Behavioral effects of family-selective inhibitors of cyclic nucleotide phosphodiesterases

The effects of family selective inhibitors of phosphodiesterase (PDEI, PDE2, PDE3, PDE4, and PDE5) on the behavior of rats under either a differential-reinforcement-of-low-rate (DRL) 72-s schedule or a variable-interval (VI) 30-s schedule were determined; previous work has shown that antidepressant drugs increase reinforcement rate under long DRL schedules. The PDE4-selective inhibitor rolipram (0.03-0.1 mg/kg) reduced response rate and increased reinforcement rate under the DRL schedule in a dose-dependent manner; similar effects were observed with the tricyclic antidepressant drug desipramine (3-10 mg/kg). Both of these drugs produced biphasic effects on behavior maintained under the VI schedule, increasing response rate at the lower doses tested (rolipram: 0.003 mg/kg; desipramine: 0.03 mg/kg) and decreasing response rate at higher doses (rolipram: 0.1 mg/kg; desipramine: 0.3-18 mg/kg). Of the other PDE inhibitors tested, only the PDE5-selective inhibitor zaprinast (10 mg/kg) produced an antidepressant-like effect on DRL behavior. However, in contrast to the biphasic effects of rolipram and desipramine on VI behavior, zaprinast produced monotonic decreases in response rate (10-30 mg/kg). The PDE2-selective inhibitor trequinsin produced biphasic effects on response rate under the VI schedule, increasing rates at low doses (3-5.6 mg/kg) and decreasing rates at higher doses (18-30 mg/kg). Trequinsin also reduced response rate under the DRL schedule (30 mg/kg); however, the reduction in response rate was not accompanied by increased reinforcement rate. The PDE3-selective inhibitor milrinone (1-10 mg/kg) tended to increase response rates under both schedules while the PDE1-selective inhibitor vinpocetine did not affect behavior at the dose range tested (1-30 mg/kg). These findings suggest that inhibition of PDE4 results in a rather unique pattern of behavioral effects, most notably an antidepressant-like effect on DRL behavior. It remains to be determined if a similar effect produced by zaprinast also implicates PDE5 in the mediation of antidepressant activity or represents an effect of this drug on PDE4 activity at high doses.