Characteristics of dopamine release from isolated nerve endings of the tuberoinfundibular neurones

In the present study the release of dopamine (DA) from a synaptosomal preparation obtained from the nerve endings of the tuberoinfundibular dopaminergic nerves has been analysed, utilizing a superfusion technique.The exposure of median eminence synaptosomes to increasing concentrations of K⁺ ions produced a dose-dependent efflux of preaccumulated [³H]DA. The removal of Ca²⁺ ions from the superfusion medium completely prevented the high K⁺-induced release of [³H]DA. Removal of Na⁺ ions from the superfusion medium, a condition creating a favourable outward Na⁺ gradient, produced a marked release of [³H]DA. In order to establish whether this efflux of dopamine was a carrier-mediated process nomifensine, a dopamine transport inhibitor devoid of dopamine releasing effect in the median eminence, was added to the superfusion medium. Nomifensine largely counteracted the release of dopamine induced by the lack of Na⁺.d-Amphetamine produced a dose-related stimulation of [³H]DA in synaptosomes from the median eminence.The possible existence of a direct control of dopamine release mediated by presynaptic receptors was tested by studying the effect of apomorphine on the efflux of preaccumulated [³H]DA. Apomorphine was unable to modify both the spontaneous and the K⁺-evoked release of dopamine.The present results give support to the idea that dopamine released from the nerve endings of tuberoinfundibular neurones into the primary plexus acts as a neurotransmitter. The release of dopamine in these nerves does not seem to be regulated by autoreceptors.     

Attenuated inhibition of medium spiny neurons participates in the pathogenesis of childhood depression

Accumulating evidence suggests that the nucleus accumbens, which is involved in mechanisms of reward and addiction, plays a role in the pathogenesis of depression and in the action of anti-depressants. In the current study, intraperitoneal injection of nomifensine, a dopamine reuptake inhibitor, decreased depression-like behaviors in the Wistar Kyoto rat model of depression in the sucrose-preference and forced swim tests. Nomifensine also reduced membrane excitability in medium spiny neurons in the core of the nucleus accumbens in the childhood Wistar Kyoto rats as evaluated by electrophysiological recording. In addition, the expression of dopamine D2-like receptor mRNA was downregulated in the nucleus accumbens, striatum and hippocampus of nomifensine-treated childhood Wistar Kyoto rats. These experimental ifndings indicate that impaired inhibition of medium spiny neurons, mediated by dopamine D2-like receptors, may be involved in the formation of depression-like behavior in childhood Wistar Kyoto rats, and that nomifensine can alleviate depressive behaviors by reducing medium spiny neuron membrane excitability.     

诺米芬辛治疗90例抑郁症

诺米芬辛是70年代后期应用于临床的非三环,非四环类新型抗抑郁药。系异喹林衍生物,具有抗抑郁作用。该药对抑郁情感效果佳,有效率78％。日服50-100mg时显效,大部分病人于服药后3-10d产生效果,无抗胆碱能效应,不良反应少。对肝功,心电图几乎无影响。因对心血管损害轻微,使用安全,故对老年患者也是值得选用的抗抑郁剂。     

Mixed anxiety/depressive illness in general practice. A therapeutic comparison of nomifensine with fluphenazine/nortriptyline

The effect of the dopamine agonist antidepressant drug, nomifensine, on mixed anxiety/depressive states in general practice was assessed by means of a double-blind comparison with a standard fluphenazine/nortriptyline preparation. 57 patients were randomly allocated to 4 weeks' treatment with either nomifensine 25-50 mg taken three times daily, or a tablet containing 1.5 mg fluphenazine with 30 mg nortriptyline (Motipress) taken once daily. The overall response to both treatments was satisfactory, but Motipress was significantly superior (P less than 0.01) to nomifensine in the relief of fatigue and loss of energy, irritability, poor concentration and difficulty in coping, and there was also evidence of greater relief of depressive symptoms. In mixed anxiety/depressive states in general practice, nomifensine offers no advantage over a simple one tablet daily Motipress regimen.     

Effect of neonatal nomifensine exposure on adult behavior and brain monoamines in rats

Summary The aim of the study was to examine the effects of early postnatal exposure to nomifensine, an inhibitor of catecholamine uptake, on concurrent active (REM) sleep, on later alcohol related behavior and on monoamine concentrations in various brain regions of rats. For these purposes rats were given daily injections of 10 mg/kg nomifensine s.c. between the 7th and the 18th postnatal days. During the nomifensine exposure active sleep, expressed as a percentage of total sleeping time, was reduced. At one month of age, the nomifensine rats showed increased ambulation and had lower defecation scores in the open-field than the controls. Neonatal exposure to nomifensine increased voluntary intake of 10% (v/v) alcohol when the rats were 2–3 months of age. The rats, however, did not exhibit perseveration in the T-maze, and similarly to control rats suppressed drinking 0.1 M lithium chloride even when thirsty. Measurement of cerebral monoamine concentrations at the age of 3 months suggested that neonatal nomifensine treatment interferes with the noradrenergic and serotonergic systems in several regions of the brain. Concentrations of noradrenaline and 5-hydroxy-indoleacetic acid (5-HIAA) were decreased in the cerebral cortex and frontal cortex, concentration of 5-HIAA was decreased in the neostriatum, and concentrations of noradrenaline, 5-hydroxytryptamine (5-HT) and 5-HIAA were elevated in the lower brain stem. Taken together, these findings show that exposure to nomifensine during the 2nd and 3rd postnatal weeks suppresses neonatal active sleep, causes changes in the adult open-field behavior, and increases voluntary alcohol intake, perhaps due to a long-lasting alteration in brain monoamines.     

Mazindol, nomifensine and desmethylimipramine inhibit potassium-induced release of dopamine: effect of stimulus strength

Summary. Catecholamine uptake blockers exhibit a second action: They suppress the potassium (K⁺)-stimulated release of [³H]-dopamine (DA) from rat striatal tissue in vitro. In the present study, a K⁺ dose-response curve was obtained for the release of both [³H]-DA and endogenous DA from striatal tissue, in the absence and presence of catecholamine uptake blockers. Three drugs were used, namely, mazindol, nomifensine, and desmethylimipramine. The data showed that diminished release in the presence of mazindol or nomifensine was dependent upon the concentration of K⁺. Marked inhibition of stimulus-induced release of either ³H-DA or endogenous DA was observed at low concentrations of K⁺ (15 and 20 mM), but not at higher concentrations of K⁺ (40 and 60 mM). In contrast, the diminished release of DA in the presence of desmethylimipramine persisted over the K⁺ range of 20–60 mM. These data show that the drug action observed previously was not restricted to a specific neuronal pool of DA that was labelled with [³H]-DA. Further, the data emphasize the importance of the concentration of the depolarizing stimulus when evaluating the effects of drugs on release of catecholamines. Accepted January 29, 1998; received December 8, 1997     

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

Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow. (Presented by Academician of the Russian Academy of Medical Sciences M. D. Mashkovskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 113, No. 6, pp. 619–622, June, 1992.     

Treatment strategy in depression. II. MAO inhibitors in depression resistant to cyclic antidepressants: two controlled crossover studies with tranylcypromine versus L-5-hydroxytryptophan and nomifensine

Antidepressants are ineffective in about 30% of the patients with major depression. Besides electroconvulsive therapy (ECT) and lithium, MAO inhibitors have been suggested as an alternative in such patients. In 2 controlled, partial crossover studies involving 47 patients with major depression who had already been treated unsuccessfully with at least 2 cyclic antidepressants, the effect of the MAO inhibitor tranylcypromine was studied. The first study was an open comparison with L-5-hydroxytryptophan (L-5HTP), the second study a double-blind comparison with nomifensine. Neither the patients treated with L-5HTP nor the patients treated with nomifensine, except one, improved. In contrast, tranylcypromine was effective in 50% of the patients. The depressions of the responders to tranylcypromine appeared to be more endogenous (according Newcastle Scale II) and of shorter duration than those of the non-responders. It is concluded that MAO inhibitors such as tranylcypromine are an effective alternative to ECT and lithium in patients with major depression who have failed to respond to cyclic antidepressants.     

Cognitive dysfunction in depression: Difference between depressed and nondepressed elderly patients and differential cognitive effects of nomifensine

The main aim of the study was to establish the degree of disturbance of the cognitive functions typical of the elderly depressed patients. The analysis was based on the results of a 4-week, double-blind, placebo-controlled therapeutic study in which the effects and tolerance of the antidepressant nomifensine were tested in a randomized group of 100 patients. Half the patients were depressed and half nondepressed (a priori stratification, HAM-D ≥ 18). Tests of central nervous arousal, attention, perceptual grouping, short-term and long-term memory, and complex reaction time were performed. The findings were analyzed as follows: First, baseline differences in cognitive performance, correlative of the stratification into depressed and nondepressed patients, were examined. Second, changes reflecting normalization of cognitive function resulting from the antidepressant treatment were analyzed. For antidepressant treatment, nomifensine, a noradrenaline and dopaminereuptake inhibitor, was used. Results showed that cognitive impairment in primary depression was fairly generalized over different cognitive functions. A global factor of cognitive impairment and a general cognitive improvement factor was found. Both factors are closely connected with the severity as well as the improvement in cardinal symptoms of depression. This relationship was interpreted as due to alterations in central nervous arousal.