Enhancement of noradrenaline release from rat cerebral cortex by neuroleptic drugs.
The effect of different neuroleptic drugs (levomepromazine, haloperidol, thioridazine, clozapine and sulpiride) on (-)-3H-noradrenaline uptake and release by parieto-occipital slices of the rat cerebral cortex was investigated. 1. All neuroleptic drugs tested increased the 3H-efflux from electrically stimulated cortical slices preincubated in (-)-3H-noradrenaline already at 1 microM, clozapine was the most potent compound followed by haloperidol, thioridazine, levomepromazine and sulpiride. The enhanced 3H-efflux due to field stimulation was found at concentrations, which did not increase the basal 3H-efflux. Only haloperidol raised the basal 3H-efflux at 1 microM. 2. All neuroleptic drugs failed to inhibit (-)-3H-noradrenaline (10(-7) M) accumulation by cortical slices at 1 microM. Sulpiride was inactive in concentrations up to 100 microM. Clozapine again proved to be most potent at 10-100 microM. 3. Clozapine was able to enhance the stimulated transmitter overflow when noradrenaline uptake was already blocked by cocaine thus indicating a different mode of action. 4. Clozapine and levomepromazine antagonized the presynaptic alpha-adrenergic effect of clonidine. 5. The antidepressant drug amitriptyline increased the transmitter efflux at the same concentrations and to a similar extent as neuroleptic agents. It is concluded that neuroleptics enhance the stimulation induced noradrenaline release mainly by acting on presynaptic alpha-adrenoceptors. The effect of clozapine, however, includes a noradrenaline uptake inhibition. These findings may explain the increased noradrenaline turnover produced by neuroleptic drugs and the weak antidepressant action of low potent neuroleptics as well.
D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism*; D003024:Clozapine / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D011395:Promazine / Q000494:pharmacology; D051381:Rats; D013268:Stimulation, Chemical
D014150:Antipsychotic Agents; D000639:Amitriptyline; D003042:Cocaine; D003024:Clozapine; D011395:Promazine; D009638:Norepinephrine