Abstract 2,3,4,5-Tetrahydro-1H-indeno[1,2-c]pyridine hydrochloride (LY87130) was a potent inhibitor of rat brain stem norepinephrine N-methyltransferase (NMT) in vitro. The inhibition was competitive with l-norepinephrine as the variable substrate and non-competitive with S-adenosyl- l-methionine as the variable substrate. The K i value for LY87130 calculated from a Dixon plot was 2 × 10 −7 M. In rats, LY87130 inhibited NMT in vivo when injected i.p. at 10–40 mg/kg doses. Epinephrine concentration in hypothalamus was lowered within 1 h after LY87130 injection; the lowering was maximum at 6 h and persisted at 24 but not 48 h after a 40 mg/kg dose of LY87130. The lowering of epinephrine at 6 h was dose-related over a 10–40 mg/kg dose range. Norepinephrine and dopamine concentrations were increased transiently; by 6 h the concentrations of these other catecholamines were normal whereas epinephrine was maximally depleted. MOPEG sulfate, a major metabolite of norepinephrine in rat brain, was markedly elevated by LY87130. The effects of low doses of LY87130 (5 and 10 mg/kg) were enhanced by iprindole, which increased LY87130 levels in brain, suggesting that ring hydroxylation is a major pathway of LY87130 metabolism. The ability of LY87130 to produce selective depletion of epinephrine in rat brain makes it a useful tool for manipulating epinephrine-forming neurons.