Effects of the selective 5-hydroxytryptamine uptake inhibitors paroxetine and zimeldine on EEG sleep and waking stages in the rat.

The effects of oral paroxetine and zimeldine on EEG sleep-waking phases in the rat were investigated over a wide dose range. To ascertain that at the doses used for the EEG studies paroxetine and zimeldine selectively affect the serotoninergic system, their effects on brain 5-hydroxytryptamine (5-HT), dopamine and noradrenaline were determined. It was found that paroxetine and zimeldine at doses of 1-18 mg/kg dose-dependently prolonged waking and shortened slow-wave sleep and paradoxical sleep. In the same dose range cortical 5-HT turnover was significantly reduced, whereas the other aminergic systems were not influenced. These results suggest that 5-HT uptake inhibitors increase vigilance in rats at oral doses which selectively stimulate the serotoninergic system.

Binding of psychoactive drugs to rat brain amine receptors, measured ex vivo, and their effects on the metabolism of biogenic amines.

Ex vivo receptor binding experiments and measurements of the concentrations of the amine metabolites HVA, MOPEG-SO4 and 5-HIAA were carried out on rat brain tissues to analyse the effects of several neuroleptics (haloperidol, chlorpromazine, thioridazine, clozapine, fluperlapine), antidepressants (amitriptyline, mianserin, zimelidine) and other drugs (pizotifen, ketanserin, prazosin) on brain aminergic systems. It was found that in all cases where drugs reduced 3H-haloperidol binding to striatal D2-receptors ex vivo (haloperidol, chlorpromazine, thioridazine, clozapine, fluperlapine, pizotifen, zimelidine), the same drugs caused a pronounced increase, in vivo, in the striatal HVA-concentration, i.e. an increase in DA-turnover. The HVA-increase was directly proportional to the extent of the reduction of 3H-haloperidol binding. These findings suggested that in the 3H-haloperidol assay binding of drugs is to functional D2-receptors regulating the release of DA. In contrast, reduction of binding of 3H-prazosin to brain stem alpha 1-receptors ex vivo (all drugs except zimelidine) was only associated with an in vivo increase in the MOPEG-SO4 concentration in some cases (haloperidol, chlorpromazine, thioridazine, clozapine, fluperlapine, ketanserine). Similarly, reduction of 3H-spiperone binding to 5-HT2-receptors in the frontal cortex (all agents except prazosin and zimelidine) was only associated with an increase in the 5-HIAA concentration in certain cases (thioridazine, clozapine, fluperlapine, pizotifen, ketanserin). The present data indicate that in the brain alpha 1- and 5-HT2-receptors do not seem to be linked directly to the processes which govern the turnover of the neurotransmitters DA, NA or 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of fluperlapine on dopaminergic systems in rat brain.

Fluperlapine has been reported to possess antischizophrenic and antidepressant properties, with low incidence of extrapyramidal side-effects. In order to get more information about the interactions of fluperlapine with rat brain dopaminergic systems, its binding to striatal D2 receptors, measured ex vivo, and its effects on DA metabolism in different brain areas were investigated. Clozapine and haloperidol served as reference compounds in these investigations. It was found that all three agents blocked D2 receptors and increased DA metabolism. Clozapine and fluperlapine differed from haloperidol in that their potency was much lower. Although occupation of striatal D2 receptors by the two dibenzo-epines developed rapidly, the duration was considerably shorter than that of haloperidol. There was no indication that the two dibenzo-epines had a stronger or longer-lasting effect on limbic or cortical DA metabolism compared to that on the striatum. Both drugs caused a weak increase in striatal DA, whereas haloperidol decreased it. It was concluded that the low incidence of extrapyramidal side-effects of fluperlapine, and also of clozapine, is probably due to their weak and relatively brief action on brain DA systems and not due to a selective action on A10 neurotransmission. The anticholinergic properties of the dibenzo-epines might even further reduce the consequences of their already weak effects on DA systems.

Measurement of cholecystokinin octapeptide-induced motility of rat antrum, pylorus, and duodenum in vitro.

Motor effects of cholecystokinin octapeptide (CCK-OP) on rat antrum, pylorus, and duodenum have been studied in vitro under standard conditions. Intraluminal pressure changes were simultaneously measured at the three locations using a perfusion manometric system with a novel intraluminal pressure-sensor device. This device comprised an acrylic cast of the rat gastroduodenal tract containing the perfusion catheters that reached the surface of the cast with their outlets in the antrum, pylorus, and duodenum. A selective and sensitive intraluminal local pressure measurement was achieved with this pressure sensor due to its shape. CCK-OP increased base-line pressure in the antrum, pylorus, and duodenum; frequencies of phasic contractions in the antrum and pylorus; and amplitudes in the duodenum. The peptide also decreased contraction amplitudes in the antrum and pylorus and frequency of phasic contractions in the duodenum. It is concluded that the novel intraluminal pressure sensor is a useful tool for measuring local pressure changes in the gastroduodenal tract of the rat. In this experimental model, effects of CCK-OP on antral, pyloric, and duodenal base-line pressure are comparable with those observed in isolated muscle strips and in the intact organ of humans, dogs, and opossums. A different behavior, however, was observed in the force of antral and frequency of duodenal phasic contractions.

Mechanism of action of cholecystokinin octapeptide on rat antrum, pylorus, and duodenum.

The mechanism of action of cholecystokinin octapeptide (CCK-OP) on tonic and phasic contraction of antral, pyloric, and duodenal smooth muscles was studied with a novel perfusion manometric system in isolated esophagogastroduodenal preparations of the rat. CCK-OP increased baseline pressure at each site, frequencies of phasic contractions in the antrum and pylorus, and amplitudes in the duodenum. It decreased antral and pyloric amplitudes and frequency of duodenal phasic contractions. CCK-OP action on tonic contraction was tetradotoxin (TTX) susceptible and its action on phasic contractions was TTX resistant. Phentolamine, phenoxybenzamine, propranolol, catecholamine depletion of preparations by reserpine-tetrabenazine, and the block of catecholamine synthesis at different levels significantly inhibited CCK-OP-induced tonic contraction, whereas atropine had no influence. Adrenergic and cholinergic neural actions on phasic contractions altered the level of amplitudes and frequencies on which CCK-OP action occurred. It is concluded that CCK-OP action on tonic contraction of the rat gastroduodenal junction is mediated by a neural noncholinergic pathway, whereas its effect on muscles responsible for phasic contractions is a direct one.

Receptor dynamics: effect of repeated administration of desmethylimipramine on the noradrenergic systems in rat brain.

The effects of a single and of repeated administration of desmethylimipramine (DMI) on the densities of various receptors and on the metabolism of noradrenaline (NA) were determined in rat brain. Inhibition of the uptake of NA into cortex slices, measured in vitro, was not diminished after repeated administration of DMI. The turnover of NA was inhibited only after the single administration of the drug. After repeated administration the turnover of NA was again within the normal range, but now the density of beta-receptors was significantly reduced. Repeated administration of DMI had no significant effect on the densities of alpha-adrenergic, dopaminergic, cholinergic, histaminergic, opiate and serotoninergic receptors. These results indicate that the continued blockade of NA-reuptake caused a selective desensitization of beta-receptor-regulated systems in the brain.

The pharmacology of 5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiadiazole (DS 103-282), a novel myotonolytic agent.

5-Chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiadiazole (DS 103-282) is a centrally acting agent with a novel chemical structure and a pharmacological profile different from that of myotonolytic drugs in current use such as diazepam, baclofen and dantrolene. It inhibits alpha- and gamma-rigidity in rats, reflex muscle tone in rabbits and the linguomandibular reflex in cats at low doses, but has little or no effect on gross spinal reflexes or electrically-induced segmental reflexes in cats. The mechanism underlying the muscle relaxation is unknown. Effects on convulsions induced by impaired GABA-transmission and by strychnine suggest a possible influence on glycine-mediated neurotransmission. In muscle-relaxing doses, DS 103-282 is without appreciable sedative, haemodynamic or neurochemical effects. Clinical investigations have confirmed the pharmacological predictions with regard to both the myotonolytic activity and the low propensity to produce side-effects.

Two novel prolactin release-inhibiting 8 alpha-amino-ergolines.

Prolactin secretion inhibition and changes in striatal dopamine metabolism in rats were compared after the administration of 8 alpha-amino-ergoline CH 29-717 and 2 derivates. CQ 32-084 was similar to but less potent than CH 29-717, while 32-085, the l-methyl derivative, showed delayed dopaminomimetic effects.

Neurochemical and neuropharmacological investigations with four ergot derivatives: bromocriptine, dihydroergotoxine, CF 25-397 and CM 29-712.

Neurochemical and neuropharmacological investigations with four ergot derivatives reveal differential pharmacodynamic effects of these compounds. Bromocriptine and CM 29-712 showed actions typical of postsynaptic dopamine receptor stimulants, in particular in the extrapyramidal system. CM 29-712 proved to be more potent than bromocriptine, with an early onset of action. CF 25-397 and dihydroergotoxine, while not showing all actions typical of central dopamine agonists, appeared to exert some of their effects by means of a stimulation of central serotoninergic sites. In the rat sleep-wakefulness cycles and in reserpine-induced ponto-geniculooccipital waves in the cat, they mimicked the effects of 5-hydroxytryptophan. In the latter test, CF 25-397 proved to be particularly potent. In addition, bromocriptine, dihydroergotoxine and CM 29-712 showed neurochemical effects consistent with central alpha-adrenergic blockade or an enhanced impulse flow in central noradrenergic neurons.

Animal models for tardive dyskinesia: effects of thioridazine.

After repeated administration of classical neuroloptics to the rat, supersensitivity of striatal dopamine (DA) receptors towards DA-receptor agonists can be demonstrated. This effect can be quantified (a) by measuring the turning response to apomorphine in rats with unilateral striatal lesions or (b) by measuring the changes induced by neuroleptics in the DA metabolism in the striatum of intact rats. In these test systems, thioridazine induces an increase in DA-receptor sensitivity which is significantly less intense and of shorter duration than that induced by haloperidol. The tendency of a drug to increase DA-receptor sensitivity has been related to its propensity to induce tardive dyskinesia in man, and on this basis it may be expected that tardive dyskinesias following treatment with thioridazine will be rare and less intense than those seen after classical neuroleptics.

Effects of clozapine and other dibenzo-epines on central dopaminergic and cholinergic systems. Structure-activity relationships.

Structure-activity relationships of 16 dibenzoepines, including clozapine, loxapine, clothiapine and perlapine, have been investigated with regard to locomotor inhibition, cataleptogenesis, apomorphine antagonism, arousal inhibition, effect on striatal dopamine metabolism, and in vivo and in vitro anticholinergic potency. Thioridazine and the classical neuroleptics haloperidol and chlorpromazine were included in the study for comparison. The classical tests used to detect neuroleptic activity in laboratory animals were found to be poor predictors of possible clinical effectiveness of the dibenzo-epines.

Anticholinergic properties of antipsychotic drugs and their relation to extrapyramidal side-effects.

The effects of haloperidol, alone and in combination with atropine, were compared with the effects of clozapine, alone and in combination with physostigmine, in a variety of tests commonly used to characterize neuroleptic compounds. It was found that clozapine in combination with physostigmine did not present the profile of activity of a classical neuroleptic agent; neither did haloperidol in combination with atropine present that of clozapine. In fact, some effects of haloperidol (catalepsy) were antagonized by atropine, while others (induction of striatal DA-receptor hypersensitivity) were enhanced. It is concluded that the interaction between dopaminergic and cholinergic systems in the striatum is highly complex, and that a neuroleptic possessing both potent DA-receptor blocking and muscarinic anticholinergic activity, while being less likely to cause parkinsonism in patients, would be more likely to induce tardive dyskinesias.