The effect of niaprazine on the turnover of 5-hydroxytryptamine in the rat brain

Abstract 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 α-phenyl-α-propyl-benzcneacetic 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 14 C-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.