Electrophysiological profile of the new atypical neuroleptic, sertindole, on midbrain dopamine neurones in rats: Acute and repeated treatment

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Abstract

Sertindole (Lundbeck code No. Lu 23-174) (1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2- imidazolidinone) is a new potential neuroleptic compound.

After 3 weeks of treatment sertindole shows an extreme selectivity to inhibit the number of spontaneously active dopaminergic (DA) neurones in ventral tegmental area (VTA) while leaving the number of active DA neurones in substantia nigra pars compacta (SNC) unaffected. Acute injection of apomorphine or baclofen reverse the inhibition of activity seen after repeated treatment with sertindole. This suggests that sertindole induces a depolarization inactivation of the DA neurones. The depolarization inactivation is reversible since normal activity of DA neurones is found in both SNC and VTA after two weeks withdrawal from repeated treatment with a low dose with sertindole. One or two weeks administration of a high dose of sertindole induced only minor effects on the DA neurones in VTA; i.e., in order to obtain the depolarization inactivation sertindole requires 3 weeks of treatment as has also been reported for other neuroleptics.

Three weeks of treatment with clozapine induces a selective inhibition of the active DA neurones in VTA but at much higher doses than seen with sertindole, while haloperidol induces a non-selective decrease of spontaneously active DA neurones in both areas.

In acute electrophysiological experiments intraveneous (i.v.) administration of sertindole—in contrast to both clozapine and haloperidol—neither reverse d-amphetamine- nor apomorphine-induced inhibition of the firing frequencies of DA neurones in SNC or in VTA. In addition, sertindole does not—even in high doses—increase the firing frequency of DA neurones in SNC or VTA.

In conclusion the study indicates that sertindole is a potential antipsychotic compound which should induce fewer extrapyramidal side-effects than seen after classical neuroleptics.

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