Modulation of the PCP/NMDA receptor complex and sigma binding sites by psychostimulants.
The present study was undertaken to determine the role and modulation of the PCP/NMDA receptor complex and sigma binding sites in the central nervous system of animals treated with psychostimulant agents. Repeated exposure of mice to cocaine (45 mg/kg/day; for 7 days) was associated with a progressive increase in convulsive response and lethality rate. The sensitization to the toxic effects of cocaine in mice was completely abolished by pretreatment with either the noncompetitive NMDA receptor antagonist MK-801 (0.35 mg/kg/day), or the nitric oxide synthase inhibitor Ng-nitro-L-arginine methyl ester (100 mg/kg/day). Parallel in vitro receptor binding assays indicated first, upregulation of cortical NMDA receptors labeled with [3H]CGP 39653, and second, glutamate-dependent sensitization of [3H]MK-801 binding to the PCP site in cortical membranes of the mice treated for 7 days with cocaine. Repeated exposure of rats to methamphetamine (4.0 mg/kg/day; for 10 days) resulted in a significant upregulation of the sigma-1 binding site labeled with (+)[3H]pentazocine in the frontal cortex and substantia nigra. The cocaine-related studies suggest that the PCP/NMDA receptor complex is involved in the development of sensitization to the neurotoxic effects of the drug, such as "pharmacological kindling". The methamphetamine-related studies insinuate a potential role of sigma-1 binding sites in psychostimulant-induced behavioral disorders.
Itzhak
Y
Y
Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, FL 33101.
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester; D009928:Organ Specificity; D010423:Pentazocine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D017478:Receptors, Phencyclidine / Q000187:drug effects / Q000378:metabolism*; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology
D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; C069052:CGP 39653; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D001120:Arginine; D003042:Cocaine; D010423:Pentazocine; D019331:NG-Nitroarginine Methyl Ester