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.

[Effects of anticholinergics and clozapine on the activation of the striatal dopaminergic system in the rat by haloperidol. Neurochemical findings (author's transl)]. / Einfluss von Anticholinergika sowie Clozapin auf die durch Haloperidol induzierte Aktivierung des dopaminergen Systems im Striatum der Ratte: Neurochemische Ergebnisse

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.

Effect of clozapine on the metabolism of serotonin in rat brain.

Clozapine, but not chlorpromazine, haloperidol, thioridazine, or loxapine, increases the concentrations of tryptophan, serotonin, and 5-hydroxyindoleacetic acid in the brain of the rat. This effect of clozapine is due to an increased serotonin synthesis as demonstrated by an enhanced accumulation of 3H-serotonin in the brain after i.v. infusion of 3H-tryptophan. Clozapine also elevates the plasma concentration of free tryptophan, and reduces the plasma concentration of total tryptophan. Therefore, clozapine may increase the brain serotonin concentration by enhancing the availability of tryptophan in the brain, thereby promoting serotonin synthesis. Measurement of the rate of disappearance from the brain of 3H-serotonin or of endogenous serotonin after synthesis inhibition with 6-fluorotryptophan shows that clozapine has no direct effect on the release and degradation of serotonin. The effect of clozapine on brain serotonergic systems may possibly be related to the pronounced sedative and sleep-inducing properties of this drug.

Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine.

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.

Effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat.

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.