2-Amino-7-phosphonoheptanoic acid, a selective antagonist of N-methyl-D-aspartate, prevents barbital withdrawal-induced convulsions and the elevation of cerebellar cyclic GMP in dependent rats.
Female Sprague-Dawley rats were maintained on a diet of barbital for 8 weeks, a period of time previously shown to result in tolerance to and dependence on the drug. After completing this course, the barbital was abruptly withdrawn and the selective antagonist of N-methyl-d-aspartate (NMDA), 2-amino-7-phosphonoheptanoic acid (APH), or saline was infused intracerebroventricularly over 48 hr. Control rats which had not received barbital, were similarly infused with either saline or APH. All animals were observed for 12-48 hr following the withdrawal of the barbital; spontaneous convulsions, previously reported to be numerous and severe after withdrawal of the drug, were counted and graded according to severity. Forty-eight hr after withdrawal of barbital, the rats were killed by focussed microwave irradiation and cerebellae were collected for later determination of levels of cGMP. Nine convulsions occurred in 29 rats withdrawn from barbital and infused intracerebroventricularly with APH, this contrasted markedly with 61 convulsions seen in 29 animals withdrawn from the drug and infused with saline. There was a 3-fold elevation of levels of cGMP in the saline-infused, barbital-withdrawn rats when compared to control rats infused with saline. This evaluation was markedly, although not completely, prevented by the intracerebroventricular infusion of APH. These data provide evidence that dicarboxylic amino acid pathways, specifically those acting through NMDA receptors, are involved in seizure activity seen following abrupt abstinence from barbital.
McCaslin
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PP
Morgan
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WW
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D001462:Barbital / Q000009:adverse effects*; D001463:Barbiturates / Q000009:adverse effects*; D002531:Cerebellum / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D005260:Female; D016202:N-Methylaspartate; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders / Q000378:metabolism
D000596:Amino Acids; D001463:Barbiturates; D001224:Aspartic Acid; D001462:Barbital; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D006152:Cyclic GMP; C031231:2-amino-7-phosphonoheptanoic acid