A series of acute and chronic experiments was conducted on 4-fluorotranylcypromine (FTCP), an analog of the monoamine oxidase (MAO)-inhibiting antidepressant tranylcypromine (TCP) in which the 4 position of the phenyl ring is protected from metabolism. These studies demonstrated that FTCP is a more potent inhibitor of MAO ex vivo than is the parent drug. Despite its similarity in structure to pchloroamphetamine, FTCP does not cause a depletion of brain levels of 5-hydroxytryptamine (5-HT) after chronic administration; in fact, it increases brain 5-HT to levels similar to those produced by TCP. After chronic administration, FTCP produces a downregulation of ฮฒ-adrenergic and tryptamine receptors, in common with TCP and several other antidepressants. Pretreatment of rats with iprindole or trifluperazine, drugs known to block cytochrome P450-mediated hydroxylation reactions and to elevate brain levels of TCP, had no effects on FTCP brain levels, suggesting that metabolic drug-drug interactions may be less of a concern with FTCP than with TCP. In vitro uptake experiments in prisms prepared from hypothalamus or striatum revealed that TCP and FTCP are both potent inhibitors of norepinephrine (NE) uptake; FTCP is a more potent inhibitor of 5-HT uptake than is TCP. FTCP is a more potent releaser of 5-HT than is TCP. Drug Dev.