Effects Of Nomifensine Research Articles

Nicotine and epibatidine alter differently nomifensine-elevated dopamine output in the rat dorsal and ventral striatum

We studied the effects of nicotine and epibatidine given in combination with dopamine uptake inhibitor, nomifensine, on striatal extracellular dopamine and its metabolites by using brain microdialysis in freely moving rats. Nomifensine (3 mg/kg) elevated extracellular dopamine in the caudate-putamen, and clearly more in the nucleus accumbens. In the caudate-putamen, nicotine (0.5 mg/kg) and epibatidine (0.6 μg/kg but not 3.0 μg/kg) enhanced nomifensine's effect on dopamine. The effect of nomifensine on accumbal dopamine was enhanced by nicotine, but inhibited by epibatidine at 0.6 μg/kg. The larger dose of epibatidine had no effect. Thus, the effects of the smaller epibatidine dose (0.6 μg/kg) on the dopamine output in the caudate-putamen but not in the accumbens resemble those of nicotine 0.5 mg/kg. Discrepancies in the effects of epibatidine and nicotine are most probably due to differences in their affinities to nicotinic receptor subtypes regulating dopamine release. Further, different responses to low concentrations of epibatidine between the brain areas suggest that there are differences in the nicotinic regulation of nigrostriatal and mesolimbic dopaminergic pathways.

Modification of the striatal dopaminergic neuron system by carbon monoxide exposure in free-moving rats, as determined by in vivo brain microdialysis

Acute carbon monoxide (CO) intoxication in humans results in motor deficits, which resemble those in Parkinson's disease, suggesting possible disturbance of the central dopaminergic (DAergic) neuronal system by CO exposure. In the present study, therefore, we explored the effects of CO exposure on the DAergic neuronal system in the striatum of freely moving rats by means of in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) for 40 min caused an increase in extracellular dopamine (DA) levels and a decrease in extracellular levels of its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum depending on the CO concentration. Reoxygenation following termination of the CO exposure resulted in a decline of DA to the control level and an overshoot in the recovery of DOPAC and HVA to levels higher than the control. A monoamine oxidase type A (MAO-A) inhibitor, clorgyline, significantly potentiated the CO-induced increase in DA and completely abolished the subsequent overshoot in the recovery of DOPAC and HVA. Tetrodotoxin, a Na(+) channel blocker, completely abolished both the CO-induced increase in DA and the overshoot of DOPAC and HVA. A DA uptake inhibitor, nomifensine, strongly potentiated the CO-induced increase in DA without affecting the subsequent overshoot of DOPAC and HVA. Clorgyline further potentiated the effect of nomifensine on the CO-induced increase in DA, although a slight overshoot of DOPAC and HVA appeared. These findings suggest that (1) CO exposure may stimulate Na(+)-dependent DA release in addition to suppressing DA metabolism, resulting in a marked increase in extracellular DA in rat striatum, and (2) CO withdrawal and subsequent reoxygenation may enhance the oxidative metabolism, preferentially mediated by MAO-A, of the increased extracellular DA. In the light of the neurotoxicity of DA per se and reactive substances, such as quinones and activated oxygen species, generated via DA oxidation, the significant modification of the striatal DAergic neuronal system by CO exposure might participate in the neurological outcome following acute CO intoxication.

Changes in the kinetics of dopamine release and uptake have differential effects on the spatial distribution of extracellular dopamine concentration in rat striatum.

The objective of this study was to examine whether the limited diffusion distance of dopamine in rat striatum produces spatial heterogeneity in the extracellular dopamine concentration on a dimensional scale of a few micrometers. Such heterogeneity would be significant because it would imply that the concentration of dopamine at a given receptor depends on the receptor's ultrastructural location. Spatially resolved measurements of extracellular dopamine were performed in the striatum of chloral hydrate-anesthetized rats with carbon fiber microdisk electrodes. Dopamine was monitored during electrical stimulation of the nigrostriatal pathway before and after administration of drugs that selectively affect the kinetics of evoked dopamine release and dopamine uptake. The effects of nomifensine (20 mg/kg), L-DOPA (250 mg/kg), and alpha-methyl-p-tyrosine (250 mg/kg) on the amplitude of the stimulation responses were examined. The outcome of these experiments was compared with predictions derived from a mathematical model that combines diffusion with the kinetics of release and uptake. The results demonstrate that the extracellular dopamine concentration is spatially heterogeneous on a micrometer scale and that changing the kinetics of dopamine release and uptake has different effects on this spatial distribution. The impact of these results on brain neurochemistry is considered.

Spectral analysis of the effect of nomifensine on the eeg in rats

Spectral analysis of the effect of nomifensine on the eeg in rats

Nomifensine but not amantadine increases dopamine-induced responses on rat substantia nigra zona compacta neurons

Responses of substantia nigra zona compacta neurons to nomifensine and amantadine were studied with intracellular recording techniques (current and voltage clamp) in in vitro slice preparation of rat mesencephalon. The application of nomifensine (1–10 μM) slightly hyperpolarized the cells and inhibited action potential discharge that occurs spontaneously. In voltage-clamp experiments (−50, −60 mV, holding potential) an outward current was observed. The membrane responses to exogenously-applied dopamine were potentiated by the concomitant superfusion of nomifensine. The effects of nomifensine were antagonized by (−)-sulpiride (1 μM), a D 2 receptor antagonist. By contrast, the superfusion of amantadine (1–30 μM) on substantia nigra zona compacta cells was ineffective on firing rate, membrane potential or on sensitivity to exogenous dopamine. In the presence of high doses (300 μM to 1 mM) of amantadine a depolarization and an increase in firing activity was observed. While our results provide electrophysiological evidence for an inhibition of the dopamine uptake system by nomifensine, they do not support a dopaminergic mechanism for the actions of amantadine in the substantia nigra zona compacta.

Seasonal and circadian variations of behavioural response to antidepressants in the forced swimming test in rats

In order to verify whether the variability reported to occur in the effectiveness of antidepressants in the forced swimming test (FST) was due to seasonal and/or circadian variations, the anti-immobility effect induced by several antidepressants was assessed in rats every month throughout the year or every 4 hours for 2 consecutive days. Amineptine (20 mg/kg), amitriptyline (15 mg/kg), desipramine (20 mg/kg), imipramine (15 mg/kg) and mianserin (15 mg/kg) exerted the maximal effect in March. The effect of nomifensine (5 mg/kg) was constant throughout the year. Unlike imipramine and mianserin, nomifensine induced an anti-immobility effect that was maximal during the light phase of the light/dark cycle and was constant in continuous darkness.

Effect of nomifensine on platelet monoamine oxidase activity in chronic schizophrenic patients

1. The levels of platelet MAO activity increase and the frequency of affective symptoms diminish in the depressed chronic schizophrenics treated with nomifensine. 2. Nomifensine has no inhibitory effect in vitro on platelet MAO activity in depressed schizophrenic pellets.

Effects of acute and chronic treatment with an atypical antidepressant drug, nomifensine, on the sleep-wake activity in rats.

After the chronic administration of saline, rats were treated with nomifensine (0.1 or 1.0 mg/kg, twice a day, at light and dark onset) for 11 days. The sleep-wake activity was recorded for 24 h on the baseline day (saline), on nomifensine days 1, 5 and 11, and also on day 12, when saline was injected again (withdrawal day). Another group of rats was treated with saline throughout the experiment, without significant effect on the sleep-wake activity. The smaller dose of nomifensine increased non-REM sleep (NREMS) at the expense of wakefulness (W) in the light period. The effect persisted throughout the chronic treatment. A late increase in REM sleep (REMS) was noted on nomifensine days 5 and 11. Nomifensine failed to affect the sleep-wake activity in the dark period. On withdrawal, the baseline percentages of the vigilance states were recovered. As evaluated through spectral analysis of the EEG, the increase in NREMS was accompanied by an increase in slow wave activity. The higher dose of nomifensine elicited an increase in W and a reduction in both sleep states, followed by changes in W and NREMS in the opposite directions. These effects were evident in both the light and the dark periods of the day. Chronic treatment resulted in circadian variations in the effects. Withdrawal of the drug abolished the arousal reaction, but the late increase in NREMS persisted. The dose-dependent biphasic effects of nomifensine on sleep-wake activity can be explained by considering the proposed indirect dopamine and possibly noradrenaline agonist activity of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse effects of nomifensine

Adverse effects of nomifensine

Adverse effects of nomifensine (continued)

Adverse effects of nomifensine (continued)

Disturbed prolactin responses to dopamine-related substances in patients with acromegaly and hyperprolactinemia.

We undertook this study, because conflicting data were reported about the dopaminergic regulation of prolactin (PRL) secretion in patients with acromegaly and hyperprolactinemia. In order to clarify the dopaminergic regulation of PRL secretion in patients with acromegaly and hyperprolactinemia, the effects of nomifensine, a central dopamine agonist, FK 33-824, a centrally antidopaminergically acting agent, and domperidone, a peripheral dopamine antagonist, on plasma PRL in these patients were studied. The results were compared with those observed in normal subjects and hyperprolactinemic patients, with or without a pituitary tumor. Nomifensine did not lower the PRL levels and FK 33-824 did not raise the PRL levels in acromegalic patients. In hyperprolactinemic patients, nomifensine did not lower the PRL levels and FK 33-824 failed to raise the PRL levels. Domperidone did not increase PRL in about a third of acromegalic patients, while TRH increased PRL in the all normoprolactinemic acromegalic patients. These results suggest that in acromegalic patients there may be a disturbance in dopamine related neurotransmission and that such disorders also seem to be present in patients with hyperprolactinemia, with or without a pituitary tumor.

The Effects of Nomifensine in Cyclical Oedema

The Effects of Nomifensine in Cyclical Oedema

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 μg) injected intracerebrally. This protective effect was markedly decreased with an increased amount of 6-hydroxydopamine (8 μg), or by lower doses of nomifensine (6.7 mg/kg). These doses of nomifensine are higher than those required to protect dopaminergic nerve terminals.

Effects of nomifensine and its metabolites on dihydropteridine reductase.

Nomifensine and three of its metabolites were studied as potential inhibitors of dihydropteridine reductase. Purified enzyme preparations from human liver and the P2 fraction of rat striatal synaptosomes were used as enzyme sources. Nomifensine and its 3'-hydroxyl derivative inhibit this enzyme from both sources at 1.3 to 3.5 X 10(-4)M (150 values). 4'-Hydroxylated nomifensines, however, non-competitively inhibited this enzyme with Ki values of 2.8 to 4.4 X 10(-5)M. Dihydropteridine reductase regenerates tetrahydrobiopterin, the required cofactor for the hydroxylation of tyrosine and tryptophan, from quinonoid dihydrobiopterin. Inhibition of this enzyme could reduce the availability of the biopterin cofactor for the synthesis of dopamine and 5-hydroxytryptamine.

Multicentric experience on the acute effect of nomifensine in hyperprolactinemic women.

The inhibitory effect of nomifensine ( Nom ; 200 mg orally) on prolactin (PRL) secretion was studied in 15 subjects with puerperal hyperprolactinemia and in 59 pathologic hyperprolactinemic women. The latter were grouped as follows: i) patients with surgically proven PRL secretory pituitary adenomas (proven tumors; 27 cases); ii) patients presenting radiological signs of sella indicative of a pituitary tumor (presumptive tumors; 10 cases); iii) subjects with non-drug induced hyperprolactinemia (hyperprolactinemia of uncertain etiology; 22 cases). A mean PRL fall of 30% or more of baseline hormone levels in samples collected within the 120-240 min post-treatment interval was adopted to define responsiveness to Nom . In 24 out of 27 subjects with proven tumors and in 9 out of 10 subjects with presumptive tumors Nom did not induce significant variations in PRL secretion. In only 11% of the patients with surgery-confirmed or highly suspected tumors a hormone decrease greater than 30% was observed. In addition, 13 subjects with hyperprolactinemia of uncertain etiology did not respond to Nom administration. In 5 of these, additional data suggesting the existence of an adenoma were collected. Finally, 3 out of 9 Nom -responder patients presented either a polycystic ovary syndrome or transitory hyperprolactinemia. The finding that hyperprolactinemic women, who did not show clinical or radiological signs of a tumor and patients with highly presumptive or proven pituitary tumors may present comparable responses to Nom , suggests that this pattern may be indicative of an early manifestation of a PRL-secreting adenoma which has yet to evolve. The follow-up of Nom -non-responder hyperprolactinemic subjects who did not show clinical signs of harboring a tumor, is therefore advisable.

Effects of acute and chronic administration of antidepressant drugs on the central cholinergic nervous system: Comparison with anticholinergic drugs

The purpose of this investigation was to study the effects of antidepressant drugs on the central cholinergic system of the rat after acute and chronic administration. Drugs (antidepressants and non-antidepressants) were first divided into highly potent, moderately potent or weak anticholinergic categories based upon the ability of each compound to displace [ 3H]-QNB ([ 3H]quinuclidinyl benzilate from synaptosomal membranes. One antidepressant drug and one non-antidepressant drug, with similar anticholinergic properties, were chosen as representative agents of each category of anticholinergic potency. Acute administration of amitriptyline or atropine (highly potent anticholinergics) increased the level of high affinity uptake of choline in the hippocampus and striatum. Imipramine and thioridazine (moderately potent anticholinergics) increased the uptake of choline only in the striatum. After acute administration, the effects of nomifensine and d-amphetamine (weak anticholinergics) differed on striatal uptake of choline. Following 30 days pretreatment with any drug, an acute challenge dose of that drug no longer altered the uptake of choline in either region. After chronic administration, amitriptyline increased the density of muscarinic receptors in the cortex whereas atropine increased the density of receptors in the cortex, hippocampus and striatum. The other agents did not alter receptor parameters in the regions examined. Since the central cholinergic actions of the antidepressants were similar to the central actions of the non-antidepressants, it is concluded that the effects of the antidepressants on the central cholinergic nervous system are more closely related to the side effects of these agents than to their therapeutic mechanism of action.

Effect of nomifensine on cortisol, prolactin and biogenic amines in neurotic depressed patients.

The effect of nomifensine on plasma levels of cortisol, prolactin, dopamine, noradrenaline, adrenaline and serotonin were studied in neurotic depressive patients. Cortisol levels were elevated in the morning and were significantly decreased by nomifensine treatment. Prolactin levels were within the normal range and nomifensine did not modify them. A significative increase in catecholamine plasma levels was observed at the 6th week of treatment in depressed patients (dopamine: 106%; noradrenaline: 14%; adrenaline: 10%) whose nomifensine plasma levels ranged between 84 and 105 ng/ml. No statistical differences were found between pre- and post-treatment serotonin concentration. Reduction of plasma cortisol and clinical improvement may be related to increased catecholamine levels.

Evaluation of tuberoinfundibular dopamine function by neuropharmacologic means in old male rats.

Baseline prolactin (PRL) levels and the PRL-lowering effect of nomifensine (Nom), an indirect dopamine (DA) agonist, were evaluated in young adult (3-5 months) and old (21 and 27 months) male rats. In addition, PRL responsiveness to acute or repeated administration of haloperidol (Hal), a DA receptor antagonist, was assessed in either young or old rats. Baseline PRL levels did not differ significantly between young and aged rats either when rats were killed by decapitation or underwent sampling from the retro-orbital venous plexus. Administration of Nom (10.0 mg/kg i.p.), a drug which inhibits PRL levels in normal rats and humans but lacks any action in conditions of impaired tuberoinfundibular DA (TIDA) function, affected PRL levels in aged rats not differently than in young rats. The PRL inhibition induced by the drug was greater in both groups when basal PRL levels were higher. Acute administration of Hal (0.5 mg/kg i.p.) increased significantly and to the same extent as PRL levels in aged and young rats. In aged rats treated chronically with Hal (0.5 mg/kg i.p., twice daily for 14 days) and sampled at the 8th day, 1 h after the first daily Hal injection, plasma PRL rose to levels about 3-fold as high as those after the first injection; in young rats, instead, the PRL-releasing effect of Hal was similar to that evoked by the first administration. 3 days after Hal withdrawal, baseline PRL levels were significantly higher in aged Hal-treated rats than in vehicle-injected or young Hal-treated rats and so were pituitary concentrations of PRL.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of amfonelic acid and some other central stimulants on mouse striatal tyramine, dopamine and homovanillic acid.

1 The concentrations of p- and m-tyramine, dopamine and homovanillic acid were measured in the mouse striatum following the subcutaneous administration of amfonelic acid, (+)-amphetamine or nomifensine.2 The administration of 2.5-25 mg/kg of amfonelic acid produced a reduction in p-tyramine that lasted at least 8 h. m-Tyramine was significantly increased and this was observed between 2 and 24 h after drug treatment. The levels of homovanillic acid were increased within 4 h after amfonelic acid administration.3 (+)-Amphetamine treatment (5 mg/kg) produced a reduction in p-tyramine observed up to 4 h after its administration and no significant changes in m-tyramine.4 The administration of 10 mg/kg of nomifensine produced no significant changes in p-tyramine, m-tyramine or homovanillic acid. By increasing the dose to 20 mg/kg, nomifensine produced an increase in p-tyramine and homovanillic acid.5 The present results support the view that amfonelic acid and (+)-amphetamine would respectively release granular or newly synthesized dopamine, both actions being accompanied by an increase in tyrosine hydroxylase activity and dopamine turnover which in turn reduces p-tyramine but produces no change or an increase in m-tyramine.6 The effects of nomifensine were observed after the administration of a relatively high dose (20 mg/kg), that was lethal to some mice (about 20%, at 2 h), and more likely to posses unspecific actions.

Effects of Nomifensine on Growth Hormone and Prolactin Secretion in Normal Subjects and in Pathological Hyperprolactinemia*

We have studied the effect of the oral administration of 200 mg nomifensine (nom), a drug which activates the dopaminergic system, on GH and PRL secretion in 15 normal subjects, 18 patients with idiopathic hyperprolactinemia, and 17 patients with tumoral hyperprolactinemia. GH levels increased significantly after nom in normal subjects (basal, 0.96 +/- 0.76 ng/ml; peak 4.6 +/- 0.61 ng/ml; P less than 0.01) and patients with hyperprolactinemia, both idiopathic (basal, 1.0 +/- 0.38 ng/ml; peak, 4.2 +/- 1.0 ng/ml; P less than 0.05) and tumoral (basal 0.88 +/- 0.3 ng/ml, peak 6.68 +/- 1.2 ng/ml; P less than 0.01). Peak GH levels higher than 5 ng/ml were observed in 8 of 15 normal subjects, 6 of 18 patients with idiopathic hyperprolactinemia, and 8 of 17 patients with tumoral hyperprolactinemia. PRL levels decreased in response to nom in normal subjects, but not in patients with idiopathic or tumoral hyperprolactinemia. A reduction in plasma PRL levels of at least 30% below the baseline was observed only in two patients with idiopathic hyperprolactinemia and in none of the patients with tumoral hyperprolactinemia. These results demonstrate that nom does not discriminate between idiopathic and tumoral hyperprolactinemia. Since nom probably requires a hypothalamic pool of dopamine to bring about its GH stimulatory effect, the suggestion that the lack of a PRL-lowering effect of the drug is attributable to a dopamine deficiency is not supported by our data.