Psychostimulant-like effects of p-fluoroamphetamine in the rat.
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.
Marona-Lewicka
D
D
Departments of Pharmacology and Toxicology, and Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, IN 47907, USA.
Rhee
G S
GS
Sprague
J E
JE
Nichols
D E
DE
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000662:Amphetamines; D015102:3,4-Dihydroxyphenylacetic Acid; C051570:N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine; D015104:3,4-Methylenedioxyamphetamine; D000661:Amphetamine; C040639:4-fluoroamphetamine