Changes in rat striatal dopamine turnover and receptor activity during one years neuroleptic administration

Administration of trifluoperazine (2.5--3.5 mg/kg/day p.o.) or thioridazine (30--40 mg/kg/day) for up to 1 year initially increased homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations in striatum. However, by 1 month and thereafter metabolite levels returned almost to control values. Dopamine concentrations were elevated after 3 months administration of both drugs and also after 12 months administration of trifluoperazine. Trifluoperazine administration for 1 month produced a marked increase in the dissociation constant (KD) for striatal 3H-spiperone binding but a reduction in receptor numbers. Thereafter receptor numbers increased at 6 and 12 months in both trifluoperazine and thioridazine treated animals compared to control values. The KD for both drug treated groups returned to normal at 6 months; however, by 12 months drug treated animals again demonstrated high KD values. Dopamine stimulation of striatal adenylate cyclase was inhibited after administration of trifluoperazine or thioridazine for 1 week or 1 month. However, by 6 and 12 months this effect was replaced by an enhanced stimulation. Administration of lower doses of trifluoperazine (0.7--0.9 mg/kg/day p.o.) or thioridazine (6--9 mg/kg/day p.o.) for up to 1 year produced similar although generally less marked changes in these biochemical indices of dopamine function. This study provides evidence of biochemical changes which parallel the behavioural findings of enhanced dopamine receptor activity that occur during continuous long-term neuroleptic administration to rodents.