dizocilpine-maleate and Neonatal-Abstinence-Syndrome

There is increasing evidence that the N-methyl-D-aspartate (NMDA) receptor and the nitric oxide system are involved in opiate dependence in the adult rat, but whether these results in the adult apply to the infant rat is unknown.. Here we examined the effects of NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors, which reduce the opiate abstinence syndrome in adult animals, on morphine withdrawal in the infant rat.. Neonatal rats were injected with morphine sulfate (10.0 mg/kg) twice daily for 6.5 days. On the 7th day, pups were injected with NOS inhibitors (L-NAME or 7-NI), NMDA receptor antagonists (MK-801 or AP-5), or vehicle. After 15 min, the pups were injected with naltrexone (1 mg/kg) to precipitate withdrawal. Behavior for each pup was identified and recorded every 15 s for 10 min before naltrexone injection and 15 min after naltrexone injection.. Both L-NAME and 7-NI significantly reduced most withdrawal behaviors in the infant rat, a result in line with previous studies in the adult rat. In contrast, AP-5 reduced some withdrawal behaviors but also increased others (e.g., moving paws). MK-801 was likewise ineffective in reducing most withdrawal behaviors and increased certain withdrawal behaviors (walking and wall climbing).. In the infant rat, the production of nitric oxide is involved in opiate withdrawal whereas the NMDA receptor may not yet be functionally active or may play only a minor role.

Topics: 2-Amino-5-phosphonovalerate; Aging; Animals; Animals, Newborn; Dizocilpine Maleate; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Humans; Indazoles; Infant, Newborn; Male; Morphine; Naltrexone; Narcotic Antagonists; Narcotics; Neonatal Abstinence Syndrome; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate

Alcohol exposure during development can produce central nervous system dysfunction, resulting in a wide range of behavioral alterations. The various mechanisms by which alcohol causes these behavioral changes, however, remain unknown. One mechanism that has been suggested is NMDA receptor-mediated excitotoxic cell death produced by ethanol withdrawal. The present study examined whether MK-801, an antagonist of the NMDA receptor that has been shown to protect against NMDA receptor-mediated excitotoxicity, could block alcohol's adverse effects on behavior. Sprague-Dawley rat pups were exposed to alcohol (6.0 g/kg) in a binge-like manner on postnatal day 6 using an artificial rearing procedure. Subjects then received an injection of MK-801 (0.1 mg/kg) or vehicle during withdrawal, 21 hr after ethanol exposure. At postnatal day 40, all subjects were tested on a serial spatial discrimination reversal task. Ethanol-exposed subjects were impaired in both discrimination and reversal learning, and committed a significantly greater number of perseverative-type errors, compared with controls. MK-801 administration during ethanol withdrawal significantly attenuated ethanol-induced deficits in reversal learning and increases in perseverative-type errors, whereas MK-801 exposure by itself had no significant effect on performance. Thus, exposure to MK-801 during ethanol withdrawal partially protected against alcohol-related disruptions in spatial reversal learning. These results support the suggestion that NMDA receptor-mediated excitotoxicity may be one mechanism by which alcohol induces behavioral teratogenicity.

Topics: Alcohol Withdrawal Delirium; Animals; Animals, Newborn; Behavior, Animal; Brain; Discrimination Learning; Dizocilpine Maleate; Female; Fetal Alcohol Spectrum Disorders; Humans; Infant, Newborn; Male; Maze Learning; Mental Recall; Neonatal Abstinence Syndrome; Orientation; Pregnancy; Rats; Receptors, N-Methyl-D-Aspartate; Reversal Learning