EFFECTS OF INTERMITTENT AND CONTINUOUS SUBCHRONIC ADMINISTRATION OF RACLOPRIDE ON MOTOR-ACTIVITY, DOPAMINE TURNOVER AND RECEPTOR OCCUPANCY IN THE RAT

With the purpose of finding means to circumvent the marked pharmacokin etic differences of raclopride between rats and man, the effects of in termittent and continuous administration of raclopride were compared i n rats. Intermittent administration of raclopride via subcutaneous inj ections resulted in a prompt increase of dopamine (DA) turnover and de crease of motor activity but these effects were of short duration, pro bably due to rapidly decreasing raclopride DA D-2 receptor occupancy. In contrast, but similar to schizophrenic patients on raclopride treat ment, stable plasma raclopride levels and a steady DA D-2 receptor occ upancy above 70% were produced in the caudate-putamen and nucleus accu mbens/olfactory tubercle, when raclopride was administered continuousl y via minipumps at daily doses above 2 mg/kg. Tolerance to the acute e ffects of raclopride on DA turnover and locomotion was found with both routes of administration but it was more marked with continuous admin istration. At continuous raclopride administration, tolerance to the e ffects of raclopride on DA turnover and spontaneous motor activity as well as supersensitivity to amphetamine-induced motor activity occurre d when 70% or more of DA D-2 receptor sites were occupied, i.e. the sa me degree of receptor occupancy as found in patients given therapeutic doses of raclopride.