Is phosphoadenosine phosphate phosphatase a target of lithium's therapeutic effect?

Lithium, which is approved for treating patients with bipolar disorder, is reported to inhibit 3′(2′)-phosphoadenosine-5′-phosphate (PAP) phosphatase activity. In yeast, deletion of PAP phosphatase results in elevated PAP levels and in inhibition of sulfation and of growth. The effect of lithium on PAP phosphatase is remarkable for the low Ki (~0.2 mM), suggesting that this system would be almost completely shut down in vivo with therapeutic levels of 1 mM lithium, thereby elevating PAP levels. To test the hypothesis that lithium inhibition of PAP phosphatase is pharmacologically relevant to bipolar disorder, we fed rats LiCl for 6 weeks, and assayed brain PAP levels after subjecting the brain to high-energy microwaving. We also measured PAP phosphatase mRNA and protein levels in frozen brain tissue of lithium-treated mice. Brain adenosine phosphates were extracted by trichloroacetic acid and assayed by HPLC with a gradient system of two phases. PAP phosphatase mRNA was measured by RT-PCR, and PAP phosphatase protein was measured by Western blotting. Brain PAP levels were below detection limit of 2 nmol/g wet weight, even following lithium treatment. Lithium treatment also did not significantly change brain PAP phosphatase mRNA or protein levels. These results question the relevance of PAP phosphatase to the therapeutic mechanism of lithium. A statistically significant 25% reduced brain ADP/ATP ratio was found following lithium treatment in line with lithium's suggested neuroprotective effects.