Effects of Intermittent and Continuous Subchronic Administration of Raclopride on Motor Activity,Dopamine Turnover and Receptor Occupancy in the Rat

Abstract: With the purpose of finding means to circumvent the marked pharmacokinetic differences of raclopride between rats and man, the effects of intermittent and continuous administration of raclopride were compared in rats. Intermittent administration of raclopride via subcutaneous injections resulted in a prompt increase of dopamine (DA) turnover and decrease of motor activity but these effects were of short duration, probably due to rapidly decreasing raclopride DA D₂ receptor occupancy. In contrast, but similar to schizophrenic patients on raclopride treatment, stable plasma raclopride levels and a steady DA D₂ receptor occupancy above 70% were produced in the caudate-putamen and nucleus accumbens/olfactory tubercle, when raclopride was administered continuously via minipumps at daily doses above 2 mg/kg. Tolerance to the acute effects of raclopride on DA turnover and locomotion was found with both routes of administration but it was more marked with continuous administration. At continuous raclopride administration, tolerance to the effects of raclopride on DA turnover and spontaneous motor activity as well as supersensitivity to amphetamine-induced motor activity occurred when 70% or more of DA D₂ receptor sites were occupied, i.e. the same degree of receptor occupancy as found in patients given therapeutic doses of raclopride.