Phenytoin and phenobarbital: a comparison of their state-dependent effects

Two commonly used antiepileptic drugs, phenytoin sodium and phenobarbital sodium, were investigated for state-dependency effects at different doses. Male Wistar strain rats trained to a criterion in an inhibitory avoidance task and a food-motivated T-maze task under varying drug and nondrug states were subjected to retention tests 24 and 48 h, respectively, following acquisition. The treatment instituted at the time of retrieval was either the same as, or different from, that used during training. The results indicated that phenytoin produced state-dependency effects at test doses of 20, 40, and 60 mg/kg in the avoidance task and at test dose of 20 mg/kg in the T-maze task experiments. These state-specific effects were comparable to those of phenobarbital sodium (5 and 10 mg/kg). The reinstitution of the drug state in an additional test session produced approximately equal and significant recovery of conditioned responses in the T-maze paradigm both in phenytoin and phenobarbital groups. These results demonstrate, for the first time, the ability of phenytoin to produce state-dependency effects in a pattern similar to that observed with a widely studied compound such as phenobarbital. Overall, the data provide no support for the view that the degree of discriminability of a drug is an indicator of potential state-dependency effects and is restricted only to the dosage high enough to produce noticeable intoxication.