J. Maj

Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats

In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. The authors previously reported that combined administration of imipramine and the uncompetitive NMDA receptor antagonist amantadine reduced immobility time in the forced swimming test in rats to a much greater extent than either treatment alone. The present paper investigates the possibility of synergistic interactions between three antidepressants (imipramine, venlafaxine, fluoxetine) with three uncompetitive NMDA receptor antagonists (amantadine, memantine and neramexane). Most combinations resulted in synergistic (hyperadditive) antidepressive-like effects in the forced swim test. Most interesting was the observation that fluoxetine, which was inactive when given alone, showed a positive effect when combined with amantadine (10 and 20 mg/kg), memantine (2.5 and 5 mg/kg) or neramexane (2.5 and 5 mg/kg). The specificity of these observations is supported by control open field studies, which demonstrated no significant increase, or even a decrease in general locomotion after coadministration of the compounds. The present results suggest that the combination of traditional antidepressant drugs and NMDA receptor antagonists may produce enhanced antidepressive effects, and this is of particular relevance for antidepressant-resistant patients.

Effects of MK-801 and antidepressant drugs in the forced swimming test in rats

The effects of MK-801, a non-competitive NMDA receptor antagonist, and of antidepressant drugs were studied in the forced swimming test in rats. MK-801 reduced immobility time. Combined treatment with MK-801 + imipramine induced a stronger effect in Porsolts test than administration of either drug alone. Citalopram was inactive when given alone but it potentiated the antidepressant-like effect of MK-801. Haloperidol and prazosin antagonized the effect induced by MK-801 + IMI or CIT. Mianserin interacted with MK-801 in a similar way but to a lesser extent. Its effect was antagonized by haloperidol but not by prazosin. The reduction of the immobility time was also observed in those experimental paradigms in which the locomotor activity was not increased. The results indicate that synergism may exist between antidepressants and MK-801.

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.

Trazodone, a central serotonin antagonist and agonist

We examined the effect of trazodone (TR), a non-tricyclic antidepressant drug with an unknown mechanism of action, as well as its supposed metabolitesβ-(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.

The central antiserotonergic action of mianserin

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.

Effect of antidepressant drugs administered repeatedly on the dopamine D3 receptors in the rat brain

Previous studies have indicated that antidepressant drugs displaying different pharmacological profiles, administered repeatedly, increase the locomotor hyperactivity induced by various dopaminomimetics, among others by quinpirole. As this drug, according to a recent study, shows high affinity not only for dopamine D2 but also for dopamine D3 receptors, the question arises if dopamine D3 receptors are involved in the increase in quinpirole-elicited locomotor hyperactivity induced by repeated treatment with antidepressant drugs. In the present study we administered imipramine, amitriptyline, citalopram and mianserin (in a dose of 10 mg/kg p.o., twice a day, 14 days) to male Wistar rats and then (+/-)-7-OH-DPAT (7-hydroxy-dipropylaminotetralin), a dopamine D3 receptor agonist, was given (3 mg/kg s.c.). Hyperlocomotion induced by (+/-)-7-OH-DPAT was significantly increased by repeated administration of antidepressant drugs. The receptor autoradiography technique with [3H]7-OH-DPAT as a radioligand was applied to measure the effects of antidepressant drugs treatment on the dopamine D3 receptors in the islands of Calleja and in the shell of the nucleus accumbens septi, which are brain regions with highly selective expression of dopamine D3 receptors. The biochemical studies indicated that in both examined brain regions there was an increase in the binding of [3H]7-OH-DPAT following the repeated administration of antidepressant drugs. In some cases this increase was also observed after the acute administration of antidepressants. The results obtained in the present study indicate that antidepressant drugs administered repeatedly enhance the responsiveness of dopamine D3 receptors, probably via an increase in the density of these receptors. This mechanism is probably similar to that observed already in the case of dopamine D2 receptors. Therefore it is hypothesized that dopamine D3 receptors are also involved in the increased responsiveness to dopamine D3 receptor agonists observed after antidepressants.

Antidepressant effects of pramipexole, a novel dopamine receptor agonist

SummaryPramipexole (2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochloride), a new dopamine receptor agonist with preference for D3 compared to D2 and D4 receptors, was tested in rats in respect of its potential antidepressant activity. In the forced swimming test the drug under study, given three times in rats, reduced the immobility time. In the forced swimming test, joint treatment with antidepressants (imipramine, amitriptyline) and pramipexole evoked a more potent effect than any of the drugs given alone; however, the locomotor hyperactivity was weaker after joint administration. Citalopram and fluoxetine, inactive per se in the forced swimming tests, visibly enhanced the antidepressant-like effect of pramipexole but, on the other hand, they attenuated the locomotor hyper-activity evoked by the drug. Repeated treatment with pramipexole (0.3 or 1 mg/kg, twice daily for 14 days) increased the locomotor activity measured at 1h after the last dose. Repeated administration of pramipexole (as above) potentiated the D-amphetamine- or quinpirole-induced locomotor hyperactivity.The obtained results indicate that, in the tests used, pramipexole evokes effects similar to those of typical antidepressants and, at the same time, enhances their activity (the forced swimming test in rats); therefore it may be regarded as a potential antidepressant drug.

Repeated treatment with antidepressant drugs increases the behavioural response to apomorphine.

The effect of repeated treatment (twice a day for 14 days) with antidepressant drugs (AD): imipramine, amitriptyline, zimelidine, citalopram and mianserin on the behavioural response to apomorphine in rats (open field test) was investigated. AD studied, given alone in a single dose or repeatedly, do not change the rats behaviour. A repeated but not single-dose treatment with AD facilitates the behaviour stimulation induced by apomorphine. This facilitation is observed 2 hours after the last dose of imipramine, zimelidine, citalopram and mianserin but 72 hours after the last dose of amitriptyline. The results presented suggest that the AD given repeatedly are able to increase the responsiveness of the brain DA system, probably the mesolimbic one.

Antidepressant drugs given repeatedly increase binding to α1-adrenoceptors in the rat cortex

The effect of antidepressant drugs, administered repeatedly, on binding to α 1 -adrenoceptors in the rat cerebral cortex was studied using [ 3 H]prazosin as a ligand. Imipramine, amitriptyline, citalopram and mianserin increased the binding (B max ) assessed at 8:00 h. At 20:00 h such an effect was produced by imipramine, citalopram and mianserin. [ 3 H]Prazosin binding in control rats was higher at 20:00 h than at 8:00 h. An increase in the density of α 1 -adrenoceptors may be associated with the therapeutic activity antidepressant drugs.

Chronic treatment with antidepressant drugs: Potentiation of apomorphine-induced aggressive behaviour in rats

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.