Objective To investigate effect of inhibiting melatonin biosynthesis on activities of protein kinase A （PKA）

glycogen synthase kinase-3 （GSK-3） and tau phosphorylation at PS214 and M4 epitopes using haloperidol

a specific inhibitor of 5-hydroxyindole-O-methyltransferase. Methods Brain ventricular and intraperitoneal injections were used for haloperidol administration

Western blots for tau phosphorylation

32P-labeling for PKA and GSK-3 activity

and high performance liquid chromatograph for detection of serum melatonin levels. Results Haloperidol injection through the lateral ventricle and intraperitoneal reinforcement significantly stimulated PKA activity with a concurrent hyperphosphorylation of tau at M4 （Thr231/Ser235） and PS214 （Ser214） sites. Prior treatment of the rats using melatonin supplement for one week and reinforcement during the haloperidol administration arrested PKA activity and attenuated tau hyperphosphorylation. GSK-3 activity showed no obvious change after haloperidol injection

however

melatonin supplements and reinforcements during haloperidol infusion inactivated basal activity of GSK-3. Conclusion Decreased melatonin may be involved in Alzheimer-like tau hyperphosphorylation

and overactivation of PKA may play a crucial role in this process.