Activity of two primary human metabolites of nomifensine on stimulated efflux and uptake of dopamine in the striatum: in vitro voltammetric data in slices of rat brain.
Several antidepressant drugs have active metabolites. This study sought to establish whether two of the main human metabolites of nomifensine (M2: 8-amino-2-methyl-4-(3-methoxy-4-hydroxyphenyl)-1,2,3,4- tetrahydroisoquinoline and M3: 8-amino-2-methyl-4-(3-hydroxy-4-methoxyphenyl)-1,2,3,4- tetrahydroisoquinoline) had actions on the release and uptake of dopamine (DA). Experiments were conducted in superfused striatal slices of the rat. The efflux of DA was evoked by single constant-current pulses (0.1 msec, 10 mA) and trains (20 pulses, 50 Hz), applied alternately every 10 min and monitored using fast cyclic voltammetry at carbon fibre microelectrodes. Nomifensine (5 x 10(-7) M) significantly increased the efflux of DA on both single pulse (302% of pre-drug) and train stimuli (529%) and increased the uptake half-life (178% of pre-drug). The M2 metabolite had similar potency on the efflux of DA (260%: pulse, 570%: train) but without any effect on uptake of DA. Nomifensine and M2 increased efflux of DA more on trains than on single pulses. The M3 metabolite (5 x 10(-7) M) increased efflux of DA only moderately. The selective blocker of the uptake of DA, GBR 12909 (3 x 10(-7) M), increased efflux of DA on single pulse (430%) and train stimuli (645%) and blocked uptake of DA (t1/2: 292%). Amfonelic acid, the psychomotor stimulant (10(-7) M) blocked uptake of DA (t1/2: 234%) and elevated efflux of DA to a greater extent on trains (1007%) than on single pulses (495%).(ABSTRACT TRUNCATED AT 250 WORDS)
Anaesthetics Unit, London Hospital Medical College, Royal London Hospital, Whitechapel, U.K.
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Hafizi
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Palij
J A
JA
Stamford
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004558:Electric Stimulation; D004566:Electrodes; D006207:Half-Life; D066298:In Vitro Techniques; D008297:Male; D009627:Nomifensine / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
D015259:Dopamine Agents; D009627:Nomifensine; D004298:Dopamine