Nefiracetam and physostigmine: separate and combined effects on learning in older rabbits

Physostigmine and nefiracetam were tested alone and in combination in 104 rabbits with a mean age of 28 months conditioned in the 750 ms delay eyeblink classical conditioning procedure. In Experiment 1, five doses of physostigmine (0.0005–0.2 mg/kg) enhanced conditioning. In Experiment 2, combinations of 10 mg/kg nefiracetam and 0.01, 0.1 and 0.2 mg/kg physostigmine improved the rate and magnitude of learning over rabbits treated with vehicle or 10 mg/kg nefiracetam alone. Brain AChE levels were significantly lower than vehicle for all doses of physostigmine and physostigmine plus nefiracetam. Control rabbits tested in the explicitly unpaired condition demonstrated that physostigmine alone and nefiracetam plus physostigmine had no non-associative effects. Physostigmine had a dramatic cognition-enhancing effect in older rabbits, and when nefiracetam was combined with physostigmine at a low dose, the ameliorating effect of physostigmine on learning was improved indicating that drug combinations for cognition enhancement may have therapeutic efficacy.