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The pharmacological profile of a new bicyclic substance, Lu 10-171 (1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitril), is described and compared with that of existing tricyclic thymoleptics. In mice and rats the compound exhibited marked 5-HT potentiating properties both in vivo and in vitro, being 5-10 times as active as chlorimipramine. The tests included 5-HT-, 5-HTP- and tryptophan-potentiation. In monoamine oxidase inhibitor treated dogs and rabbits the compound caused a marked hyperthermia. In rabbits this effect was completely blocked by pretreatment with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine. Hyperthermia induced by the central catecholamine displacing substance H 77/77 in rats was not affected by Lu 10-171, whereas the substance abolished the temperature rise induced by H 75/12. Reserpine- and tetrabenazine-induced ptosis and tetrabenazine-induced immobility in mice were antagonized by relatively low doses of existing tricyclic thymoleptics, whereas Lu 10-171 was very weak in this respect. Very weak in vitro anticholinergic and antihistaminergic properties were also registered for Lu 10-171. It is concluded that Lu 10-171 is a very potent and highly specific potentiator of 5-HT both in vivo and in vitro probably due to inhibition of 5-HT uptake. Thus this compound might be a useful agent in studying the role of 5-HT neurone systems in the control of mood. The substance does not possess the NA potentiating and anticholinergic and antihistaminergic properties characteristic of the tricyclic antidepressants.
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PMID:Pharmacology of a new phthalane (Lu 10-171), with specific 5-HT uptake inhibiting properties. 1 88

Some central effects of Ro 19-6327--a new MAO-B inhibitor--were studied in mice and rats. Given in low doses (1 or 3 mg/kg) Ro 19-6327 did not affect the locomotor activity of mice but its high dose (10 mg/kg) increased the activity. In rats Ro 19-6327 inhibited the locomotor activity but the effect was not dose dependent and not always significant. Ro 19-6327 did not change the locomotor activity in mice induced by L-DOPA (plus benserazide--an inhibitor of peripheral decarboxylase). The drug suppressed the reserpine-induced hypothermia and ptosis in mice and partly counteracted the apomorphine-induced hypothermia. It markedly enhanced (10 mg/kg) the amphetamine-induced stereotypy in rats. L-5-Hydroxytryptophan (L-5-HTP)-induced head twitch response was unchanged by Ro 19-6327. The drug given three times was inactive in forced swimming test. Repeated treatment with Ro 19-6327 (twice daily for 14 days) produced the enhancement of (+)-amphetamine- and nomifensine-induced hyperactivity in rats. Unlike a number of antidepressants, Ro 19-6327 did not potentiate the clonidine aggressiveness in mice, but--in contrast--inhibited it. The results suggest that Ro 19-6327 given repeatedly produces no changes in the responsiveness of the alpha-adrenergic system (in references to effects mediated by alpha 1-adrenoceptors). Adaptive changes in dopamine system are doubtful.
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PMID:Central effects of Ro 19-6327 given acutely and repeatedly. 166 12

Behavioural effects on dopaminergic transmission of a phenylindane derivative, Lu 19-005 [(+/-)-trans-3-(3,4-dichlorophenyl)-N-methyl-l-indanamine, HCI], with potent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake in rats and the effect on DA, NA and 5-HT activity in mice have been studied and compared with those of other known DA, NA and 5-HT uptake inhibitors with different selectivity ratios. Lu 19-005 induced stereotyped behaviour after parenteral and oral administration with a duration of action of more than 24 h. The stereotyped licking and biting induced by Lu 19-005 was antagonized by reserpine and cis(Z)-flupentixol, but not affected by prazosin, p-chlorophenylalanine and alpha-methyl-p-tyrosine pretreatments. Metergoline slightly facilitated the onset of stereotypy. Lower doses of Lu 19-005 induced ipsilateral circling in unilaterally 6-hydroxy-DA-lesioned rats. Finally, Lu 19-005 antagonized the catalepsy induced by perphenazine. In mice, Lu 19-005 potentiated the apomorphine-induced gnawing, reversed tetrabenazine-induced ptosis and potentiated the behavioural effects of 5-HTP within a similar dose range. The effects of Lu 19-005 were compared with those of other reference compounds. Nomifensine had qualitatively similar effects in rats although of much shorter duration. In mice, nomifensine selectively reversed tetrabenazine-induced ptosis. Weaker effects in all test models were found with bupropion, LR 5182 and GBR 13.069, compounds with inhibitory effect on DA and NA uptake. The DA-, NA- and 5-HT-uptake inhibitor diclofensine, however, had no effect in rats except in the 6-hydroxy-DA-circling test and had low potency in mice. The specific 5-HT- and NA-uptake inhibitors citalopram and talsupram, respectively, were ineffective in all rat models.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacology in vivo of the phenylindan derivative, Lu 19-005, a new potent inhibitor of dopamine, noradrenaline and 5-hydroxytryptamine uptake in rat brain. 240 54

The central action of 2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazole hydrochloride (pirlindole, PIR) in mice and rats was studied. PIR inhibited the 3H-5-hydroxytryptamine (5-HT) uptake in the rat cerebral cortex, not affecting the uptake of 3H-noradrenaline. PIR counteracted the reserpine ptosis but did not alter the apomorphine hypothermia. It enhanced the L-dopa effect on the locomotor activity and the L-5-hydroxytryptophan (L-5-HTP)-induced head twitch reaction in mice. PIR also facilitated the effect of L-dopa and L-5-HTP on the hind limb flexor reflex of the spinal rat. The clonidine sedation (but not hypothermia) was attenuated by PIR. PIR given repeatedly for 18 days increased the binding of 3H-prazosin in the brain cortex (decreasing the KD value), but did not affect the binding of 3H-dihydroalprenolol. The obtained results indicate that PIR inhibits the 5-HT uptake, displays characteristics of a monoamineoxidase inhibitor and, when given repeatedly, increases the binding to alpha 1-adrenoceptors in the cerebral cortex.
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PMID:Central action of the antidepressant drug pirlindole. 349 Aug 54

A potential antidepressant activity and an antiserotonin action of Org 8282, delta (13b, 4a), 4a-carba-mianserin, was studied in mice and rats. Org 8282 did not affect the reserpine-induced hypothermia, hypoactivity and ptosis, did not modify the apomorphine-induced hypothermia and the TRH-induced hyperthermia in mice, did not change the motor stimulation and stereotypy produced by amphetamine. It was inactive in the behavioral despair test in rats and mice. On the other hand, Org 8282 inhibited the head twitch reaction after 5-HTP in mice, the tryptamine-induced clonic convulsions of forepaws in rats, the hyperthermia produced by fenfluramine and m-CPP in rats kept at a high ambient temperature, and the quipazine-induced stimulation of the flexor reflex activity in the spinal rat. These results indicate that Org 8282 is inactive in tests commonly applied for assessment of antidepressant action but--like mianserin--it exerts an antiserotonin activity.
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PMID:The lack of antidepressant properties and a potent central antiserotonin activity of Org 8282. 377 30

Carbamazepine (CBZ) was studied in mice and rats with regard to its antidepressant activity. CBZ did not counteract hypothermia and ptosis induced by reserpine, hypothermia evoked by apomorphine, or sedation and hypothermia induced by clonidine. CBZ shortened the immobility time in the behavioral despair test in rats (but not in mice). It attenuated hyperactivity evoked by d-amphetamine, not affecting stereotypy induced by that drug. CBZ inhibited head twitches evoked by 5-HTP, as well as the hind limb flexor reflex of the spinal rat, having no effect on its stimulation by noradrenaline and 5-hydroxytryptamine agonists. CBZ administered repeatedly did not enhance clonidine aggressiveness or d-amphetamine locomotor hyperactivity, acting differently than many antidepressant drugs. The obtained results indicate that CBZ is not similar in its action to typical and many atypical antidepressants.
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PMID:The central action of carbamazepine as a potential antidepressant drug. 404 Oct 37

Maprotiline, a tetracyclic antidepressant drug, was evaluated for antidepressant and neuroleptic activity. In antidepressant tests, maprotiline antagonized reserpine-induced ptosis in rats but, unlike the tricyclic antidepressants, was found to antagonize methamphetamine stereotypy in rats, to decrease the intensity of L-dopa induced behavioural syndrome in pargyline-pretreated mice and to be ineffective in intensifying the 5-HTP induced behavioural syndrome. In neuroleptic tests, maprotiline was found to, antagonize apomorphine-induced cage climbing behaviour, induce catalepsy, inhibit the CAR and traction response, decrease the spontaneous motor activity and exploratory behaviour, and to potentiate the hypnotic effect of pentobarbitone. Our results indicate that maprotiline exhibits a profile of activity which resembles the neuroleptics and most probably exerts post-synaptic striatal DA receptor blocking activity.
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PMID:Experimental evaluation of the antidepressant and neuroleptic activity of maprotiline. 612 95

24 h pretreatment with molindone enhanced the behavioural effects of L-dopa and 5-HTP, precursors of biogenic amines (catecholamines and 5-HT respectively) preferentially deaminated by MAO-A, confirming that a metabolite of molindone inhibits MAO-A. 24 h pretreatment with molindone enhanced the behavioural effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats L-tryptophan induced behavioural effects, probably because of the MAO-A inhibitory activity exerted by a metabolite of molindone. Since 24 h pretreatment with molindone, unlike 30 min pretreatment with clomipramine, failed to antagonize fenfluramine and p-chloramphetamine-induced behavioural syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potentiation of 5-HTP-induced behavioural syndrome is due to a metabolite's MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behaviour in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behaviour, it appears that, at 24 h, the tissue levels of molindone are inadequate to block postsynaptic striatal and mesolimbic DA receptors and that, though a metabolite of molindone is biologically active so far as inhibition of MAO-A is concerned, the metabolites are devoid of neuroleptic activity. Further, since 2 h pretreatment with molindone failed to enhance the behavioural effects of L-dopa, it suggests that at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is not sufficient to counteract the neuroleptic activity of the parent compound.
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PMID:Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic. 614 85

Dexamisole antagonized the reserpine-induced hypothermia but was ineffective in the apomorphine-induced hypothermia in mice. It reduced ptosis produced by reserpine in mice but this effect was very weak. The effect of dexamisole on the amphetamine-induced hyperactivity depended upon the animal species. Dexamisole reduced the duration of immobility in the despair test in rats. It did not modify the 5-HTP-induced head twitch reaction in mice but produced stimulation of the hind limb flexor reflex in spinal rats. The latter effect was blocked by phenoxybenzamine but not by cyproheptadine and metergoline. Dexamisole also exerted a sedative and hypothermic effect. The above findings indicate that the pharmacological profile of dexamisole resembles in some respects that of tricyclic antidepressants; they also point out that this drug has a central noradrenergic activity.
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PMID:Psychopharmacological profile of dexamisole. 745 9

The aim of the present study was to investigate several neuropharmacological effects of the methanol extract of the aerial parts in blossom of Hypericum canariense, H. glandulosum, H. grandifolium and H. reflexum (Hypericaceae). These extracts did not alter significantly the locomotor activity, body temperature or the pentobarbital-induced sleeping time, with the exception of H. reflexum which significantly potentiated pentobarbital-induced sleeping time at both doses assayed (500 and 1000 mg/kg p.o.). Additionally, neither muscle relaxant nor anticholinergic activity was observed. These extracts antagonized the ptosis and/or motor depression induced by tetrabenazine and also shortened the immobility time in the forced swimming test. Moreover, the H. glandulosum and H. grandifolium extracts at 1000 mg/kg p.o. potentiated the head twitches induced by 5-HTP. These observations suggest that the methanol extract of the Hypericum species in doses of 500-1000 mg/kg p.o. possess antidepressant activity in mice, without inducing significant muscle relaxation, anticholinergic and sedative properties.
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PMID:Antidepressant effects of the methanol extract of several Hypericum species from the Canary Islands. 1174 5


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