The effect of niaprazine on the turnover of 5-hydroxytryptamine in the rat brain.
Niaprazine (60 mg/kg i.p.) increased rat brain 5-hydroxyindole acetic acid (5-HIAA) concentrations 30 min after treatment, and reduced them at 3-8 hr after treatment. Rat brain 5-hydroxytryptamine (5-HT) levels were unchanged. Niaprazine also produced a short-lasting depletion of rat brain noradrenaline (NA) and dopamine (DA). Pretreatment with alpha-phenyl-alpha-propyl-benzeneacetic acid, 2-(diethylamino) ethyl ester hydrochloride (SKF 525A) (75 mg/kg i.p.) potentiated the increase in 5-HIAA and depletion of catecholamines produced 1 hr after niaprazine, but abolished the reduction in 5-HIAA produced 8 hr after the drug. This suggested that a metabolite might be responsible for the delayed reduction in 5-HIAA levels. A potential metabolite, p-fluoro-phenylpiperazine (FPP) (5-40 mg/kg i.p.) reduced rat brain 5-HIAA and 3,4-dihydroxyphenyl acetic acid (DOPAC), and inhibited 5-HT and NA uptake in vitro. Unlike niaprazine, FPP produced no behavioural sedation, but in large doses produced a behavioural syndrome indicative of serotonergic stimulation. Studies of the metabolism of 14C-niaprazine in rats indicated the presence of a urinary metabolite with the same chromatographic characteristics as FPP. These results suggest that niaprazine itself depletes brain catecholamines and increases 5-HT turnover, while a metabolite, FPP, subsequently reduces the turnover of 5-HT and DA.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors
D001679:Biogenic Amines; D010879:Piperazines; C033820:4-fluoro-phenylpiperazine; D009536:Niacinamide; D012701:Serotonin; D011335:Proadifen; C021062:niaprazine