Effects of haloperidol and apomorphine on catecholamine metabolism in brain slices. Reserpine-like effects of haloperidol.
The accumulation, release and catabolism of [3H]dopamine (DA) and [3H]norepinephrine (NE) synthesized from [3H]tyrosine were measured in mouse striatal and substantia nigral slices. Apomorphine inhibited both [3H]NE and [3H]DA accumulation (IC50 less than 10(-6) M), presumably by acting on a presynaptic receptor. Haloperidol (10-8M) caused a small, but significant increase in [3H]DA accumulation from [3H]tyrosine in the presence of 26 mM K+, possible reflecting blockade of presynaptic receptors activated by release DA. However, at higher concentrations (10(-6) to 10(-5) M), haloperidol inhibited [3H]DA and [3H]NE accumulation. Reserpine also potently inhibited catecholamine synthesis; chlorpromazine had only a weak effect, and fluphenazine was ineffective. Both haloperidol (10(-5) M) and reserpine (10(-7) M), but not chlorpromazine and fluphenazine, markedly increased the formation of labeled dihydroxyphenylacetic acid (DOPAC) and increased the spontaneous release of labeled DA from striatal slices preloaded with [3H]tyrosine or [14C]DA. These data suggest that haloperidol has some direct effects on DA metabolism that are unrelated to DA-receptor blockade. Because the effects of haloperidol are apparently independent of DA release, haloperidol may elevate cytoplasmic DA by altering its vesicular storage. This would, in turn, increase the spontaneous release of labeled DA by diffusion, the oxidation of DA to DOPAC by monoamine oxidase, and the end-product inhibition of tyrosine hydroxylase.
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism*; D002746:Chlorpromazine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005476:Fluphenazine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology*
D002395:Catecholamines; D009419:Nerve Tissue Proteins; D012110:Reserpine; D006220:Haloperidol; D001058:Apomorphine; D005476:Fluphenazine; D002746:Chlorpromazine; D004298:Dopamine