, 1, 2, 6, and 12 hours after PCP treatment and the cytosolic fractions were prepared by homogenization and centrifugation. NOS activity was assessed by quantifying the release of [ 3 H]-citrulline from [ 3 H]-arginine. PCP signi® cantly inhibited rat brain NOS in vitro in a concentration (0.05± 2 mM)-dependent manner. The kinetic evaluation of arginine, NADPH, and Ca 2+ activation of NOS revealed that PCP (0.5 mM) inhibited NOS activity competitively with respect to arginine and NADPH and noncompetitively inhibited with respect to Ca 2+ . PCP also caused a time-dependent reduction of brain NOS activity in vivo as early as 1 hour after treatment. Even after 12 hours of PCP treatment, NOS activity did not reverse to its normal level as compared to the control group, suggesting sequestration and persistence of the drug in the central nervous system. These results suggest that inhibition of brain NOS by PCP might be one of the mechanisms through which PCP causes neurotoxicity.

Fire Ant Venom Alkaloid, Isosolenopsin A, a Potent and Selective Inhibitor of Neuronal Nitric Oxide Synthase

“…These data compare favorably with the inhibitory potency of widely used nNOS inhibitors, such as 7-nitroindazole, which is not a selective inhibitor for nNOS (Alderton, Cooper, and Knowles 2001;Babbedge et al 1993). Isosolenopsin A exerts a noncompetitive inhibition like the imidazole derivatives (Sorrenti et al 2001), contrary to the competitive NOS inhibitors (Zhang et al 1997;Desaiah et al 1999;Frey et al 1994).…”

Effects of nitric oxide synthase inhibitors on the discriminative stimulus effects of cocaine in rats

“…These drugs were no more effective in this regard after L-NAME pretreatment, except for 3.0 mg/kg PCP. The effectiveness of L-NAME for enhancing cocaine-appropriate responses after 3.0 mg/kg PCP may have resulted from the unique ability of PCP vs other NMDA antagonists to either inhibit DA uptake to some degree (Snell et al 1988) or to inhibit neuronal NOS enzyme activity (Desaiah et al 1999). In rodents, L-NAME enhances hyperlocomotion induced by 3.0 mg/kg PCP (Noda et al 1995), but does not produce PCP-like discriminative stimulus effects (Wiley et al 1999; but see Jewett et al 1996 for contrasting discrimination results in pigeons).…”