The effect of 9-amino-1,2,3,4-tetrahydroacridine (THA) on histamine N-methyltransferase (HMT), an enzyme catalyzing the methylation of histamine to form tele-methylhistamine in the brain, was studied in vitro using a partially purified enzyme preparation from bovine brain and in vivo in the mouse brain. THA inhibited the HMT activity in competitive and non-competitive mixed type manners with respect to histamine. The Ki and Ki' values were 75 nM and 1.2 microM, respectively. The IC50 values for THA, 9-aminoacridine and physostigmine in the inhibition of HMT determined at fixed concentrations of histamine (20 microM) and S-adenosylmethionine (50 microM) were 0.2, 0.37 and 20 microM, respectively. Neostigmine exhibited only 15% inhibition even at a concentration of 100 microM. THA (2-10 mg/kg, s.c.) dose-dependently inhibited HMT in the mouse brain. The inhibition of HMT by THA (10 mg/kg) was marked at 30 and 60 min after treatment, but disappeared by 120 min after. THA (10 mg/kg) significantly increased the histamine level and decreased the tele-methylhistamine level in the mouse brain. These results indicate that THA is a potent inhibitor of HMT.