Biomedical subjects
Publications and source records attributed to J Maj.
The effects of antidepressant drugs on clonidine-induced aggressive behavior were determined in mice. Imipramine, mianserin and iprindole used in a single dose attenuated clonidine-induced aggression. Their chronic administration enhanced it.
The influence of zimelidine and clomipramine on two p-chloroamphetamine (PCA)- or fenfluramine-induced pharmacological effects, regarded as resulting from the serotoninergic stimulation, was studied. In the flexor reflex test in the spinal rat zimelidine prevented potentiation induced by PCA but not that induced by fenfluramine. Clomipramine antagonized both the PCA- and fenfluramine-induced effects. Zimelidine counteracted also the hyperthermia in rats induced by PCA at a high ambient temperature but not that induced by fenfluramine. These findings seem to indicate that: (1) zimelidine and clomipramine differ in their mechanism of presynaptic action on serotonin neurons; (2) fenfluramine and PCA are taken up to serotonin neurons via different mechanisms.
The antidepressant drugs, imipramine (10 mg/kg s.c.), amitriptyline (10 mg/kg s.c.), mianserin (2 mg/kg i.p.), danitracen (3 mg/kg i.p.) or the vehicle were administered to rats twice a day for 4 or 10 days. Clonidine (0.5 mg/kg s.c.) induced in rats chronically treated with the compounds studied an increase in locomotor activity but, at the same time, did not affect or decreased this activity in rats chronically treated with the vehicle or a single dose of an antidepressant. This refers, in particular, to imipramine, amitriptyline and danitracen which have a similar effect. This effect, an increase in motility, was most pronounced and common for all the three drugs (after a 4- and 10-day treatment) when clonidine was administered 72 hours after the last dose of an antidepressant. Only in a few cases the amphetamine-induced hypermotility was enhanced by a chronic administration of antidepressants (a 4-day amitriptyline treatment, 72 hours after the last injection; a 4-day mianserin or danitracen treatment, 48 hours after the last injection). The results obtained seem to suggest that a chronic administration of the antidepressant drugs may cause a change in the sensitivity of the central noradrenaline receptors.
We examined the effect of trazodone (TR), a non-tricyclic antidepressant drug with an unknown mechanism of action, as well as its supposed metabolites beta-(3-oxo-s-triazolo-[4, 3 a]-pyridin-2-yl-propionic acid (OTPA) and 1-(m-chlorophenyl)-piperazine (CPP) on the serotonin (5-HT) -system in a model of the hind limb flexor reflex of the spinal rat. When given alone at low doses (1 mg/kg) TR does not change the flexor reflex but counteracts its serotonergic stimulation induced by LSD, quipazine or fenfluramine. At higher doses (6--8 mg/kg), after a period of latency, it enhances the reflex; this effect is antagonized by the 5-HT receptor blockers (cyproheptadine, WA-335 and metergoline) but not by imipramine. From the two TR metabolites studied only CPP exerts an effect in the flexor reflex model. It considerably enhances (0.05--1 mg/kg) the reflex, this effect being antagonized by cyproheptadine, WA-335 and metergoline, but not by imipramine. Our findings indicate that TR has a double effect on the central 5-HT system: at low doses it acts as a 5-HT antagonist, whereas at higher ones--as a 5-HT agonist. The latter effect may be connected with formation of a metabolite, CPP, or a compound chemically related to CPP.
Chronic (14 days) but not acute treatment with antidepressants (amitriptyline, imipramine, desipramine, clomipramine, mianserin, danitracen, iprindole) potentiated the aggressive behaviour induced by apomorphine (APO) in rats. The APO stereotypy was not changed. A similar potentiation was caused by chronic treatment with phentolamine or thioridazine but not with spiperone or deazepam. In rats treated chronically with amitriptyline the APO-induced fighting was antagonized by phenoxybenzamine or spiperone, and not by metergoline. The results allows us to postulate that the chronic treatment with antidepressants potentiates the APO-induced aggressiveness via the noradrenergic mechanism, i.e., through an enhanced response to the endogenous NA.
Amitriptyline (AMI) was studied in rats snd mice in order to find out whether it had a central antiserotonin activity, previously demonstrated for doxepin - a compound chemically related to AMI. It was observed that AMI at low doses antagonized the head twitch response to L-5-hydroxytryptophan or 5-methoxytryptamine, as well as tryptamine-induced convulsions. In the hind limb flexor reflex preparation of the spinal rat AMI acted as a serotonin antagonist: when administered alone, it did not change the flexor reflex but prevented its stimulation induced by serotoninmimetics (LSD, quipazine, fenfluramine) not affecting that one evoked by noradrenalinemimetics (clinidine). At higher doses, AMI revealed a noradrenolytic activity. The results indicate that AMI, similarly as doxepin, has a central antiserotonin activity.
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The central antiserotonergic action of mianserin (MS) was tested in mice, rats, and rabbits. MS, like cyproheptadine, to which it was compared, inhibits the head-twitch response to 5-hydroxytryptophan in mice and rats without affecting the pinna reflex. MS does not change the flexor reflex of the hind limb of the spinal rat; it antagonizes its stimulation induced by fenfluramine, LSD, and quipazine, but not that induced by clonidine. The hyperthermia in rabbits caused by the serotonergic stimulants cited above is also antagonized by pretreatment with MS. Unlike cyproheptadine, MS is not active in the oxotremorine test. The results indicate that at low doses MS is a central serotonergic-receptor blocker.
It was found that spiperone and pimozide in doses which themselves do not influence the flexor reflex of the hind limb of the spinal rat inhibit stimulation of this reflex induced by serotoninomimetic drugs (LSD and fenfluramine). Higher doses of spiperone depress the flexor reflex and inhibit the stimulating effect of clonidine. Pimozide has no such effect. Haloperidol in doses which do not influence the action of LSD and fenfluramine produces a depression of the flexor reflex and antagonizes the action of clonidine. Our findings indicate that, irrespective of their antidopamine action, spiperone has a central antiserotonin effect and an antinoradrenaline one, pimozide--an antiserotonin one and haloperidol--an antinoradrenaline one.
Studies on the interaction of two dopamine (DA) agonists (selected as most specific): apomorphine (APO) and 1,3-dimethyl-5-aminoadamantane (DMAA) with serotonin (5-HT) and noradrenaline (NA) brain systems have revealed that the drugs induce the activation of 5-HT and NA neurons in an indirect way (via primary DA stimulation). These interactions are relevant for some pharmacological effects of DA agonists.
Bromocriptine (CB-154) is regarded as a dopamine agonist, hence is used in the treatment of Parkinson's disease. In the paper presented a possibility of the influence of bromocriptine on central serotonin neurons has been studied. It was demonstrated that CB-154, like tryptophan, 5-hydroxytryptophan, LSD or fenfluramine in previous experiments, potentiates the flexor reflex of the spinal rat, and this effect of CB-154 is prevented by serotonin antagonists--cryproheptadine and danitracen. CB-154, like fenfluramine used as a comparative serotonergic agent, rises the body temperature in rabbits. The hyperthermic effect of CB-154 is prevented by cyproheptadine, danitracen and mianserin. Haloperidol prevents the hyperthermia caused by a lower dose of CB-154 or on fenfluramine-induced hyperthermia. The results obtained indicate that CB-154, besides a dopaminomimetic action, possesses central serotonin actions as well.
The antidepressant drug-Doxepin (DX) was examined in order to investigate its central antiserotonin activity. The drug antagonized the behavioral syndrome elecited by L-5-hydroxytryptophan in rats and mice, but did not affect the pinna reflex. In the flexor reflex preparation, DX acted like other sero-tonin receptor blockers: By itself, it had no influence on the flexor reflex but it prevented the potentiation induced by serotonergic agents (fenfluramine, LDS, mescaline). The hyperthermia provoked by serotonergic agent (fenfluramine, LSD)in rabbits was antagonized by DX. DX abolished the syndrome induced by oxotremorine. The results obtained indicate that DX blocks central 5-HT receptors, like the two other antidepressants, mianserin and danitracen.
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The effects of serotonergic and antiserotonergic drugs on the hind limb flexor reflex (measured as a contraction of musculus tibialis anterior or as a flexion of the paw) in the spinal rat was studied. All serotonergic drugs used (L-5-hydroxytryptophan, L-tryptophan, LSD, fenfluramine, p-chloroamphetamine) stimulate the flexor reflex. Serotonin receptor blockers (cyproheptadine, WA-335, methergoline), which given alone are inactive, inhibit the stimulation induced by serotonergic drugs but do not influence that one caused by noradrenergic agents (amphetamine, clonidine). Both types of stimulation (serotonergic and noradrenergic) are antagonized by noradrenaline receptor blockers (phenoxybenzamine, clozapine). The antiserotonergic action of serotonin antagonists used was confirmed on the basis of the antagonism to the head twitches induced by L-5-hydroxytryptophan. The flexor reflex in the spinal rat may be a good model to evaluate the effect on the central (spinal cord) serotonin receptor and to differantiat this effect from that on the noradrenaline system.
The anticataleptic action of cyproheptadine, a tricyclic compound known as antiserotonin, anticholinergic and antihistaminic drug in comparison to that of atropine, promethazine, imipramine, desipramine, chlorimipramine and nomifensine was studied in rats. The catalepsy induced by spiperon, pimozide or fluphenazine was antagonized by cyproheptadine, atropine and promethazine. Imipramine and nomifensine were less active, desipramine and chlorimipramine without effect. The reserpine- and alpha-methyltyrosine-catalepsy was counteracted by cyproheptadine, promethazine and nomifensine, but not by atropine or tricyclic antidepressants. Only cyproheptadine and promethazine antagonized the catalepsy caused by a combined treatment with reserpine and alpha-methyltyrosine. The pilocarpine-catalepsy was abolished by atropine, promethazine and nomifensine and unaffected by tricyclic antidepressants. Atropine and promethazine antagonized also the physostigmine-catalepsy. The catalepsy induced by both cholinomimetic drugs was not changed or increased by cyproheptadine. The results presented indicate that cyproheptadine differs in its anticataleptic activity from all the drugs used for comparison. Possible mechansims of this activity are discussed.
In a previous study, anticataleptic action of cyproheptadine was reported. The present investigation deals with the influence of WA-335 (9,10-dihydro-10-(1-methyl-4-piperidylidene)-9-anthrol), another antagonist of serotonin, on catalepsy induced in rats with spiroperidol, pimozide, fluphenazine and reserpine. WA-335 antagonized catalepsy induced by these neuroleptics (the effect on reserpine-induced catalepsy was weakest). Joint administration of WA-335 and L-DOPA with an inhibitor of peripheral decarboxylase, or WA-335 and amantadine produced a stronger antagonistic effect (spiroperidol catalepsy) than either of these substances separately. WA-335 did not prevent catalepsy induced with physostigmine.