Development of tolerance and reverse tolerance to haloperidol- and SCH23390-induced cataleptic effects during withdrawal periods after long-term treatment

Abstract

The development of tolerance and reverse tolerance and reverse tolerance to the cataleptic effects of selective D 1 antagonist, SCH23390, and the mainly D 2 antagonist, haloperidol, was investigated in mice that had been chronically treated (7 or 30 days) with haloperidol (l mg/kg SC), SCH23390 (0.5 mg/kg SC), or saline (5 ml/kg SC). In control animals, SCH23390 (0.1–1.0 mg/kg IP) and haloperidol (0.1–1.0 mg/kg IP) produced 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 SCH23390 (0.3 mg/kg IP) and haloperidol (0.3 mg/kg IP) were significantly reduced 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) when given 7–21 days, but not 1–3 days, after the last injection of the SCH23390 pretreatment course. In contrast, haloperidol catalepsy was not affected by long-term SCH23390 treatment. However, after the last dose of long-term haloperidol treatment both SCH23390 and haloperidol exhibited tolerance to their cataleptic effects at 1–3 days, a normal response at 7 days, and an exaggerated response (reverse tolerance) at 15–21 days. These results suggest that a prolonged withdrawal period after 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 receptors. Long-term treatment with a D 2 receptor antagonist caused supersensitivity of D 1 and D 2 receptors during the early withdrawal period and subsensitivity after a longer period of withdrawal. These results 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 be affected by supersensitivity of D 1 receptors, but not by their subsensitivity.