Biomedical subjects
Publications and source records attributed to H R Bürki.
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.
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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.
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.
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.
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.
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Tardive dyskinesias, often seen in patients treated with classical neuroleptics, have been attributed to the development of receptor hypersensitivity following prolonged blockade of dopamine (DA)-receptors. In rats with unilateral striatal lesions, development of DA-receptor hypersensitivity following a 6-day treatment with haloperidol can be demonstrated by means of the increased turning response to apomorphine. Addition of atropine to the haloperidol treatment schedule resulted in a further increase in receptor sensitivity, but with a delay of 24 h in its appearance. This finding provides pharmacological support for the observation that tardive dyskinesias are more frequent and more severe in patients treated with a combination of a classical neuroleptic and an anticholinergic agent. Clozapine, despite its anticholinergic property, did not enhance the haloperidol-induced hypersensitivity.
The increase in the concentration of homovanillic acid (HVA) in the haloperidol for 6 days compared to a single administration of the drug. The induction of tolerance is probably due to a functional modification of the striatal dopamine (DA)-receptors after repeated administration of the neuroleptic. Atropine given in combination with haloperidol enhances the induction of tolerance. Clozapine (20 mg/kg orally) had no such effect.
The present study has compared the abilities of clozapine, haloperidol, chlorpromazine and loxapine to induce dopamine (DA)-receptor hypersensitivity in rats, as measured by the apomorphine response after withdrawal of the antipsychotic drugs. Haloperidose during 1-2 weeks after withdrawal. Clozapine, given prior to apomorphine, reduced the responses of the haloperidol and loxapine groups to the control level. The effects of haloperidol and clozapine were quantified in rats with unilateral striatal lesions. Biochemical investigations showed that tolerance developed to the increase in striatal homovanillic acid (HVA) after chronic treatment with haloperidol, chlorpromazine and loxapine, whereas clozapine (20 mg/kg p.o.) failed to affect the HVA content, and no tolerance developed to the increase seen at 80 mg/kg. Cross-tolerance to the rise in HVA was seen with haloperidol, chlorpromazine and loxapine, but chronicc pretreatment with clozapine failed to affect the rise in HVA induced by a singel dose of the former compounds.
The effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat have been investigated. Haloperidol, perlapine and thioridazine induce catalepsy and enhance the turnover of DA in the striatum as indicated by the dose-dependent increase in the DA-metabolites, HVA and DOPAC. These effects are due to blockade of dopaminergic transmission, haloperidol being far more potent than perlapine or thiridazine. Clozapine differs from these agents in that it elevates the concentration of striatal DA. The increase of the concentrations of HVA and DOPAC by clozapine is not accompanied by development of catalepsy. Therefore, clozapine seems to influence striatal DA by a mechanism other than DA-receptor blockade. All four drugs enhance the turnover of NA in the brain stem. This effect is probably secondary to the blockade of NA-receptors. There was no correlation between the effects on NA-metabolism and the EEG-arousal inhibitory activities of these agents or their clinical antipsychotic effects. Clozapine increase the concentration of 5-HT and 5-HIAA in the brain. This effect was not seen with the other drugs. Perlapine seems to enhance the turnover of 5-HT, whereas haloperidol reduced the 5-HT concentration. Thioridazine appears to have no effect on the metabolism of 5-HT.