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.
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 cycle and in reserpine-induced ponto-geniculo-occipital 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 α-adrenergic blockade or an enhanced impulse flow in central noradrenergic neurons.
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.
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