DEVELOPMENT OF TOLERANCE AND REVERSE TOLERANCE TO HALOPERIDOL-INDUCEDAND SCH23390-INDUCED CATALEPTIC EFFECTS DURING WITHDRAWAL PERIODS AFTER LONG-TERM TREATMENT

The development of tolerance and reverse tolerance and reverse toleran ce to the cataleptic effects of selective D-1 antagonist, SCH23390, an d the mainly D-2 antagonist, haloperidol, was investigated in mice tha t had been chronically treated (7 or 30 days) with haloperidol (1 mg/k g SC), SCH23390 (0.5 mg/kg SC), or saline (5 ml/kg SC). In control ani mals, SCH23390 (0.1-1.0 mg/kg IP) and haloperidol (0.1-1.0 mg/kg IP) p roduced cataleptic responses in a dose-dependent manner, although the responses had different time course profiles. SCH23390 catalepsy had a rapid onset but a short duration, whereas haloperidol catalepsy had a slower onset and longer duration. This could be due to differences in lipid solubility of the drugs, or at least pertly to an action of the drugs on different neuronal pathways. The cataleptic effects of SCH23 390 (0.3 mg/kg IP) and haloperidol (0.3 mg/kg IP) were significantly r educed in mice when given 24 h, but not 72 h, after the last dose of a 7 day-pretreatment course (short-term treatment) of SCH23390. However , after long-term treatment (30 days) with SCH23390, a challenge dose of SCH23390 exhibited reverse tolerance (i.e., increased catalepsy) wh en given 7-21 days, but not 1-3 days, after the last injection of the SCH23390 pretreatment course. In contrast, haloperidol catalepsy was n ot affected by long-term SCH23390 treatment. However, after the last d ose of long-term haloperidol treatment both SCH23390 and haloperidol e xhibited tolerance to their cataleptic effects at 1-3 days, a normal r esponse at 7 days, and an exaggerated response (reverse tolerance) at 15-21 days. These results suggest that a prolonged withdrawal period a fter chronic D-1 antagonist treatment is necessary for the development of reverse tolerance to a D-1 antagonist (an increase in catalepsy), which may be a reflection of a long-lasting subsensitivity of D-1 rece ptors. Long-term treatment with a D-2 receptor antagonist caused super sensitivity of D-1 and D-2 receptors during the early withdrawal perio d and subsensitivity after a longer period of withdrawal. These result s also provide evidence that the cataleptic effects of SCH23390 may be mediated by indirect blockade of D-2 receptor function through its D- 1 blocking action, whereas the cataleptic effects of haloperidol may b e affected by supersensitivity of D-1 receptors, but not by their subs ensitivity.