The role of nucleotide phosphodiesterase inhibitors in memory

The effects of memory impairing of cyclic nucleotide phosphodiesterase (PDE) inhibitors zaprinast, 7-benylamino-6-chloro-piperazino-4 pyrrolidino-pteridine (DC-TA 46) and rolipram were tested by means of Morris water maze (MWM); their ability to increase cyclic nucleotide levels in the hippocampus (HF) and striatum (CP) was also assayed. DC-TA 46 causes memory impairment at maximal dose of 20 mg/kg; lower doses reveal no such effect. Zaprinast proves to be effective at a 10 mg/kg dose, while rolipram is effective at 3 mg/kg and 30 mg/kg. Rolipram shows efficacy in raising cAMP concentration in the CP mainly at a 3 mg/kg dose, while in the HF doses of 3 mg/kg and 30 mg/kg, the same which determine the memory impairment, were effective. On the contrary, the same dose of DC-TA 46 determining memory impairment causes the highest increase in striatal cAMP level. Zaprinast is effective in increasing cGMP and cAMP concentration in both regions, but its efficacy in increasing cAMP cellular level is higher in the CP than in the HF. In both CP and HF zaprinast determines the highest increase in cAMP levels, at the same dose that impairs memory. Moreover, in the CP this drug determines an increase of both cyclic nucleotides. This does not happen in the HF because, although the cGMP level is higher compared to controls, the difference is not statistically significant in all doses utilized. This is also supported by zaprinast inhibition assays of CP and HF cGMP and cAMP PDE activities, which demonstrate that this drug is less effective in inhibiting cGMP PDE activity in HF than in CP.