Region‐ and domain‐dependent action of nomifensine

The dopamine (DA) terminal fields in the rat dorsal striatum (DS) and nucleus accumbens core (NAcc) are organized as patchworks of domains that exhibit distinct kinetics of DA release and clearance. The present study used fast‐scan cyclic voltammetry recordings of electrically evoked DA overflow to test the hypothesis that nomifensine might exhibit domain‐dependent actions within the NAcc, as we previously found to be the case within the DS. Within the NAcc, nomifensine preferentially enhanced evoked DA overflow in the slow domains compared with the fast domains. To seek a kinetic explanation for nomifensine's selective actions, we quantified the apparent K_M of DA clearance by numerically evaluating the derivative of the descending phase of the DA signal after the end of the stimulus. For comparison, we likewise quantified the apparent K_M in the domains of the DS. As expected, because it is a competitive inhibitor, nomifensine significantly increased the apparent K_M in both the fast and slow domains of both the NAcc and DS. However, our analysis also led to the novel finding that nomifensine preferentially increases the apparent K_M in the NAcc compared with the DS; the apparent K_M increased by ~500% in the NAcc and by ~200% in the DS.     

Functional and anatomical evidence for different dopamine dynamics in the core and shell of the nucleus accumbens in slices of rat brain

The characteristics of dopamine (DA) uptake and release were compared in the core and shell of the nucleus accumbens (NAc). DA release was elicited from rat brain slices by local electrical stimulation, and its extracellular concentration was monitored with fast-scan cyclic voltammetry using Nafion-coated, carbon-fiber microelectrodes. The voltammetric results show that the values of DA release and uptake in the shell NAc are approximately one-third of those measured in the core region, and DA uptake in the shell was less sensitive than the core to inhibition by either cocaine or nomifensine. The density of [³H]mazindol binding sites in the NAc was examined by autoradiography and the shell was found to have an average of half the number of DA uptake sites measured in the core region. This combination of anatomical and functional results shows that DA neurotransmission in the shell NAc is distinct from that in the core region. These data are consistent with the view that multiple functional forms of the DA transporter, exhibiting disparate kinetics and pharmacology, exist in different brain regions that exhibit disparate kinetics and pharmacology. Different forms of the transporter, combined with different release kinetics and auto- and heteroreceptor activity, give a vast range of possibilities for regional variation in DA neurotransmission. © 1996 Wiley-Liss, Inc.     

Dysregulation of dopamine signaling in the dorsal striatum inhibits feeding

Dopamine signaling is an important component of many goal-directed behaviors, such as feeding. Acute disruption of dopamine signaling using pharmacological agents tends to inhibit normal feeding behaviors in rodents. Likewise, genetically engineered dopamine-deficient (DD) mice are unable to initiate sufficient feeding and will starve by approximately 3 weeks of age if untreated. Adequate feeding by DD mice can be achieved by daily administration of L-3,4-dihydroxyphenylalanine (L-dopa), a precursor of dopamine, which can be taken up by dopaminergic neurons, converted to dopamine, and released in a regulated manner. In contrast, adequate feeding cannot be restored with apomorphine (APO), a mixed agonist that activates D1 and D2 receptors. Viral restoration of dopamine production in neurons that project to the dorsal striatum also restores feeding in DD mice. Administration of amphetamine (AMPH) or nomifensine (NOM), drugs which increase synaptic dopamine concentration, inhibits food intake in virally rescued DD mice (vrDD) as in control animals. These results indicate that the dysregulation of dopamine signaling in the dorsal striatum is sufficient to induce hypophagia and suggest that regulated release of dopamine in that brain region is essential for normal feeding and, probably, many other goal-directed behaviors.     

Effect of nomifensine on the toxicity of 6-hydroxydopamine for mesotelencephalic dopamine neurons

The ability of nomifensine to protect the dopaminergic cells of the substantia nigra and ventral tegmental areas against 6-hydroxydopamine-induced destruction was evaluated. Nomifensine at high doses (20 mg/kg, i.p.) protected the cells from the effects of low amounts of 6-hydroxydopamine (2 micrograms) injected intracerebrally. This protective effect was markedly decreased with an increased amount of 6-hydroxydopamine (8 micrograms), or by lower doses of nomifensine (6.7 mg/kg). These doses of nomifensine are higher than those required to protect dopaminergic nerve terminals.     

Conjugates of biogenic amines in ventriculocisternal perfusates of conscious african green monkeys

To determine the importance of conjugation relative to alternate metabolic pathways for the inactivation of catecholamines and serotonin, free and conjugated norepinephrine, dopamine and serotonin, together with the acid metabolites homovanillic acid and 5-hydroxyindoleacetic acid, were measured in ventriculocisternal perfusions in awake African green monkeys. Measurements were made of endogenous transmitters and their metabolites using high performance liquid chromatography with electrochemical detection. Efflux of amines and metabolites was measured both under conditions of spontaneous overflow and during release evoked by 40 mM K+ or by 5 X 10(-5) M amphetamine. Conjugated amines were of greater importance under basal conditions than during evoked release. Although more conjugated amines were produced in African green monkey than has been previously detected in other species, conjugation was still minor relative to O-methylation and oxidative deamination. When nomifensine (5 X 10(-5) M), a blocker of neuronal uptake of dopamine, was added to perfusion fluids, the efflux of free dopamine was increased. Efflux of conjugated dopamine was not decreased in the presence of nomifensine, suggesting that conjugation did not occur subsequent to reuptake of transmitter into dopaminergic neurons. Evidence is also presented that different enzymes are responsible for the conjugation of catecholamines and serotonin.     

Striatal dopamine uptake and swim performance of the aged rat

The striatum and olfactory tubercle of 30-month-old F344 rats contain significantly (21-24%) less dopamine compared with young adult (8-month) animals. However, rats of the two age groups show identical Km and Vmax values for the kinetics of [3H]dopamine uptake into striatal homogenates; uptake into the olfactory tubercle also appeared unaffected in old age. The preservation of dopamine uptake despite reductions in content of the transmitter suggests that the forebrain dopaminergic nerve terminals are intact, but that reduced dopamine synthesis and/or enhanced degradation may occur in the existing terminals. Administration to senescent animals of the dopamine uptake blockers nomifensine or bupropion (but not the norepinephrine uptake blocker desmethylimipramine) improved their swim performance to levels comparable with young adult animals. The findings suggest that amine reuptake may limit the synaptic effectiveness of dopamine released in the aged striatum.     

Follow-up study on 24 patients with nomifensine-induced immune haemolytic anaemia

Summary. There is as yet only scarce information regarding the natural history and long-term clinical sequelae of patients who survive the acute complications of severe drug-related immune haemolysis, the effect of the mode of drug administration for sensitization and possible alterations of serological characteristics of drug-dependent antibodies during the post-sensitization period. We therefore followed 24 patients with nomifensine-induced haemolytic anaemia for up to 6 years after the haemolytic attack. All patients had suffered from a severe haemolytic episode. None of the patients showed any abnormal findings upon reinvestigation (complete history and physical examination; extended biochemical and haematological laboratory status), particularly with respect to renal function. Drug-dependent antibodies remained detectable in 19 of 21 sera, while drug-independent autoantibodies, demonstrable in six patients during the acute phase of haemolysis, could no longer be detected. With regard to the mode of drug administration, the majority of patients (15 out of 24) had developed the haemolysis at the beginning (immediately after a single dose) or during a second course of drug therapy ( n = 8 and 7, respectively). The immune response did not appear to be dose- or time-dependent. This study confirms the benign long-term prognosis of patients who survive life-threatening complications in drug-induced immune haemolytic anaemia. In addition, it indicates that drug-dependent antibodies may remain detectable over long periods of time, and that irregular drug administration might be associated with a higher risk of drug sensitization.     

Pharmacologically induced, subsecond dopamine transients in the caudate-putamen of the anesthetized rat

Subsecond dopamine (DA) concentration transients have previously been observed in behaving rats. Here, we demonstrate for the first time that DA transients can be pharmacologically induced in anesthetized rats. Coadministration of the D2 receptor antagonist, haloperidol, and the DA uptake inhibitor, nomifensine, results in significantly more DA transients than either drug alone. The results show that both D2 autoreceptors and the dopamine transporter regulate subsecond DA neurotransmission.     

KCl-induced calcium-independent release of endogenous dopamine from rat brain slices

Effects of the absence of calcium on the KCl- and electrical stimulation-induced releases of endogenous dopamine (DA) from rat brain slices were studied and the findings were compared with the effects on the release of endogenous noradrenaline (NA). DA and NA were extracted by the aluminum-adsorption method and assayed electrochemically by high-performance liquid chromatography. KCl, 15 mM, induced a significant increase in the release of DA from both the striatum and the hypothalamus, even in the Ca2+-free medium containing 1 mM EGTA. In the normal medium, the KCl-induced release of DA was concentration-dependent (15, 30 and 50 mM), while that in the Ca2+-free medium showed a plateau at 30 mM of KCl. The release of DA induced by electrical stimulation (10 cycles/s, 2 ms, 30 mA, for 5 min) was abolished in the Ca2+-free medium as was NA induced by both KCl and electrical stimulation. Nomifensine, 10 microM, a DA transport inhibitor, abolished the 15 mM KCl-induced release of DA in the Ca2+-free medium. On the other hand, the release of DA induced by electrical stimulation was considerably enhanced by nomifensine. Therefore, the mode of DA release induced by KCl sometimes differed from that induced by electrical stimulation. The present results also suggest that DA released by KCl in the Ca2+-free medium originates from cytoplasmic DA storage sites, through a carrier-mediated process.     

Suppression of insulin-induced prolactin secretion in man by nomifensine

In 12 healthy male volunteers we studied the effect of nomifensine, an inhibitor of endogenous catecholamine reuptake, on insulin-induced prolactin and growth hormone (GH) secretion. The effect of the drug on TRH-induced prolactin secretion was also studied. Nomifansine was able to suppress completely the insulin-stimulated prolaction secretion, whereas no effect on GH secretion was observed. TRH-induced prolactin secretion was uninfluenced by the drug.