The present study was undertaken to compare the pharmacological properties of p-fluoroamphetamine with those of amphetamine and of other halogenated amphetamines, using several in vivo and in vitro tests. These included substitution testing in (+)-amphetamine (1 mg/kg, 5.4 mu mol/kg, i.p.)-, (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine [(+)-MBDB] (1.75 mg/kg, 7.8 mu mol/kg, i.p.)-, and 5-methoxy-6-methyl-2-aminoindan (MMAI) (1.71 mg/kg, 8 mu mol/kg, i.p.)-trained rats, [3H]5-HT and [3H]dopamine uptake inhibition in whole brain synaptosomes, and changes in striatal extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) as measured by in vivo microdialysis in freely moving rats. In drug discrimination substitution tests, p-fluoroamphetamine fully mimicked (+)-amphetamine (ED50 0.43 mg/kg, 2.11 mu mol/kg), whereas 'no substitution' was observed in rats trained to discriminate the serotonin (5-hydroxytryptamine, 5-HT)-releasing agents (+)-MBDB or MMAI from saline. p-Chloroamphetamine did not substitute for amphetamine but fully substituted for the (+)-MBDB and MMAI cues (ED50 0.17 mg/kg, 0.82 mu mol/kg, and 0.14 mg/kg, 0.69 mu mol/kg, respectively). p-Fluoroamphetamine, in comparison with p-chloroamphetamine and p-iodoamphetamine, showed much stronger inhibition of [3H]dopamine than [3H]5-HT uptake into rat brain synaptosomes but was less selective than amphetamine. p-Fluoroamphetamine (7.0 mg/kg, i.p.), 1 h after administration, strongly elevated (849% of baseline) extracellular dopamine in rat striatum measured using in vivo microdialysis. Amphetamine (2 mg/kg, i.p.) increased extracellular dopamine in rat striatum with a maximum at the same time as did p-fluoroamphetamine, but the latter gave a smaller increase. The data presented suggest that p-fluoroamphetamine resembles amphetamie more than it does the 5-HT-releasing type amphetamines.