Discriminative stimulus effects of R-(+)-3-amino-1-hydroxypyrrolid-2-one, [(+)-HA-966], a partial agonist of the strychnine-insensitive modulatory site of the N-methyl-D-aspartate receptor.
The strychnine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex is a target for development of a host of therapeutic agents including anxiolytics, antidepressants, antiepileptics, anti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2-one], a low-efficacy partial agonist of the glycine site, was explored. Male, Swiss-Webster mice were trained to discriminate (+)-HA-966 (170 mg/kg i.p.) from saline in a T-maze under which behavior was controlled by food. Other glycine partial agonists, 1-amino-1-cyclopropanecarboxilic acid and D-cycloserine, fully substituted for the discriminative stimulus effects of (+)-HA-966 despite known differences in other pharmacological effects of these compounds. The glycine site antagonist, 7-chlorkynurenic acid, did not substitute for (+)-HA-966. Likewise other functional NMDA antagonists acting at nonglycine sites of the NMDA receptor also did not substitute: neither the high (dizocilpine) or low affinity (ibogaine) ion-channel blocker, the competitive antagonist, NPC 17742 [2R,4R,5S-2-amino-4,5-(1, 2-cyclohexyl)-7-phosphonoheptanoic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did not substitute, this compound fully blocked the discriminative stimulus effects of (+)-HA-966. In a separate group of mice trained to discriminate 0.17 mg/kg of dizocilpine from saline, (+)-HA-966 produced a maximum of only 50% dizoclipine-appropriate responses. These data suggest that the discriminative stimulus effects of (+)-HA-966 are based upon its partial agonist actions at the strychnine-insensitive glycine site.(ABSTRACT TRUNCATED AT 250 WORDS)
Psychobiology Section, Addiction Research Center, National Institute on Drug Abuse, National Institutes of health, Baltimore, Maryland, USA.
J M
JM
Witkin
S
S
Brave
D
D
French
B
B
Geter-Douglass
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism; D007050:Ibogaine / Q000494:pharmacology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013331:Strychnine / Q000494:pharmacology*
D000596:Amino Acids; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; C060212:NPC 12626; D007050:Ibogaine; D016291:Dizocilpine Maleate; C001369:1-hydroxy-3-amino-2-pyrrolidone; D013331:Strychnine; C010739:ifenprodil; D005998:Glycine