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J Maj

Publications and source records attributed to J Maj.

At least 91 records · Page 5Linked to original sources
PubMed1983

Reserpine-induced locomotor stimulation in mice chronically treated with typical and atypical antidepressants.

Previous studies have shown that chronic treatment with antidepressants (AD) leads to an increased responsiveness of NA systems to noradrenaline (NA) or its agonist. In the present paper the influence is described of a prolonged treatment with AD of different pharmacological profiles on the effect of reserpine in the first phase of its action (amine release). It has been found that in mice treated chronically (14 days, twice a day, i.p.) with imipramine, amitriptyline, maprotiline, (+)-oxaprotiline, zimelidine, citalopram, mianserin and iprindole, the injection of reserpine induces stimulation of the locomotor activity. Only (-)-oxaprotiline and fluvoxamine do not evoke this effect. AD given alone (both single and repeated doses), reserpine alone, AD in a single dose administered jointly with reserpine do not induce the locomotor stimulation. These results suggest that a prolonged treatment with AD increases the responsiveness of the dopamine (DA) mesolimbic system and/or the NA system.

Animals↗
PubMed1983

Chronic treatment with imipramine: further functional evidence for the enhanced noradrenergic transmission in flexor reflex activity.

The chronic administration of imipramine (IMI; 10 mg/kg orally, twice daily for 14 days) enhanced the flexor reflex of the hind limb in the spinal rat. This effect was maintained for at least 72 h after termination of drug administration. Phenoxybenzamine but not cyproheptadine abolished the enhanced activity of the flexor reflex. After chronic administration of IMI high levels of desipramine (DMI) were found in the spinal cord, whereas IMI was not detectable there. No correlation was found between the levels of DMI in the spinal cord and the enhancement of the flexor reflex amplitude. A single i.v. dose of DMI facilitated the flexor reflex for a short period of time. In rats treated chronically with IMI, the binding of 3H-prazosin, a ligand of alpha 1-adrenoceptors, to spinal cord tissue was increased. The present results are a further argument for the previously advanced hypothesis that chronic administration of antidepressant drugs leads to an enhanced noradrenergic transmission, probably by increasing the number of alpha 1-adrenoceptors.

Animals↗
PubMed1983

[Pharmacodynamics and pharmacokinetics of memantine].

The adamantane derivative memantine (1-amino-3,5-dimethylaminoadamantane, D-145, Akatinol) is clinically used as well in the therapy of neurogenic motor diseases (e.g. spasticity) as in the treatment of cerebral disorders like coma, cerebrovascular and geronto-psychiatric disturbances. The aim of the paper is to summarize experimental evidences that may help to explain the clinical observations. Biochemical, pharmacological, and electrophysiological studies show that memantine interferes with the metabolism of the transmitters dopamine, noradrenaline (norepinephrine), and serotonin and modulates synaptic transMission. In order to explain the antispastic activity of memantine, a spinal action must be assumed in addition to the supraspinal effect on transmitter systems. Since memantine reduces the membrane resistance as well as the membrane conductance of sodium, potassium, and chloride ions, it is very likely that memantine Is directly involved in the generation of action potentials.

Amantadine↗
PubMed1983

The effect of selective inhibitors of noradrenaline and serotonin uptake on reserpine- and apomorphine induced hypothermia in mice.

The antidepressant action of combined treatment with selective inhibitors of noradrenaline (NA) and serotonin (5HT) uptake was investigated using the reserpine and apomorphine hypothermia tests. Desipramine and maprotiline, NA uptake inhibitors, but not fluoxetine and citalopram, selective 5HT uptake inhibitors, antagonized the hypothermias. A combination of NA and 5HT uptake inhibitors antagonized reserpine hypothermia less effectively than the inhibitor of NA uptake alone. The apomorphine hypothermia was antagonized similarly by a NA uptake inhibitor given alone and in combination with a 5HT uptake inhibitor. The results indicate that for antidepressant (antireserpine and antiapomorphine) effect the essential role is played by a noradrenergic mechanism, while the serotonergic mechanism may even produce opposite effect.

Animals↗
PubMed1982

Fluvoxamine, a new antidepressant drug, fails to show antiserotonin activity.

Fluvoxamine, (E)-5-methoxy-4'-(trifluoromethyl)valerophenone O-2(2-aminoethyl)oxime, a new antidepressant drug inhibiting serotonin (5-HT) uptake, was studied in rats and mice in order to check whether it has any central anti-5-HT activity, as do some tricyclic antidepressants, e.g. amitriptyline and doxepin. Fluvoxamine did not influence either the 5-hydroxytryptophan-induced head twitch response in mice or the tryptamine convulsions in rats. In the hind limb flexor reflex of the spinal rat the stimulation induced by fenfluramine was inhibited, that induced by LSD was not changed. Fluvoxamine also antagonized the hyperthermia (at ambient temperature of 28 degrees C), induced in rats by fenfluramine or p-chloroamphetamine. The hyperthermia caused by m-chlorophenylpiperazine was not inhibited. Fluvoxamine did not antagonize the 5-HT pressor effect in pithed rats. It has no effect on the immobility time in the behavioural despair test in rats. The results indicate that fluvoxamine fails to show anti-5-HT activity.

5-Hydroxytryptophan↗
PubMed1982

Comparison of the pharmacological actions of desmethylclomipramine and clomipramine.

This research compares the effects, in mice and rats, of desmethylclomipramine (DCLOM) and clomipramine (CLOM). DCLOM antagonized the hypothermia induced in mice by reserpine or apomorphine to a much greater extent than CLOM. Reserpine ptosis in mice was depressed by DCLOM only. Similarly, only DCLOM was effective in the behavioral despair test in rats. DCLOM increased the 5-hydroxytryptamine (5-HT) pressor effect in pithed rats, but to a lesser extent than CLOM by several factors. Only DCLOM increased the noradrenaline (NA) pressor effect. The depletion of NA induced by 6-hydroxydopamine was depressed by DCLOM only. The 5-HT depletion induced by p-chloromethamphetamine was antagonized only by CLOM. The results obtained show that the noradrenergic mechanism is of prime importance in the action of DCLOM and of much more importance than in the action of CLOM.

Animals↗
PubMed1982

Effects of chronic treatment with antidepressants on aggressiveness induced by clonidine in mice.

It has previously been found that a number of typical and atypical antidepressants, given chronically, intensify clonidine-induced aggressiveness in mice. Further experiments now show that chronic, but not acute, administration of nisoxetine, a selective inhibitor of noradrenaline uptake, potentiates clonidine-induced aggressiveness. Citalopram and fluvoxamine, two selective inhibitors of serotonin uptake, have no such action. Of the two isomers of flupenthixol, only the trans-form potentiates clonidine-induced aggressiveness of chronic experiments. The cis-form induces an inhibiting effect. Clonidine-induced aggressiveness is also intensified by chronic, but not by acute, administration of pizotifen, an antagonist fo serotonin and noradrenaline. The results seem to support the previous hypothesis that potentiation of clonidine-induced aggressiveness is mediated by an alpha 1-adrenergic mechanism.

Aggression↗
PubMed1982

Different pharmacokinetic and pharmacological effects following acute and chronic treatment with imipramine.

Two schedules of imipramine (IM) administration were compared, a single intraperitoneal dose (10 mg/kg) (I) and chronic oral dosage (10 mg/kg twice a day for 14 days) (II). During schedule I, IMI reached maximal concentration in brain twice as high as that of its metabolite, desipramine (DMI), but disappeared more rapidly. During schedule II, DMI achieved concentrations twice as high as those of IMI which were maintained in a long-lasting plateau and there were considerable differences in areas of brain concentration curves. During schedule I, depletion of brain noradrenaline (NA) induced by H77/77 and of 5-hydroxytryptamine (5-HT) by p-chloro-amphetamine, were inhibited. During schedule II, after DMI concentration had become high and that of IMI low, only NA depletion but not that of 5-HT, was inhibited. At the same time, fenfluramine-induced hyperthermia was not antagonized although it was inhibited in schedule I. These findings may be relevant to those obtained clinically and may help to shed light on mechanisms of antidepressant action.

Animals↗
PubMed1982

Atypical antidepressant drugs - psychopharmacological profile and mechanism of action.

The psychopharmacological profile and mechanism of action of ten atypical novel and potential antidepressive drugs (AD) have been investigated. It has been shown that they form a pharmacologically heterogeneous group. Some of them may be considered as central 5-hydroxytryptamine (5-HT) antagonists. Two typical AD, amitriptyline and doxeprine, turned out to be potent 5-HT antagonists also. These observations justify the conclusion that these drugs rather block than facilitate 5-HT neurotransmission. Some data indicate that 5-HT antagonists can shift the balance between the noradrenergic and serotoninergic systems in favour of the former. Both atypical and typical AD when administered chronically, induce effects not observed after single-dose treatment. The effects observed indicate that the chronic administration of AD leads to the development of the increased responsiveness (or activation) of the noradrenergic system.

Aggression↗
PubMed1982

Central action of amitriptyline N-oxide.

The central action of amitriptyline N-oxide (AMINO) has been compared with amitriptyline (AMI) in biochemical and pharmacological studies in rats and mice. It has been found in rats that both drugs prevent 6-OH-dopamine-induced depletion of brain noradrenaline (NA). At the same time AMINO increases and AMI lowers the NA level, both being without effect on 3-methoxy-4-hydroxyphenylglycol concentrations in the brain. AMINO and AMI potentiate the depletion of 5-hydroxytryptamine (5-HT) induced by p-chloroamphetamine in the rat brain and it may be considered as evidence that both drugs do not inhibit 5-HT uptake in vivo. Neither AMINO nor AMI affects the rat brain level of 5-HT but at higher doses they elevate the 5-hydroxy-indoleacetic acid concentrations. AMINO antagonizes the head twitch reaction induced by 5-hydroxytryptophan in mice and tryptamine convulsions in rats. The hyperthermia induced by fenfluramine (in rats at a high ambient temperature) as well as the stimulation of the hind limb flexor reflex in spinal rats, induced by fenfluramine or LSD, are also inhibited. AMINO antagonizes the 5-HT-induced increase in blood pressure in pithed rats. All the above effects are similar to those induced by AMI, only the active doses of AMINO are higher. The results presented indicate that AMINO, like AMI, inhibits NA uptake and is a 5-HT antagonist.

5-Hydroxytryptophan↗
PubMed1982

[Effect of memantine on central neurotransmitter systems. Review of the results].

In the present review the effects of 1,3-dimethyl-5-amino-adamantane (DMAA, D-145, Memantine, Memantine) on various neurotransmitter systems were presented. The most marked effect of DMAA seems to be the stimulation of dopaminergic neurons as reflected by the respective behavioural changes and biochemical effects. The stimulatory action on noradrenaline and serotonin neurons (at least partially indirectly through the activation of dopamine system) as well as on GABA neurons is apparent. No direct effects on Dopamine, alpha 1, alpha 2, Serotonin, GABA, benzodiazepine and opiate receptors were found. DMAA can be assigned to a new class of compounds which act mainly as dopaminomimetics, but its mode of action is apparently different from those of amphetamine or apomorphine. It differs quantitatively and qualitatively from amantadine, another derivative of adamantane.

Acetylcholine↗
PubMed1981

Chronic treatment with some atypical antidepressants increases the brain level of 3-methoxy-4-hydroxyphenylglycol (MHPG) in rats.

We examined the effects of some atypical antidepressants with central antiserotonergic activity (mianserin, trazodone, danitracen, pizotifen), and 5-HT receptor blocking agents (cyproheptadine and metergoline), on whole rat brain levels of the main noradrenaline (NA) metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG). In acute experiments, when drugs were injected in a single dose 1, 2, 4, 24 or 48 h before decapitation, only mianserin elevated the MHPG level. In chronic experiments (drugs given b. i. d. for 3 weeks, the last dose being given 4 or 48 h before decapitation), all the drugs significantly increased the concentration of whole brain MHPG. The results indicate that chronic administration of atypical antidepressants leads to activation of the central NA system. It seems, with the exception of mianserin, that this is a secondary phenomenon, resulting from the antiserotonergic activity of the drugs. Our results further corroborate the existence of a serotonergic-noradrenergic interaction, consisting of an inhibitory influence of serotonin on the noradrenergic system.

Animals↗
PubMed1981

Chronic treatment with antidepressants: protentiation of clonidine-induced aggression in mice via noradrenergic mechanism.

The chronic (10 mg/kg i.p. twice daily, 10 days)-and not the acute-administration of amitriptyline, maprotiline or zimelidine enhances aggressiveness induced by clonidine in mice. An analogous potentiation of clonidine-induced aggressiveness was obtained with chronic administration (the schedule as above) of levomepromazine (2 mg/kg) or thioridazine (5 mg/kg) but not of spiperone (0.2 mg/kg). Fluoxetine (10 mg/kg), atropine (5 mg/kg), propranolol (10 mg/kg) or metergoline (0.5 mg/kg) given chronically (the schedule as above) also had no effect. The enhancement of clonidine aggressiveness induced by prolonged treatment with imipramine (10 mg/kg) was prevented by cycloheximide, an inhibitor of protein synthesis. The results supply further evidence for the previously proposed hypothesis that chronic administration of antidepressants enhances the responsiveness of central postsynaptic noradrenaline receptors.

Aggression↗
PubMed1981

Influence of proadifen, an inhibitor of the metabolism of drugs, on the action of imipramine and desipramine in rats.

The influence of proadifen (SKF-525-A), an agent inhibiting the metabolism of drugs, on the antidepressant action of imipramine (IMI) and desipramine (DMI) in rats was investigated. Proadifen antagonized the action of IMI when investigated in reserpine hypothermia and ptosis and in the behavioral despair test. The action of DMI in the same tests was not changed by proadifen. Proadifen lowered the level of DMI and increased the level of IMI in rat brains. The results permit to draw the conclusion that DMI plays an essential role in the action arising from IMI administration, that is, the noradrenergic--and not the serotonergic--mechanism is of essential importance.

Animals↗