1. In mice pretreated chronically with
cocaine (indirect
dopamine agonist: 10 mg/kg, s.c. on alternating days for 15 days),
haloperidol (
dopamine D2 antagonist: 0.3 mg/kg i.p.) exerted an enhanced cataleptic response, but
SCH23390 (
dopamine D1 antagonist: 0.3 mg/kg i.p.) produced an attenuated response at 24 h, which converted to a supernormal response, when it was administered 15-60 days after withdrawal from
cocaine. 2. A challenge dose of
SCH23390 exhibited enhanced
catalepsy when given 15 days, but not at 24 h, after the last pretreatment dose of
SCH23390 (0.1-1.0 mg/kg s.c.). In contrast,
haloperidol catalepsy was not affected by the
SCH23390 pretreatment. 3. However, in animals chronically pretreated with
haloperidol (0.1-1.0 mg/kg s.c.), a challenge dose of
SCH23390 as well as
haloperidol exhibited attenuated cataleptic effects at 24 h and normal cataleptic responses at 15 days after the last dose of the pretreatment regimen. 4. Challenge doses of
haloperidol or
SCH23390 given to mice 24 h after chronic
cocaine pretreatment produced enhanced and attenuated cataleptic responses, respectively; however, these responses were no longer produced when
haloperidol or
SCH23390 was given to mice pretreated chronically with a combination of
cocaine and either
haloperidol or
SCH23390. 5. The enhanced
catalepsy produced by a challenge dose of
SCH23390 (15-60 days after chronic
cocaine) was further potentiated when it was administered to animals that had been pretreated chronically with a combination of
SCH23390 and
cocaine, but was antagonized in animals pretreated chronically with
haloperidol and
cocaine. In contrast, the degree of enhanced cataleptic responses produced by a challenge dose of
haloperidol 30-60 days after pretreatment chronically with a combination of
cocaine +
SCH23390 was similar to that seen after chronic
cocaine alone. However, this enhanced response was antagonized in animals that had been pretreated chronically with the combination of
cocaine +
haloperidol. 6. The results suggest that the coadministration of
SCH23390 with
cocaine was able to block indirectly
dopamine D2 receptor inhibition (subsensitivity) induced during the early withdrawal period from chronic
cocaine, despite the fact that by itself
SCH23390 did not have an effect on
haloperidol catalepsy. Accordingly, the stimulatory effects of
dopamine D2 receptors by a single administration of
cocaine may be mediated mainly by an indirect stimulation of
dopamine D2 receptor function via its D1 receptor stimulating action. 7. The coadministration of
SCH23390 with
cocaine rather aggravate the subsensitive effect of
dopamine D1 receptors (increased
SCH23390 catalepsy) produced during long-term withdrawal period from chronic
cocaine, but did not affect that of the
dopamine D2 receptor. On the other hand, the coadministration of
haloperidol with
cocaine normalized both D1 and D2 receptor subsensitive effect. 8. These result suggest that a single administration of
SCH23390 or
haloperidol after long-term withdrawal periods from chronic
cocaine may not be effective as
antipsychotic drugs because of further aggravation of suppressive behaviors. These results also provide evidence that D2 receptor antagonists may be more effective as
antipsychotic drugs than
dopamine D1 receptor antagonist, since the coadministration of
haloperidol with
cocaine normalized the abnormal behaviors seen during early and long-term withdrawal periods from chronic
cocaine.