Norepinephrine-dopamine Reuptake Inhibitor Research Articles

Disposition of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice before and after monoamine oxidase and catecholamine reuptake inhibition.

The distribution of radioactivity in pigmented mice after a single intravenous injection of 1-(3H) methyl-4-phenyl-1,2,3,6-tetrahydropyridine (3H-MPTP) was studied by quantitative whole body autoradiography and liquid scintillation counting. Pretreatment with the monoamine oxidase inhibitors clorgyline, pargyline and deprenyl, or the catecholamine reuptake inhibitor nomifensine was performed 30 min. prior to the 3H-MPTP administration. A high uptake of radioactivity was observed in the striatum, nucleus accumbens, midbrain area and locus coeruleus, and also in the adrenal medulla. This uptake was inhibited by deprenyl or pargyline pretreatment, but not after clorgyline or nomifensine pretreatment. An extensive uptake which was not influenced by deprenyl or pargyline treatment was found in the melanin-containing tissues of the eye. This accumulation is due to the melanin affinity of MPTP and its metabolites. A comparatively rapid elimination from the brain of MPTP and its metabolites was observed, which may be due to the lack of neuromelanin in mice.

Differential behavioral effects of tryptophan and 5-hydroxytryptophan in vervet monkeys: influence of catecholaminergic systems.

In previous studies tryptophan and 5-hydroxy-tryptophan (5-HTP) treatments produced opposite effects on aggression and vigilance and differing effects on eating and locomoting in vervet monkeys. This study examined the effects of the serotonin reuptake inhibitor fluoxetine, and the catecholamine reuptake inhibitor desmethylimipramine (DMI) on tryptophan and 5-HTP induced behavioral changes. Thirty-two adult males from 16 different social groups were studied. Tryptophan (10, 20, and 40 mg/kg/day) produced dose-dependent reductions in aggression, vigilance, and locomotion and increases in eating. In contrast, 5-HTP (20, 40, and 80 mg/kg/day) increased aggression and vigilance and did not affect locomotion or eating. Fluoxetine (0.5, 1.0, and 2.0 mg/kg/day) produced effects identical to tryptophan while DMI (1.5, 3.0, and 6.0 mg/kg/day) resulted in dose-dependent increases in aggression, vigilance, and locomotion, and decrements in eating. When combined with tryptophan, fluoxetine augmented and DMI diminished the effects of tryptophan on all behaviors. Fluoxetine decreased and DMI increased the effects of 5-HTP on aggression and vigilance. Thus concurrent DMI enhanced and concurrent fluoxetine reduced the differences between 5-HTP and tryptophan. These results suggest that 5-HTP's effects on catecholaminergic systems may underlie the differing behavioral effects of tryptophan and 5-HTP on behavior in a species closely related to humans.

Spinal facilitation in cholinergic-sympathetic efferents by desipramine.

Electrodermal potentials (EDPs) evoked by electrical stimulation of the cholinergic-sympathetic system at different levels were recorded in the forepaws of anaesthetized cats and used as a measure of sudomotor activity. After pretreatment with yohimbine (0.25 mg/kg i.v.) to block alpha 2-adrenoceptors, unilateral electrical stimulation of the hypothalamus (square wave pulses 1 ms duration, 16 Hz, 2 s train length at intervals of 1 min) induced EDPs in both forepaws. Injection of the inhibitor of neuronal catecholamine reuptake, desipramine (1 mg/kg i.v.), facilitated the EDPs in both forepaws, even though access of the drug to the sweat glands was prevented by application of a tourniquet to one paw. The facilitation was abolished by injection of the specific alpha 1-adrenoceptor antagonist, prazosin (0.5 mg/kg i.v.). An equal enhancement of this effect by desipramine (1 mg/kg i.v.) and its abolition by prazosin (0.5 mg/kg i.v.) was obtained in cats with the brain stem transected at the level of the medulla oblongata and electrical stimulation of the spinal cord at C1. EDPs evoked in the right forepaw by preganglionic electrical stimulation of the right stellate ganglion were inhibited by desipramine (1 mg/kg i.v.). From these and previous results it is concluded that inhibition of neuronal reuptake of catecholamines results in facilitation of activity in sudomotor efferents. This effect is mediated by spinal alpha 1-adrenoceptors and provides an explanation of the occasional occurrence of excessive sweating in psychiatric patients treated with tricyclic antidepressants.

The amphetamine-like releasing effect of the alkaloid (−)cathinone on rat nucleus accumbens and rabbit caudate nucleus

Kalix, Peter: The amphetamine-like releasing effect of the alkaloid (−) cathinone on rat nucleus accumbens and rabbit caudate nucleus. Prog. Neuro-Psychopharmacol. S Biol. Psychiat. 6: 1. (−) Cathinone, a new alkaloid from khat leaves, has recently been reporte to have amphetamine-like behavioral effects. In order to investigate the effects of this compound on the cellular level, slices of rat nucleus accumbens, prelabelled with 3H-dopamine, were superfused with solutions of (−) cathinone. 2. It was found that (−) cathinone, as (+) amphetamine, enhanced the release of radioactivity from rat nucleus accumbens tissue. 3. In similar experiments on rabbit caudate nucleus it was observed that the catecholamine reuptake inhibitors benztropine, nomifensine and mazindol were able to block the (−) cathinone-induced release, indicating that the alkaloid has to penetrate to intraneuronal sites in order to evoke release. 4. It is concluded that the pharmacological similarity between (−) cathinone and (+) amphetamine extends to the cellular level and that the behavioral effects of (−) cathinone are due to stimulation of release from central catecholamine storage sites.

Suppression of insulin‐induced prolactin secretion in man by nomifensine

AbstractIn 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.

Effects of nomifensine, an inhibitor of endogenous catecholamine re-uptake, in acromegaly, in hyperprolactinaemia, and against stimulated prolactin release in man.

1. Nomifensine, an inhibitor of endogenous catecholamine re-uptake, did not affect the growth hormone (GH) or prolactin levels in patients with acromegaly or hyperprolactinaemia. It does not, therefore, have any therapeutic role in these conditions at the dosage used in this study. 2. It had no effect on thyrotrophin-releasing hormone (TRH)-induced thyrotrophin (TSH) or prolactin release in males, yet caused marked suppression of monoiodotyrosine (MIT)-induced prolactin release in males but not in females. 3. The significant suppression of MIT-induced prolactin release in males is likely to reflect the dopamine (DA) agonist activity of the drug and its lack of effect in the other situations tested could be dose related. 4. It is proposed that the difference in male and female patterns of prolactin response to MIT after nomifensine, could be due to a "damping" effect of oestrogen on the hypothalamic dopaminergic system.

Affective disorders: The catecholamine hypothesis revisited

Publisher Summary This chapter reviews the catecholamine hypothesis for affective disorders. The catecholamine hypothesis of affective disorders states that depression is associated with a functional deficit of one, or more neurotransmitter catecholamines at critical synapses in the central nervous system, and conversely mania is associated with a functional excess of these amines. The weight of the available clinical evidence suggests that the monoamine oxidase inhibitors are not very effective antidepressants in patients with more severe, primary, or endogenous depressions, that is, the group that has been the major focus of studies concerned with catecholamine dysfunction. Amphetamine, a stimulant in normals, is generally conceded not to be an effective antidepressant agent, although the occurrence of transient improvement in some depressed patients may have predictive value for subsequent response to tricyclics. Cocaine, a powerful stimulant in normals, is a potent inhibitor of catecholamine reuptake at the synapse, an effect similar to that of the tricyclic antidepressants.