The discriminative stimulus effects of N-methyl-D-aspartate antagonists in phencyclidine-trained rats.
The discriminative stimulus effects of two competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-7-phosphonoheptanoate (APH) and 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonate (CPP), were assessed in rats trained to discriminate phencyclidine from saline. Systemically administered APH (10-60 mg/kg i.p.) failed to elicit phencyclidine-lever responding; however, partial generalization from phencyclidine occurred following intracerebroventricular (i.c.v.) administration of APH (1.5-30 micrograms). Systemic and central administration of CPP (3-30 mg/kg i.p.; 0.1-10 micrograms i.c.v.) also resulted in partial generalization from phencyclidine. Partial generalization was also obtained with methohexital (5-30 mg/kg i.p.). However, generalization to APH, CPP and methohexital was usually accompanied by decreased response rates, and response rate decreases frequently occurred without appreciable phencyclidine-lever selection, indicating that these drugs also had no phencyclidine-like behavioral effects. The drug di-ortho-tolyl guanidine (DTG) which binds with high-affinity to sigma receptors failed to elicit phencyclidine-lever responding, even at doses which reduced response rates. These findings suggest that although competitive NMDA antagonists share some discriminative stimulus properties with phencyclidine, there is not a complete overlap in the discriminative stimulus properties of competitive and non-competitive NMDA antagonists. Furthermore, the discriminative stimulus effects of APH and CPP were no more similar to phencyclidine than those of methohexital.
Willetts
J
J
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613.
Balster
R L
RL
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D008723:Methohexital / Q000494:pharmacology; D016202:N-Methylaspartate; D010622:Phencyclidine; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000596:Amino Acids; D010879:Piperazines; D001224:Aspartic Acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D008723:Methohexital; D010622:Phencyclidine; C031231:2-amino-7-phosphonoheptanoic acid