Maria Grabowska

Pharmacological evidence for a stimulation of dopamine neurons by noradrenaline neurons in the brain

The effects of yohimbine (3 mg/kg i.p.), phenoxybenzamine (20 mg/kg i.p.) and clonidine (0.1 mg/kg i.p.) on the synthesis and the utilization of dopamine and noradrenaline in the central nervous system of rats were investigated. Dopa accumulation following decarboxylase inhibition and the alpha-methyltyrosine-induced disappearance of the amines were used as the measure of these effects. The synthesis and the utilization of dopamine and noradrenaline were accelerated by yohimbine. Clonidine plus phenoxybenzamine inhibited the synthesis and utilization of dopamine and the combination also partly antagonized the effects of yohimbine on the trunover of dopamine. The effects of the three drugs on the synthesis and utilization of dopamine might be secondary to their actions on alpha-adrenoreceptors of noradrenaline synapses since, at the doses used, yohimbine increases the release of noradrenaline, phenoxybenzamine blocks postsynapptic noradrenaline receptors and clonidine reduces the release of noradrenaline. This hypothesis is supported by the findings that yohimbine and phenoxybenzamine did not change the increased synthesis of dopamine in reserpine-treated rats and that clonidine did not inhibit the increased synthesis of dopamine after axotomy or treatment with reserpine.

Effect of apomorphine on motility in rats

Abstract Apomorphine, which stimulates central dopamine receptors, was used to study the role of dopaminergic systems in motility changes in rats. Motility was measured by a photocell method. Apomorphine-induced increase in motility was blocked by haloperidol, spiroperidol or phenoxybenzamine but not by reserpine. The effect of apomorphine was partly inhibited by α-methyltyrosine, dimethyldithiocarbamate and disulfiram in both normal and reserpinized rats. It was potentiated by nialamide given with L-DOPA, but not by nortriptyline, desipramine or cocaine. It was concluded that apomorphine increases the motility in rats by direct stimulation of dopamine receptors but another factor is also of importance: noradrenergic neurotransmission. Both dopamine and noradrenaline neurones are probably involved in the control of motility in rats.

Possible involvement of brain serotonin in apomorphine-induced hypothermia.

Abstract Apomorphine lowered body temperature in rats and mice and raised the brain 5-HIAA level. Hypothermia was inhibited by butyrophenones and LSD but not by methysergide and PCPA. LSD also inhibited the apomorphine-induced enhancement of 5-HIAA; this effect was similar to that previously described for butyrophenone. It was noted that apomorphine directly stimulated central dopamine receptors which indirectly increased 5-HT turnover, this latter action leading to hypothermia. The effectiveness of LSD resulted from its ability to stabilize 5-HT inside the neuron.

On the role of serotonin in apomorphine-induced locomotor stimulation in rats

Abstract The locomotor activity of rats injected with apomorphine (1.0 or 5.0 mg/kg) was measured. The increase of locomotion caused by apomorphine was stronger in rats pretreated with BOL or methysergide and in some case with p-chloroamphetamine. LSD did not change the stimulation evoked by apomorphine or decreased it. The results are discussed according to the previously expressed suggestion about the possible inhibitory role of serotonin in apomorphine-induced locomotor stimulation in rats.

The effect of L-DOPA on brain catecholamines and motility in rats

Normal rats and those pretreated with reserpine or α-methyltyrosine were given L-DOPA alone or with extracerebral decarboxylase inhibitor (Ro 4-4602). Motility was measured at two different time intervals and the brain levels of noradrenaline (NA) and dopamine (DA) were subsequently determined.No simple correlation between the DA or NA level and motility was observed. The L-DOPA-induced increase in motility appeared only in rats in which: 1. the DA levels were markedly increased; 2. a sufficient amount of NA was present. Increasing the dose of L-DOPA did not cause an increase in the NA levels.The present results are in agreement with other published data and suggest that under the conditions studied NA can be displaced by DA formed from L-DOPA and that both amines (DA and NA) are of importance in L-DOPA-induced increase of motility.

Influence of apomorphine on brain serotonin turnover rate

Apomorphine (5.0 mg/kg) accelerated the disappearance of 5-HIAA from the brain of pargylinepretreated rats as well as depletion of brain 5-HT caused by inhibition of its synthesis. The latter effect has been abolished by spiroperidol. The results obtained suggest that apomorphine increases the 5-HT turnover rate, secondary to the stimulation of central dopamine receptors.

Influence of midbrain raphe lesion on some pharmacological and biochemical effects of apomorphine in rats

The influence of apomorphine on body temperature, motor activity and forebrain content of serotonin and 5-hydroxyindoleacetic acid in midbrain raphe lesioned rats was investigated. Apomorphine elevates the brain concentration of serotonin and its metabolite and promotes hypothermia in normal and in sham-lesioned rats but it does not produce these biochemical effects and attenuates hypothermia in rats with lesions of the midbrain raphe nuclei. In the lesioned subjects apomorphine stimulates the locomotor activity more strongly. The results confirm the previously expressed hypothesis concerning the role of serotonin in the locomotor stimulation and hypothermia induced by apomorphine in rats.

FLA 136: Selective agonist at central alpha-adrenoreceptors mediating changes in the turnover of noradrenaline

Summary1.FLA 136 [4-amino-3-(2,6-dichlorobenzylidenehydrazino)-1,2,4-triazol] did not change the hindlimb flexor reflex of spinal rats, but it reduced the clonidine-induced increase in this reflex at high doses.2.The α-methyltyrosine-induced disappearance of noradrenaline in the rat central nervous system was decelerated by FLA 136, with a peak effect after 15 mg/kg i.p. The accumulation of Dopa following decarboxylase inhibition was inhibited by FLA 136 (15 mg/kg i.p.) in a noradrenaline-predominant region (brain stem). The effect on the utilization appeared to be greater than that on the synthesis in agreement with a slight increase observed in the concentration of noradrenaline in the brain and the spinal cord.3.FLA 136 reduced the α-methyltyrosine-induced disappearance of dopamine, decreased the Dopa accumulation following decarboxylase inhibition in the dopamine-rich corpus striatum and increased the concentration of dopamine. These effects might be secondary to inhibition of the noradrenergic neurotransmission.4.Yohimbine almost completely inhibited the effect of FLA 136 on the utilization and on the synthesis of noradrenaline whereas phenoxybenzamine was much less effective on the change in the utilization. Yohimbine and phenoxybenzamine were about equipotent, however, in accelerating the disappearance of noradrenaline produced by α-methyltyrosine alone.5.FLA 136 does not stimulate the postsynaptic α-adrenoreceptors mediating the increase in flexor reflex activity but it probably decelerates the utilization of noradrenaline by a stimulation of another kind of α-adrenoreceptors sensitive to yohimbine. The latter receptors might occur on the noradrenergic neurones (presynaptic receptors).

Effect of clonidine on the 5-hydroxytryptamine and 5-hydroxyindoleacetic acid brain levels☆

Abstract The effects of clonidine on the brain levels of 5-HT and 5-HIAA in rats and mice were studied. Clonidine did not change the levels of 5-HT and 5-HIAA in the whole brains of either animal species but the 5-HT concentrations were elevated in rat brain pons + medulla oblongata. Clonidine antagonized the increase in the brain 5-HIAA levels induced by apomorphine in rats and mice. The decrease in the 5-HT level and the increase in the 5-HIAA level observed in rats after L -dopa (given with peripheral decarboxylase inhibitor RO 4-4602) were counteracted by clonidine.

The influence of apomorphine and tricyclic antidepressant drugs on the level of serotonin and its metabolite in rat brain

Abstract Brain levels of serotonin and 5-hydroxyindoleacetic acid were measured in rats after combined treatment with apomorphine and tricyclic antidepressants. The apomorphine-induced elevation of 5-hydroxyindoleacetic acid was prevented by tertiary but not by secondary antidepressants. The results are discussed in relation to the possible participation of serotonin in the mechanism of action of apomorphine.