Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity

Abstract

Currently available antipsychotic medications work primarily by antagonizing D2 dopamine receptors, thus raising intracellular cAMP levels. We hypothesized that intracellular stimulation of cAMP levels in the CNS would have similar effects to treatment with antipsychotic medication. To test this hypothesis, we studied the effect of an acute treatment of rolipram, an inhibitor of type 4 phosphodiesterases that degrade cAMP, on acoustic startle and prepulse inhibition (PPI) of the acoustic startle response in C57BL/6J mice known to exhibit poor PPI. PPI is disrupted in schizophrenia patients, and the ability of a drug to increase PPI in mice is predictive of antipsychotic efficacy. We show here that acute treatment with rolipram significantly increases PPI at doses that do not alter the acoustic startle response (lowest effective dose 0.66 mg/kg). In addition, rolipram (0.66 mg/kg) blocks the disruptive effects of amphetamine (10 mg/kg) on PPI. At a slightly higher dose (1.0 mg/kg), rolipram also induces catalepsy. Thus, phosphodiesterase-4 (PDE4) inhibition has many of the same behavioral effects as traditional antipsychotic medications. In contrast to traditional antipsychotics, these effects are achieved through alteration of an intracellular second messenger system rather than antagonism of neurotransmitter receptors. Given previous reports showing rolipram improves cognition, we conclude that PDE4 represents an important novel target for further antipsychotic drug development.

Fig. 1

Rolipram increases PPI in a dose-dependent manner. Rolipram (rol), administered 15 min before testing, produced a dose-dependent increase in PPI. Overall, 10 mg/kg rolipram had the greatest effect at all prepulse intensities, with significant increases also observed for doses of 0.66 mg/kg and 1 mg/kg. In addition, the largest effects of rolipram were seen at higher prepulse intensities. n=18 per group. Post hoc ^@ vs. vehicle and 0.1 mg/kg, P<0.025–0.001; ^# vs. vehicle, 0.1 and 0.66 mg/kg, P<0.01–0.001; ^ vs. vehicle, 0.1, 0.66, and 1 mg/kg, P<0.02–0.001.

Fig. 2

Rolipram decreases startle magnitude to lower intensity stimuli only. Rolipram generally decreased startle responding at doses of 0.66 mg/kg to 10 mg/kg. Importantly, there was no effect of rolipram in response to a 120 dB stimulus, the intensity used in PPI trials; n=18 mice per treatment group. Post hoc * vs. vehicle, P<0.05.

Fig. 3

Haloperidol (hal) increases PPI in a dose-dependent manner. Across prepulse intensities, 1.0 mg/kg hal, but not 0.1 mg/kg hal significantly increased PPI relative to vehicle; n=8 per group. Post hoc for effect of treatment across trials, * vs. vehicle, P<0.05.

Fig. 4

Rolipram (rol) ameliorates the impairment in PPI caused by amphetamine. Relative to vehicle, d-amphetamine (10 mg/kg; amph) disrupted PPI; however, pretreatment with rol (0.66 mg/kg) blocked this disruption; n=14 per group. ^ Main effect of amphetamine, P=0.05; post hoc * vs. veh-veh, P<0.05; ^@ vs. veh-amph, P<0.05.

Fig. 5

Rolipram (rol) neither augments nor reverses the effects of amphetamine on startle responses to higher intensity stimuli. d-Amphetamine (10 mg/kg; amph) generally reduced acoustic startle responses to higher intensity stimuli (105 dB and greater), but not to the level of statistical significance. As above, rol (0.66 mg/kg) reduced acoustic startle responses. There was neither a rescue nor an additive effect of rol plus amphetamine on startle responses to higher intensity stimuli; however, amphetamine appeared to block the ability of rol to reduce startle responses to lower intensity stimuli; n=14 mice per treatment group. Post hoc * vs. veh-veh, P<0.05; ^@ vs. veh-amph, P<0.05; ^# vs. veh-amph and rol-amph, P<0.05.