The effect of antidepressant drugs on the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist.

It was found earlier that imipramine, amitriptyline and citalopram enhanced the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist, in rats. Now, three other antidepressants: (+)-oxaprotiline, an inhibitor of the uptake of noradrenaline, (-)-oxaprotiline, an enantiomer devoid of any effect on the uptake of noradrenaline and fluoxetine, an inhibitor of the uptake of 5-hydroxytryptamine, have been examined in male Wistar rats. All those antidepressants, given in a single dose, increased the MK-801-induced locomotor hyperactivity. That increase was completely antagonized by haloperidol and partly by SCH 23390 and (+/-)-sulpiride; prazosin was inactive. Repeated administration of antidepressants produced a similar but more potent (than acute one) enhancement of the action of MK-801. Also, in that case haloperidol and SCH 23390 produced the strongest antagonistic effect; (+/-)-sulpiride and prazosin had a distinctly less potent action. Another effect of MK-801, anticonvulsant activity (electroshock-induced convulsions), was not increased by the antidepressants studied. These results indicate that antidepressants with a different pharmacological profile, increased the MK-801-induced locomotor hyperactivity, this effect being probably indirectly mediated, at least in part, by a dopamine mechanism.

The effect of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, in the forced swimming test.

The present study examined the effects of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, in the forced swimming test in rats and mice. Administered in a single dose or three times both examined compounds reduced the immobility time in rats. Active doses used in that test either did not change the locomotor activity or decreased it. A similar effect in both tests was shown by active (R)-enantiomers CGP 40116 and CGP 43487. Reduction of the immobility time induced by CGP 37849 and CGP 39551 in the forced swimming test in rats was antagonized by haloperidol and (+/-)-sulpiride, but not by SCH 23390 or prazosin. CGP 37849, but not CGP 39551, also reduced the immobility time in the forced swimming test in mice. The results obtained indicate that CGP 37849 and CGP 39551 induce an antidepressant-like effect in the forced swimming test, probably via an indirect dopamine activation resulting from blockade of NMDA receptors.

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 Porsolt's 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.

The effect of (+)- and (-)-oxaprotiline administered repeatedly on the dopamine system.

The behavioural and biochemical effects of repeated (14 and 28 days) treatment with (+)-oxaprotiline (a noradrenaline uptake inhibitor) and (-)-oxaprotiline (levoprotiline, without influence on noradrenaline uptake; the clinically active antidepressant) were studied in rats. Both those enantiomers given repeatedly increased the locomotor and exploratory activity and reduced the immobility time in Porsolt's test. The D-amphetamine-induced locomotor hyperactivity, as well as the stereotypies induced by D-amphetamine and apomorphine, were increased by the oxaprotilines. Single-dose treatment with both the oxaprotilines was not effective in the tests mentioned above. Repeated (+)-oxaprotiline administration reduced the binding (Bmax but not KD) to dopamine D-1 receptors in the striatum and limbic system; levoprotiline was inactive. The binding to dopamine D-2 receptors was not changed by either drug. Both the enantiomers showed only low affinity for brain dopamine D-1 and D-2 receptors in vitro. The obtained results indicate that chronic treatment with (+)- and (-)-oxaprotiline increases behavioural responsiveness of the dopamine mesolimbic and striatal systems.

Some central effects of opipramol given repeatedly.

Some central effects of opipramol administered repeatedly (twice daily, 14 days) were studied in rats and mice. Repeated or acute treatment with opipramol did not change the locomotor activity of rats. Given repeatedly, but not in a single dose, opipramol increased the (+)-amphetamine-induced hyperactivity. The (+)-amphetamine-induced stereotypy was unchanged by acute or repeated treatment with opipramol. The aggressiveness induced by clonidine in mice was attenuated by a single dose of opipramol, but it was markedly enhanced after repeated treatment with this drug. The immobility time of rats (behavioral despair test) was prolonged by a single dose of opipramol; when given three times, opipramol reduced the immobility time. The obtained results seem to indicate that repeated treatment with opipramol leads to similar effects in the experimental models as those after repeated treatment with typical antidepressant drugs, i.e. enhancement of the responses mediated by dopamine receptors (probably in the limbic system, but not in the striatum) and alpha 1-adrenoceptors in the brain.

Some central pharmacological effects of (+)- and (-)-oxaprotiline.

The central action of oxaprotiline (OXA) enantiomers, administered in a single dose, was studied in rats and mice. (+)-OXA and (-)-OXA attenuated reserpine- and apomorphine-induced hypothermia [(+)-OXA in a more potent manner] in mice and reduced the immobility time in the behavioural despair test in rats. Both OXA enantiomers inhibited locomotor activity in mice and rats, and enhanced and prolonged amphetamine- and apomorphine-induced stereotypy in rats. (-)-OXA potentiated the amphetamine hyperactivity in rats, but not in mice. Nomifensine hyperactivity in rats was unaffected by either enantiomer, and locomotor hypoactivity induced by low doses of apomorphine was also unchanged, as was L-DOPA-induced locomotor hyperactivity in mice. Apomorphine-induced climbing in mice was attenuated by (+)-OXA. Clonidine locomotor hypoactivity and hypothermia were unchanged, and clonidine-induced aggressiveness was attenuated by (+)-OXA. Neither OXA enantiomer affected the action of oxotremorine. In some tests the effect of OXA was stronger at 3 h than at 1 h after administration. The above results indicate that both OXA enantiomers--in particular (-)-OXA--increase some dopaminergic behavioural effects in rats.

Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease.

Behavioural and some neurochemical effects of Ro 40-7592 (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone), a new COMT inhibitor, were studied in rats and mice. Ro 40-7592 increased the effect of L-DOPA (plus benserazide) on locomotor activity, reserpine-induced hypothermia, and catalepsy induced by pimozide, haloperidol and fluphenazine. Locomotor hyperactivity induced by amphetamine or nomifensine, as well as stereotypy induced by amphetamine (but not apomorphine), were also increased by Ro 40-7592. The drug stimulated exploratory activity in the open field test. It decreased the levels of HVA and 3-MT, increased the level of DOPAC but did not change the levels of dopamine in the striatum, nucleus accumbens and frontal cortex. These results indicate that Ro 40-7592 may improve the therapy with L-DOPA (plus decarboxylase inhibitor) of Parkinson's disease.

Antidepressant activities of WEB 1881, a new nootropic agent.

The central action, particularly potential antidepressant activity of WEB 1881, a new nootropic drug related to piracetam, was investigated in rats and mice. WEB 1881 antagonizes the reserpine- and apomorphine-induced hypothermia, potentiates the behavioral effect of DOPA and dihydroxyphenylserine, as well as the TRH-induced hyperthermia. Piracetam was only effective in the reserpine and DOPA tests. WEB 1881 is inactive in immobility test of Porsolt et al. It enhances the hind limb flexor reflex of the spinal rat, this effect being antagonized by prazosin and cyproheptadine. It exerts no effect on head twitches induced by L-5-hydroxytryptophan. The studied compound increases the noradrenaline and dopamine and turnover in the forebrain and brain stem. WEB 1881 given repeatedly potentiates the clonidine-induced aggressiveness and has no effect on the locomotor hyperactivity induced by D-amphetamine. The results indicate that in a number of tests WEB 1881 acts like other antidepressant drugs (but in others not), moreover, they suggest that this action is--at least partly--mediated by the central noradrenaline system.

The effect of repeated administration of imipramine, citalopram and mianserin on responsiveness of central serotonergic, alpha 2-adrenergic and cholinergic system in mice.

The effect of antidepressant drugs: imipramine, citalopram and mianserin given either in a single dose or twice a day for 14 days in a dose of 10 mg/kg was investigated in mice in tests for the responsiveness of central serotonergic (L-5 hydroxytryptophan-induced head twitches), alpha 2-adrenergic (donidine hypoactivity) and cholinergic (oxotremorine syndrome) systems. The effect of L-5 hydroxytryptophan was inhibited by repeated administration of citalopram and mianserin but unchanged by administration of imipramine. After a single administration only mianserin inhibited the L-5 hydroxytryptophan effect. Given repeatedly, the investigated antidepressant drugs did not affect the effect of clonidine; only mianserin potentiated the hypoactivity when given in a single dose. Repeatedly administered antidepressant drugs did not affect the action of oxotremorine, although imipramine (but not citalopram or mianserin) antagonized it after a single administration. The results indicate that under the present conditions repeatedly given mianserin and citalopram, but not imipramine, antagonize behavioral effects of L-5 hydroxytryptophan. No one of the investigated antidepressant drugs given repeatedly changed the responsiveness of alpha 2 -adrenergic and cholinergic systems to their agonists. It might be concluded that the changes in alpha 1-adrenergic and dopaminergic systems, observed previously after repeated administration of antidepressant drugs, are selective.

Antidepressants given repeatedly increase the behavioural effect of dopamine D-2 agonist.

The effects of single or repeated doses of antidepressant drugs (imipramine, amitriptyline, citalopram, mianserin) on rat locomotor hyperactivity induced by quinpirole, a dopamine D-2 receptor agonist, was investigated. Single doses of antidepressants do not change the effect of quinpirole, but enhance it when they are administered repeatedly. This enhancement is inhibited by (+/-)-sulpiride, a dopamine D-2 receptor antagonist. The results obtained indicate that the enhancement of dopaminergically-stimulated hyperactivity induced by repeated doses of antidepressants is mediated by dopamine D-2 receptors.

Pharmacological properties of EXP 561, a potential antidepressant drug.

The compound EXP 561 (1-amino-4-phenylbicyclo-[2,2,2]-octane), an inhibitor of the noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) uptake, a potential antidepressant agent, was studied in tests for evaluation of antidepressant drugs (AD). In most experiments (the apomorphine and reserpine hypothermia, the behavioural despair test, the blood pressure increases induced by NA and 5-HT) EXP 561 revealed similar activities as tricyclic AD. EXP 561 evoked stimulation of the hind limb flexor reflex in spinal rats, blocked by prazosin, metergoline and clomipramine. EXP 561 administered repeatedly in mice (twice daily for 14 days) did not evoke the adaptive changes induced by AD inhibiting the amine uptake, i.e. it did not enhance the amphetamine locomotor hyperactivity, did not potentiate the clonidine aggressiveness (at a lower dose, while at a higher one it acted less potently than when given acutely) or did not change the reserpine effect on the locomotor activity. EXP 561 showed a poor affinity to alpha 1-adrenoceptor (IC50 was 135,000 nM). The results indicate that the inability to induce adaptive changes is a feature which differentiates EXP 561 from tricyclic AD.

Some central effects of tiflucarbine, a new potential antidepressant drug.

Tiflucarbine (TVX P 4495), a new putative antidepressant drug (AD) with a chemical novel among AD's [9-ethyl-4-fluoro-1-methyl-7,8,9,10-tetrahydrothieno (3,2-e)-pyrido(4,3-b)indole lactate], a potent inhibitor of the 5-hydroxytryptamine (5-HT) uptake, was studied in rats and mice, mostly with regard to its possible effect on the noradrenaline (NA) uptake and 5-HT postsynaptic receptors. Tiflucarbine exerted no effect on the reserpine hypothermia, attenuated the apomorphine hypothermia and enhanced the TRH-induced hyperthermia. It did not prevent tryptamine convulsions or the fenfluramine-induced hyperthermia, and inhibited the L-5-hydroxytryptophan-induced head twitches (at a high dose only). It stimulated the hind limb flexor reflex preparation of the spinal rat in cyproheptadine-reversible manner. In the behavioral despair test it shortened the immobility time. Tiflucarbine administered repeatedly enhanced the D-amphetamine-induced locomotor hyperactivity and inhibited the clonidine-induced aggressiveness. The results indicate that tiflucarbine exhibits characteristics of a poor inhibitor of the NA uptake (irrespective of its strong inhibitory effect on the 5-HT uptake), and has no effect on 5-HT2 postsynaptic receptors. When used repeatedly, it enhances--like other AD--responsiveness of the central dopamine system.

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.

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.

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.

The effect of proadifen, a drug metabolism inhibitor, on action of imipramine and desipramine in mice.

Proadifen (SKF 524 A) inhibited the following effects of imipramine (IMI), without affecting those of desipramine (DMI) in mice: antagonism towards reserpine-induced hypothermia, ptosis and sedation, antagonism to apomorphine hypothermia and insignificant shortening of the immobility time in the behavioral despair test. Cerebral levels of DMI were very low after administration of IMI; pretreatment with proadifen did not affect the already low levels of DMI but significantly elevated these of IMI. This may indicate that some other than DMI metabolites (e.g., 2-hydroxy-derivatives) may be of importance for the action of IMI in mice in the tests employed in this study.

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.

The effect of the antihistaminic drugs on the central action of 5-hydroxytryptophan in mice.

Antihistaminic drugs of various chemical structure (chlorcyclizine, chloropyramine, chlorpheniramine, clemastine, diphenhydramine, mepyramine, promethazine, thenalidine) were tested on their action on the central serotonin system in mice. The test used was the antagonism to behavioral syndrome produced by D, L-5-hydroxytryptophan (5-HTP). Clemastine, promethazine and thenalidine inhibited 5-HTP-induced syndrome in doses of much lower than those inhibiting locomotor activity. Similar but weaker effect was produced by chlorcyclizine and diphenhydramine. It could be suggested that these compounds exert central antiserotonergic action. Chloropyramine and, more strongly, chlorpheniramine potentiated the action of 5-HTP; this may be due to the inhibition of serotonin uptake. Only mepyramine in these tests did not show any action on the central serotonin system.

Effects of antihistaminic drugs in tests for antidepressant action.

Antihistaminics of various chemical structures: chlorcyclizine, chloropyramine, chlorpheniramine, clemastine, diphenhydramine, mepyramine, promethazine, and thenalidine were investigated for the action in tests for antidepressant drugs. The antihistaminics did not affect significantly the spontaneous locomotor activity of rats. Most of them (chloropyramine, chlorpheniramine, diphenhydramine, promethazine and thenalidine) increased amphetamine hypermotility but chlorcyclizine significantly inhibited, and clemastine and mepyramine did not affect it. In mice, chlorcyclizine, mepyramine and promethazine inhibited amphetamine hypermotility, while others antihistaminics were without effect. L-DOPA-induced hypermotility in mice was inhibited by all compounds tested. With the exception of chlorpheniramine and mepyramine, all tested antihistaminics produced hypothermia in mice, although fife of them (chlorpheniramine, diphenhydramine, chlorcyclizine, chloropyramine and thenalidine) antagonized the reserpine-induced hypothermia. With the exception of mepyramine and clemastine, the compounds tested shortened the period of immobility of rats in the behavioral despair test. The results indicate that only few antihistaminics have pharmacological profile resembling tricyclic or atypical antidepressant drugs.