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

Abstract

Several antidepressant drugs have active metabolites. This study sought to establish whether two of the main human metabolites of nomifensine (M2: 8-amino-2-inethyl-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, 10mA) and trains (20 pulses, 50 Hz), applied alternately every 10 min and monitored using fast cyclic voltammetry at carbon fibre microelectrodes. Nomifensine (5 × 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 × 10 −7 M) increased efflux of DA only moderately. The selective blocker of the uptake of DA, GBR 12909 (3 × 10(−7) M), increased efflux of DA on single pulse (430%) and train stimuli (645%) and blocked uptake of DA ( t 1 2 : 292% ). Amfonelic acid, the psychomotor stimulant (10 −7 M) blocked uptake of DA ( t 1 2 : 234% ) and elevated efflux of DA to a greater extent on trains (1007%) than on single pulses (495%). It is concluded that the means by which M2 increased the efflux of DA is independent of blockade of uptake. The greater effect on trains than single pulses is consistent with mobilisation of the storage pool of DA, since it also occurred with amfonelic acid but not with the pure uptake blocker, GBR 12909.