cgp-37849 and Substance-Withdrawal-Syndrome

Tolerance occurred to the sedative actions of the competitive NMDA antagonists, CGP39551 and CGP37849, as measured by a decrease in spontaneous locomotor activity after 1 week or 2 weeks of administration, respectively, in studies using the TO strain of mice. Crosstolerance was seen between these compounds. When CGP37849 was given after 2 weeks treatment with CGP39551, an increase in locomotor activity was seen. Chronic barbiturate treatment, producing tolerance to the actions of pentobarbitone, did not affect the sedative properties of CGP39551 or CGP37849. Chronic treatment with CGP39551 did not alter the ataxic actions of pentobarbitone. Seven days of treatment with HA966 caused complete tolerance to its sedative actions, but no crosstolerance was seen to pentobarbitone, CGP39551, or CGP37849. A small but significant decrease was seen in the convulsion thresholds to NMDA after 15 days of treatment with CGP39551, and a small significant increase in ratings of convulsive behavior after 16 days injections of CGP37849. No significant changes were found in either Bmax or Kd for [3H]-MK-801 binding in cerebrocortical tissue 24 h after the last chronic treatment with either of the NMDA antagonists.

Topics: 2-Amino-5-phosphonovalerate; Animals; Ataxia; Behavior, Animal; Dizocilpine Maleate; Drug Tolerance; Hypnotics and Sedatives; Male; Mice; Motor Activity; N-Methylaspartate; Pyrrolidinones; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

1. The competitive antagonists at the N-methyl-D-aspartate (NMDA) receptor, CGP39551 and CGP37849, protected against the barbiturate withdrawal syndrome in mice, as measured by ratings of convulsive behaviour on handling. 2. The effective doses of these compounds were lower than those required to prevent seizures due to NMDA in naive animals; these were in turn lower than those needed to prevent the convulsive effects of the alpha-aminobutyric acid (GABA) antagonist, bicuculline. 3. The NMDA-receptor antagonists did not alter the increase in the incidence of convulsions due to the GABAA antagonist, bicuculline, that is seen during barbiturate withdrawal, although the latencies to these convulsions during barbital withdrawal were significantly increased after CGP39551. 4. Barbiturate withdrawal did not affect the convulsive actions of NMDA, whether measured by the incidence of convulsions or by intravenous infusion. 5. The Bmax for [3H]-dizocilpine ([3H]-MK801) binding was significantly increased by chronic barbital treatment in cerebrocortical but not in hippocampal tissues, while the Kd remained unaltered in either case. 6. At 1 h and 24 h after administration of a single dose of barbitone, the Bmax for [3H]-dizocilpine binding was unaltered in cerebrocortical tissue. Acute addition of barbitone in vitro did not alter [3H]-dizocilpine binding or the displacement of binding of thienylcyclohexylpyridine.

Topics: 2-Amino-5-phosphonovalerate; Animals; Barbital; Bicuculline; Cerebral Cortex; Dizocilpine Maleate; Hippocampus; Male; Mice; Motor Activity; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome