Long-term behavioral effects of phenobarbital in suckling rats.

Long-term effects of phenobarbital on behavior and learning, persisting after drug withdrawal, have not been defined. To look for such effects on the developing nervous system, we treated albino rat pups with phenobarbital for 30 days and then tested them at intervals starting 10 days after the cessation of drug therapy. Beginning at age 6 days, 12 pups were given Ph subcutaneously, gradually increasing the dose to 30 mg/kg/dose b.i.d. by 11 days and continued until 36 days. Twelve control pups were injected with saline. Serum phenobarbital concentrations at 16 days were 54 to 32 micrograms/ml and at 31 days 36 to 4 micrograms/ml. From 46 to 55 days, all animals were tested in a water T maze. The experimental animals completed the four daily runs faster than controls (P = 0.003), made fewer errors (P = 0.003), and spent less time on error-free runs (P = 0.04). When the same animals were retested in the maze at 129 to 136 days, the trend toward faster times was not significant. There were no differences in brain weights of experimental and control rats at 157 days. Twelve pups treated similarly with phenobarbital at 20 mg/kg/dose b.i.d. spent less time on error-free runs than 12 controls when tested at 48 to 57 days of age (P = 0.05) but no differences were found when 12 similarly treated pups were tested at 79 to 85 days. There were no differences in brain weights of the treated and control rats at 78 days of age. Thus it was shown that phenobarbital administration in suckling rats had an effect on behavior that was present 10 to 20 days after the drug was cleared from their serum.