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Biomedical subjects

J Maj

Publications and source records attributed to J Maj.

At least 19 recordsLinked to original sources
PubMed2004

The cleavage of vitamin E galactoside in the rat tissue homogenates.

The stability of alpha-tocopheryl beta-galactoside in the presence of endogenous galactosidases in selected tissue homogenates (liver, kidney, ileum and brain) was estimated. High degree release of alpha-tocopherol from alpha-tocopheryl beta-galactoside in tissues of ileum, kidney and brain was observed (82%, 75% and 72%, increase above endogenous alpha-tocopherol, respectively). A possible enzymatic mechanism of the galactoside decomposition was proposed.

Animals↗
PubMed2002

Effect of repeated treatment with tianeptine and fluoxetine on central dopamine D(2) /D(3) receptors.

Tianeptine (TIA) is an antidepressant drug that has been shown to decrease extracellular serotonin level and reveals no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated TIA treatment induced any adaptive changes in the central dopamine D(2)/D(3) system (behavioural and biochemical) similar to those reported earlier for tricyclic antidepressants. Experiments were carried out on male Wistar rats. TIA was administered at a dose of 5 and 10 mg/kg once or repeatedly (twice daily for 14 days). Fluoxetine (FLU), used as a reference compound, was also administered at a dose of 10 mg/kg. The results obtained showed that TIA or FLU administered repeatedly increased the hyperlocomotion induced by D-amphetamine and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT). Biochemical study revealed a decrease in the [(3)H]7-OH-DPAT binding sites after acute and repeated treatment with TIA or FLU in the islands of Calleja minor, as well as in the shell part of nucleus accumbens septi. On the other hand, both TIA and FLU administered repeatedly increased the binding of [(3)H]quinpirole (a D(2)/D(3) receptor agonist) in the nucleus caudatus as well as in the core part of the nucleus accumbens septi. Similar effects have been observed when dopamine D(2)/D(3) receptors were visualized with the use of [3H]raclopride, a dopamine D(2)/D(3) receptor antagonist. However, TIA and FLU induced a decrease in the level of mRNA encoding for dopamine D(2) receptors, not only after repeated but also after acute treatment. These results indicate that repeated TIA and FLU administration induces adaptive changes in the dopaminergic D(2)/D(3) system and especially enhances the functional responsiveness of dopamine D(2) and D(3) receptors. However, the question of whether this increased responsiveness is important for clinical antidepressant efficacy remains open.

Animals↗
PubMed2002

Effect of repeated treatment with mirtazapine on the central alpha1-adrenergic receptors.

Mirtazapine (MIR) is an antidepressant which enhances noradrenergic and serotonergic 5-HT1A neurotransmission via antagomism of central alpha2-adrenergic autoreceptors and heteroreceptors. The drugs does not inhibit noradrenaline and serotonin reuptake but blocks the 5-HT, and 5-HT3 receptors and has high affinity only for central and peripheral histamine H1 receptors. The present study was aimed at determining whether repeated MIR treatment induced adaptive changes in the alpha1-adrenergic receptors, similar to those reported by us early for tricyclic antidepressants, The experiments were carried out on male mice and rats. MIR was administered at a dose of 10 mg/kg once or repeatedly (twice daily for 14 days). The obtained results showed that MIR administrated repeatedly potentiated the methoxamine- induced exploratory hyperactivity in rats and clonidine-induced aggressiveness in mice, those effects being mediated by alpha1-adrenergic receptors. MIR given repeatedly (but not acutely) increased the binding (Bmax ) of [3H]prazosin to alpha1-adrenergic receptors in cerebral cortex, however, the ability of the alpha1-adrenoceptor agonist phenylephrine to compete for the these sites was not significantly changed. The above results indicate that repeated MIR administration increases the responsiveness of alpha1-adrenergic system (behavioural and biochemical changes), as tricyclics do. However, the question whether the increased functional responsiveness found in the present study is important for the clinical antidepressant efficacy, remains open.

Adrenergic alpha-Agonists↗
PubMed2001

Effect of repeated treatment with tianeptine and fluoxetine on the central alpha(1)-adrenergic system.

Tianeptine (TIA) is an antidepressant drug which enhances the reuptake of serotonin but, in contrast to tricyclics, shows no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated TIA treatment induced adaptive changes in the alpha(1)-adrenergic system, similar to those reported by us earlier for tricyclic antidepressants. The experiments were carried out on male mice and rats. TIA was administered at a dose of 5 or 10mg/kg once or repeatedly (twice daily for 14 days) and fluoxetine (FLU), used as a reference compound, at a dose of 10mg/kg. The obtained results showed that TIA administered repeatedly potentiated the methoxamine- and phenylephrine (PHEN)-induced exploratory hyperactivity in rats and clonidine-induced aggressiveness in mice, the effects mediated by alpha(1)-adrenoceptors. TIA given repeatedly (but not acutely) increased the binding (B(max)) of alpha(1)-adrenergic receptors in cerebral cortex for [(3)H]prazosin. However, the ability of the alpha(1)-adrenoceptor agonist PHEN to compete for these sites was not significantly changed. The above results indicate that repeated TIA administration increases the responsiveness of the alpha(1)-adrenergic system (behavioural and biochemical changes). On the other hand, FLU did not affect any behavioural and biochemical changes in this system.

Adrenergic alpha-Agonists↗
PubMed2000

The effect of repeated treatment with pramipexole on the central dopamine D3 system.

The study examined the effect of pramipexole (2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzthiazole dihydrochloride; PRA), a new potent dopamine receptor agonist with the high preference for D3 receptors, as compared to D2 or D4, on the central dopamine D3 system. Experiments were conducted on male Wistar rats. PRA was injected subcutaneously. PRA given repeatedly (14 days, twice a day, in doses of 0.3 and 1 mg/kg), but not acutely, potentiated the locomotor hyperactivity induced by (+/-)-7-OH-DPAT (3mg/kg s.c.), when given 24h after the single or the last dose of PRA. Administration of PRA, 1 mg/kg, for 3 or 7 days produced an effect similar to that described above, whereas a dose of 0.3 mg/kg produced such an effect only after 7, but not 3, days. Repeated treatment with PRA (0.3 and 1 mg/kg, 14 days, twice daily) also enhanced the D3 receptor binding in the islands of Calleja and nucleus accumbens (shell)--the brain region known to be rich in D3 receptors--when [3H]7-OH-DPAT was used as a ligand. Repeated PRA administration did not change the concentration of mRNA coding for D3 receptors in the islands of Calleja. The obtained results indicate that-- like the previously studied typical antidepressants given repeatedly--PRA increases the functional responsiveness and the binding to the brain dopamine D3 receptors. Hence PRA may be considered as a potential antidepressant drug.

Animals↗
PubMed2000

Pharmacological effects of milnacipran, a new antidepressant, given repeatedly on the alpha1-adrenergic and serotonergic 5-HT2A systems.

Milanacipran (MIL) is a representative of a new class of antidepressants (SNRIs) which inhibit selectively the reuptake of serotonin and noradrenaline but, in contrast to tricyclics, show no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated MIL treatment induced adaptive changes in the alpha1-adrenergic and serotonergic 5-HT2A systems, similar to those reported by us earlier for tricyclic antidepressants. The experiments were carried out on male mice and rats. MIL was administered at a dose of 10 or 30 mg/kg p.o. once or repeatedly (twice daily for 14 days). The obtained results showed that MIL administered repeatedly potentiated the clonidine-induced aggressiveness and the methoxamine-induced exploratory hyperactivity, the effects mediated by alpha1-adrenoceptors. MIL did not change the number or affinity (Bmax and K(D)) of alpha1-adrenergic receptors in the cerebral cortex for [3H]prazonsin, however, the ability of the alpha1-adrenoceptor agonist phenylephrine to compete for these sites was significantly enhanced. MIL given repeatedly (but not acutely) inhibited both the head twitch reaction induced by L-5-HTP or (+/-)DOI, the effects mediated by serotonergic 5-HT2A receptors. MIL also decreased the binding (Bmax) or [3H]-ketanserin to 5-HT2A receptors in the cerebral cortex. The above results indicate that repeated MIL administration increases the responsiveness of alpha1-adrenergic system (behavioural and biochemical changes) and decreases the responsiveness of the serotonergic 5-HT2A receptors (especially behavioural changes) as tricyclics do. It may be concluded that the lack of MIL affinity for neurotransmitter receptors is of no importance to the development of adaptive changes in the studied systems, observed after repeated treatment with antidepressants.

5-Hydroxytryptophan↗
PubMed2000

The role of dopamine D2 receptor in the behavioral effects of imipramine--study with the use of antisense oligonucleotides.

Antisense strategies have a potential to specifically block the production of a given protein, e.g. receptor subtype, thus may help to uncover its behavioral and/or biochemical function. In the present study we demonstrated the utility of this approach for studying the role of dopamine D2 receptors in the anti-immobility effect of imipramine in the forced swimming test. Following intracerebroventricular (i.c.v.) administration of phosphorothioate oligonucleotide complementary to mRNA encoding for dopamine D2 receptors (D2 antisense ODN; 1 nmol/1 microl H2O, twice a day for 5 days) to the rats, the decrease in the locomotor activity (shortened total distance travelled and decrease in vertical activity, without differences in the stereotypic movements of animals), as well as the decrease of specific binding of [3H]raclopride in the striatum and limbic forebrain were observed. At the same time, i.c.v. administration of D2 antisense ODN reversed the effect of imipramine in the forced swimming test, what may indicate that the dopamine D2 receptors play a significant role in the behavioral anti-immobility effects of imipramine.

Animals↗
PubMed1999

Pharmacological effects of venlafaxine, a new antidepressant, given repeatedly, on the alpha 1-adrenergic, dopamine and serotonin systems.

Venlafaxine (VEN) is a representative of a new class of antidepressants (SNRIs) which inhibit selectively the uptake of serotonin and noradrenaline, but--in contrast to tricyclics--show no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated VEN (given twice daily for 14 days) induced adaptive changes in the alpha 1-adrenergic, dopamine and serotonin systems, similar to those reported by us earlier for tricyclic antidepressants. The results indicate that VEN potentiates the clonidine-induced aggressiveness and the methoxamine-induced exploratory hyperactivity, both these effects being mediated by alpha 1-adrenoceptors. VEN increased the hyperlocomotion induced by D-amphetamine and (+/-)-7-OH-DPAT. Neither the apomorphine and quinpirole hyperlocomotion, nor the apomorphine and D-amphetamine stereotypies were changed. VEN did not affect the behavioural syndrome induced by 8-OH-DPAT (a 5-HT1A effect), and decreased both the head twitch reaction induced by L-5-HTP or (+/-)DOI and the hyperthermia induced by trifluoromethylphenylpiperazine, all those effects being mediated by 5-HT2 receptors. Repeated VEN did not change the hypothermia evoked by oxotremorine (a central cholinergic agonist). The above results indicate that repeated VEN increases--as do tricyclics--the responsiveness of alpha 1-adrenergic and dopaminergic (mainly D3) systems and decreases the responsiveness of the 5-HT2 system. It may be concluded that the lack of affinity for neurotransmitter receptors is of no importance to the development of adaptive changes in the studied systems, observed after repeated treatment.

5-Hydroxytryptophan↗
PubMed1999

The anticataleptic effect of 7-OH-DPAT: are dopamine D3 receptors involved?

The paper examined the effect of 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin), a dopamine D3 receptors-prefering agonist, on the catalepsy evoked by reserpine, haloperidol and fluphenazine in rats (male Wistar), as well as the influence of nafadotride, a dopamine D3 receptors-prefering antagonist, on that effect. The obtained results show that 7-OH-DPAT, as well as L-DOPA, a drug of choice in the therapy of Parkinson's disease, used for comparison, antagonize the catalepsy induced by reserpine, haloperidol and fluphenazine. Nafadotride, used in a dose (0.2 mg/kg) which inhibits the 7-OH-DPAT-evoked locomotor hyperactivity but does not affect the hypermotility induced by amphetamine and quinpirole, antagonizes the anticataleptic effect of 7-OH-DPAT or L-DOPA. It is therefore assumed that dopamine D3 receptors are involved in the anticataleptic effect of both 7-OH-DPAT and L-DOPA.

Animals↗
PubMed1998

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.

Administration, Oral↗
PubMed1998

Repeated trimipramine induces dopamine D2/D3 and alpha1-adrenergic up-regulation.

Trimipramine (TRI), which shows a clinical antidepressant activity, is chemically related to imipramine but does not inhibit the reuptake of noradrenaline and 5-hydroxytryptamine, nor does it induce beta-adrenergic down-regulation. The mechanism of its antidepressant activity is still unknown. The aim of the present study was to find out whether TRI given repeatedly was able to induce adaptive changes in the dopaminergic and alpha1-adrenergic systems, demonstrated by us previously for various antidepressants. TRI was given to male Wistar rats and male Albino Swiss mice perorally twice daily for 14 days. In the acute experiment TRI (given i.p.) does not antagonize the reserpine hypothermia in mice and does not potentiate the 5-hydroxytryptophan head twitches in rats. TRI given repeatedly to rats increases the locomotor hyperactivity induced by d-amphetamine, quinpirole and (+)-7-hydroxy-dipropyloaminotetralin (dopamine D2 and D3 effects). The stereotypies induced by d-amphetamine or apomorphine are not potentiated by TRI. It increases the behaviour stimulation evoked by phenylephrine (given intraventricularly) in rats, evaluated in the open field test as well as the aggressiveness evoked by clonidine in mice, both these effects being mediated by an alpha1-adrenergic receptor. It may be concluded that, like other tricyclic antidepressants studied previously, TRI given repeatedly increases the responsiveness of brain dopamine D2 and D3 (locomotor activity but not stereotypy) as well as alpha1-adrenergic receptors to their agonists. A question arises whether the reuptake inhibition is of any importance to the adaptive changes induced by repeated antidepressants, suggested to be responsible for the antidepressant activity.

5-Hydroxytryptophan↗
PubMed1997

The behavioural effects of pramipexole, a novel dopamine receptor agonist.

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydroc hlo ride) is a novel dopamine D2 family receptor agonist with a predominant action on D2 autoreceptors and with some D3 vs. D2 receptor preference. The central behavioural effects of pramipexole given subcutaneously to rats (male Wistar) and mice (Albino Swiss) are presented in this paper. Used in low doses (0.001-0.1 mg/kg), pramipexole induced locomotor hypoactivity which was antagonized by a low dose of spiperone; at higher doses (0.3, 1 mg/kg) it evoked hyperactivity which was inhibited by haloperidol, sulpiride and clozapine, but not by SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine hydrochloride). Pramipexole (0.1-1.0 mg/kg) antagonized the akinesia induced by combined pretreatment with reserpine (5 mg/kg) and alpha-methyl-p-tyrosine (250 mg/kg). Pramipexole (0.1-1 mg/kg) potentiated the hyperkinetic effect of L-DOPA (L-3,4-dihydroxyphenylalanine) (50 and 200 mg/kg, together with benserazide, 50 mg/kg) in naive and monoamine-depleted (reserpine + alpha-methyl-p-tyrosine) rats. The higher doses of pramipexole (1 and 3 mg/kg) evoked stereotypy which was antagonized by pretreatment with sulpiride or clozapine. The catalepsy induced by haloperidol, spiperone or fluphenazine was antagonized by pramipexole (1-3 mg/kg). Pramipexole (1 mg/kg) induced hypothermia in mice, which was antagonized by sulpiride. The obtained results indicate that pramipexole: (i) at low doses stimulates the dopamine D2 presynaptic autoreceptors; (ii) at higher doses stimulates dopamine D2 postsynaptic receptors. An effect on the dopamine D3 receptor cannot be excluded. At low doses pramipexole may have antipsychotic activity, and at higher ones antiparkinsonian activity.

Animals↗
PubMed1997

Repeated administration of antidepressant drugs affects the levels of mRNA coding for D1 and D2 dopamine receptors in the rat brain.

The present study examined the effects of acute and repeated administration of three antidepressant drugs (imipramine, citalopram and (+)-oxaprotiline) on the levels of mRNA coding for dopamine D1 and D2 receptors in the rat brain. Quantitive in situ hybridization with 35S-labelled oligonucleotide probes has been utilised. The level of mRNA coding for dopamine D1 receptor (D1 mRNA) is decreased following repeated administration of imipramine, both in the nucleus accumbens and in the striatum. On the other hand, the repeated administration of citalopram, the selective inhibitor of serotonin reuptake, resulted in an increase in the level of D1 mRNA in the striatum and in the core region of nucleus accumbens. A similar tendency, i.e.: an increase in the level of D1 mRNA was observed after repeated administration of (+)-oxaprotiline, a selective inhibitor of noradrenaline reuptake. The level of mRNA coding for dopamine D2 receptors (D2 mRNA) was increased in all the brain regions studied, both after administration of imipramine and citalopram. (+)-Oxaprotiline did not produce any statistically significant changes in the level of D2 mRNA. The results obtained in this study indicate that the levels of mRNA coding for dopamine D1 and D2 receptors are regulated by the antidepressant drugs. The changes concerning the dopamine D2 receptors are more consistent and fit in with the previously described binding and behavioral effects and seem to be important for the mechanism of action of antidepressant drugs.

Adrenergic Uptake Inhibitors↗
PubMed1997

Antidepressant effects of pramipexole, a novel dopamine receptor agonist.

Pramipexole (2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochl oride), 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 hyperactivity 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 1 h 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.

Animals↗
PubMed1997

Repeated treatment with antidepressant drugs induces subsensitivity to the excitatory effect of 5-HT4 receptor activation in the rat hippocampus.

The effect of repeated treatment with various antidepressant drugs on the reactivity of CA1 neurons to the 5-HT4 receptor agonist zacopride was examined. Zacopride decreased the calcium-activated afterhyperpolarization and adaptation, it also elicited a slow membrane depolarization associated with an increase in input resistance. All those effects may have contributed to the zacopride-induced increase in the amplitude of population spikes, evoked in the CA1 cell layer by stimulation of the Schaffer collateral/commissural pathway. The later effect of zacopride was concentration-dependent and was antagonized by the 5-HT4 receptor antagonist DAU 62805. Repeated (14 days, twice daily), but not single, administration of the antidepressant drugs imipramine, citalopram, fluvoxamine and paroxetine (10 mg/kg) attenuated the effect of zacopride on population spikes. Because inhibitory 5-HT1A and excitatory 5-HT4 receptors are colocalized on pyramidal neurons, and our previous data demonstrated an increase in the 5-HT1A receptor-mediated inhibition after repeated treatment with antidepressants, we conclude that treatment with antidepressant drugs may enhance the inhibitory effect of 5-HT directly, by increasing the 5-HT1A receptor responsiveness, and indirectly, by inducing subsensitivity to the 5-HT4 receptor activation.

Animals↗
PubMed1997

Roxindole, a dopamine autoreceptor agonist with a potential antidepressant activity. II. Effects on the 5-hydroxytryptamine system.

Roxindole (ROX) (EMD 49980, 5-hydroxy-3-[4-(4-phenyl-1, 2,3,6-tetrahydropyridyl(1))-butyl(1)]-indole, mesylate), a potent selective agonist of presynaptic dopamine receptors with clinical antipsychotic and antidepressant activity, was studied pharmacologically in rats (male Wistar) and mice (male Albino Swiss) with respect to its influence on the central 5-hydroxytryptamine (5-HT) system. ROX did not induce the 5-HT1A syndrome (flat body and forepaw treading) in rats, but partly antagonized the syndrome evoked by 8-OH-DPAT. The 8-OH-DPAT-induced hypothermia in mice (a 5-HT1A effect) was not inhibited by ROX. The drug evoked hypothermia, which was antagonized by pindolol, but not by (+)-WAY-100135. ROX did not inhibit the m-chlorophenylpiperazine-induced hypothermia in mice (a 5-HT1B effect), or the exploratory hypoactivity in rats (a 5-HT1C effect). Head twitches induced by a low dose of L-5-HTP were potentiated by ROX, whereas those induced by its higher dose were antagonized. ROX also antagonized the hyperthermia induced by fenfluramine or trifluoromethylphenylpiperazine at a high ambient temperature in rats (a 5-HT2A effect). The results obtained indicate that ROX inhibits 5-HT uptake and shows 5-HT2A antagonistic and probably a 5-HT1B agonistic activities.

5-Hydroxytryptophan↗
PubMed1996

Neuropharmacological profile of EMD 57445, a sigma receptor ligand with potential antipsychotic activity.

EMD 57445 ((S)-(-)-[4-hydroxy-4-(3,4-benzodioxol-5-yl) -piperidin-1-ylmethyl]-3-(4-methoxyphenyl)-oxazolidin- 2-one) is a new sigma receptor ligand with only marginal affinity for many other (including dopamine) receptors. In the present study, central, particularly neuroleptic-like, effects of this compound were evaluated and compared with those of another sigma receptor ligand, rimcazole. EMD 57445 decreased locomotor activity in rats and mice. The amphetamine-induced locomotor hyperactivity and stereotypy were reduced by EMD 57445. The drug was able to inhibit the behavioural effects induced by apomorphine, i.e., the locomotor hyperactivity, stereotypy and aggression in rats, as well as climbing in mice. The hyperlocomotion induced by quinpirole (a dopamine D2/3 receptor agonist) and the grooming induced by SKF 38393 (a dopamine D1 receptor agonist) were decreased by EMD 57445. The behavioural stimulation evoked in rats by non-competitive (MK-801, (+)-5-methyl-10,11-dihydroxy-5H-dibenzo (a,b)-cyclohepten-5,10-imine hydrogen maleate) or competitive (CGP 37849, D,L-E-amino-4-methyl-5-phosphono-3-pentenoic acid) NMDA receptor antagonists was also inhibited. EMD 57445 decreased the cocaine-, morphine- or caffeine-induced locomotor hyperactivity in rats or mice. It neither induced catalepsy nor increased muscle tone in rats. Rimcazole had somewhat different effects: it increased the amphetamine stereotypy as well as the amphetamine-, quinpirole- and cocaine-induced locomotor hyperactivity in rats. The results indicate that EMD 57445 shows functional antidopaminergic activity and may be useful as an antipsychotic drug devoid of extrapyramidal side-effects.

Animals↗