The action of 1,2,3,5,6,11b-hexahydro-[1]benzothieno [3,2-g]indolizine hydrochloride (ADT 16) on peripheral and central responses mediated by 5-hydroxytryptaminergic and adrenergic systems of the rat.

Some acute pharmacological effects have been examined of racemic ADT 16 (1,2,3,5,6,11b-hexahydro[1]benzothieno[3,2-g]indolizine hydrochloride), on peripheral and central responses mediated by 5-HT and adrenergic systems in the rat. In-vitro, ADT 16 (10-1000 nM), similarly to mianserin, antagonized the inhibitory responses to B-HT 920 of the electrically-stimulated rat isolated prostatic vas deferens. High concentrations of ADT 16 (10 microM), also resembled those of mianserin by potentiating twitch responses to electrical stimulation of the tissue.

In-vivo pharmacological studies of 2-N-carboxamidinonormianserin, a histamine and 5-hydroxytryptamine antagonist lacking central effects.

The in-vivo pharmacological properties have been examined of FCC5 (2-N-carboxamidino-1,2,-3, 4, 10, 14b-hexahydrodibenzo (c.f.) pyrazino (1, 2-alpha)azepine hydrochloride), a guanidino analogue of mianserin.

Pharmacological evaluation of two novel analogues of mianserin: 2-N-carboxamidinonormianserin (FCC5) and 2-N-carboxamidonormianserin (FCC13).

1. The pharmacological properties have been examined of FCC5 (2-N-carboxamidinonormianserin) and FCC13 (2-N-carboxamidonormianserin), two novel analogues of mianserin. 2.

The effects of desipramine (DMI) and alpha-2 adrenoceptor agonists on flexor reflex activity (FRA) in the spinalized and decerebrate rat.

In the spinalized and decerebrate rat, electrically evoked flexor reflex activity (FRA) of the right anterior tibialis muscle was facilitated by DMI (0.1-3 mg/kg i.v.

A novel in vivo test for drugs affecting central serotonergic and adrenergic systems.

In urethane-anaesthetized rats, myoclonic twitches of the anterior digastricus muscle were evoked by L-5-hydroxy-tryptophan (L-5-HTP, 50-100 mg/kg iv.), the serotonin (5-HT) receptor agonist, quipazine (1-8 mg/kg i.v.

Central action of the antidepressant drug pirlindole.

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.

The lack of antidepressant properties and a potent central antiserotonin activity of Org 8282.

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.

Antagonistic effects of some metabolites and analogues of mianserin on serotonin and alpha 1- and alpha 2-adrenergic receptors in the flexor reflex model in vivo.

Mianserin, its two metabolites desmethylmianserin (Org OH-46) and 8-hydroxymianserin (Org GF-45), and its two analogues R(-)-6-aza-mianserin (Org 44-19) and S(+)-6-aza-mianserin (Org 44-20) were tested for their antagonistic action on the central serotonin (5-HT) receptor and alpha-adrenoceptors in the flexor reflex model in vivo in the spinal rat. The ability to reduce the increase in the flexor reflex activity induced by quipazine (a 5-HT receptor agonist), St 587 (an alpha 1-adrenoceptor agonist), or clonidine (an alpha 2-adrenoceptor agonist) was a measure of their potencies as antagonists of the respective receptors. All the compounds occurred to be potent antagonists of the central 5-HT receptor (S(+)-6-aza-mianserin was most active) and, to a lesser degree, of alpha-adrenoceptors with preferential antagonistic action on alpha 2-subtype.

Involvement of postsynaptic alpha 1- and alpha 2-adrenoceptors in the flexor reflex activity in the spinal rats.

Clonidine (0.2 mg/kg i.v.

Alaproclate: further pharmacological evidence for 5-HT uptake inhibition in vivo.

Alaproclate (2-/4-chlorophenyl/-1,1-dimethyl-2-amino-propanoate hydrochloride), a new selective 5-HT uptake inhibitor has been studied for its in vivo effects on the 5-HT transmission in rats in the following tests: 1) the flexor reflex in the spinal rat, 2) hyperthermia in rats at a high ambient temperature, 3) rat stomach fundus strip preparation. Alaproclate prevented potentiation of the flexor reflex in spinal rats induced by 5-HT releasers fenfluramine and p-chloroamphetamine (PCA) but did not affect the potentiation of the reflex due to direct 5-HT agonists LSD and quipazine. Also hyperthermic response of rats to fenfluramine was antagonized by alaproclate, whereas that due to quipazine was potentiated.

Chronic treatment with imipramine: further functional evidence for the enhanced noradrenergic transmission in flexor reflex activity.

The chronic administration of imipramine (IMI; 10 mg/kg orally, twice daily for 14 days) enhanced the flexor reflex of the hind limb in the spinal rat. This effect was maintained for at least 72 h after termination of drug administration. Phenoxybenzamine but not cyproheptadine abolished the enhanced activity of the flexor reflex.

The stimulatory action of phosphodiesterase inhibitors on the flexor reflex of the hind limb in the spinal rat.

We studied the action of the following phosphodiesterase inhibitors (PDEIs): rolipram (4-[3-cyclopentoxy-5-methoxyphenyl]-2-pyrrolidione), Ro 20-1724 (4-[3-butoxy-4-methoxybenzyl]-2-imidazolidione), 1-methyl-3-isobutylxanthine (IMBX) and theophylline on flexor reflex activity of the hind limb in the spinal rat. Potentiation of this reflex is thought to be due to enhancement of either 5-hydroxytryptaminergic or alpha-adrenergic transmission in the spinal cord. All the inhibitors potentiated flexor reflex activity in a dose-dependent manner in the following order of potency: rolipram greater than Ro 20-1724 greater than IBMX greater than theophylline.

The neuronal and extraneuronal uptake and deamination of 3H-(-)-phenylephrine in the perfused rat heart.

The neuronal and extraneuronal uptake and deamination of 3H-(-)-phenylephrine was studied in perfused rat hearts obtained from reserpine-pretreated animals. 1. Under the conditions of steady-state perfusion with 5 mumol/l 3H-(-)-phenylephrine slightly more than 50% of total deamination took place in adrenergic nerve endings, slightly less than 50% in the extraneuronal tissue.

A mathematical model representing the extraneuronal O-methylating system of the perfused rat heart.

1. A mathematical model was developed to mimic the function of the extraneuronal O-methylating system of the rat heart. Its essential features are: a saturable uptake process (uptake 2), a saturable, intracompartmental enzyme (COMT), the ability of the catecholamine to penetrate the membrane of the model compartment by a diffusional flux obeying first-order kinetics, and the ability of the metabolite to leave the compartment by an efflux obeying first-order kinetics.

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 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.

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 effect of haloperidol, spiperone and pimozide on the flexor reflex of the hind limb of the spinal rat.

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.

Doxepin as a blocker of central serotonin receptors.

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).

Effect of serotonin uptake blocking agents on the flexor reflex of hind limb of the spinal rat.

Imipramine, clomipramine, FG 4963 and quipazine potentiated the flexor reflex of hind limb of the spinal rat, imipramine and clomipramine being relatively weak, and quipazine the most potent in this respect. The potentiation is prevented by serotonin receptor blocking agents, cyproheptadine and danitracen. Imipramine and clomipramine prevented the potentiation of flexor reflex by fenfluramine; this indicates a presynaptic mechanism of action of the latter compound.

The influence of bromocriptine on serotonin neurons.

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.

On the anticataleptic action of cyproheptadine.

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.