MODIFICATION OF CATALEPTIC RESPONSES TO DOPAMINE-RECEPTOR ANTAGONISTSAFTER WITHDRAWAL FROM CHRONIC COCAINE OR COCAINE PLUS DOPAMINE ANTAGONIST ADMINISTRATION

1. In mice pretreated chronically with cocaine (indirect dopamine agon ist: 10 mg/kg, s.c, on alternating days for 15 days), haloperidol (dop amine D2 antagonist: 0.3 mg/kg i.p.) exerted an enhanced cataleptic re sponse, but SCH23390 (dopamine D1 antagonist: 0.3 mg/kg i.p.) produced an attenuated response at 24 h, which converted to a supernormal resp onse, when it was administered 15-60 days after withdrawal from cocain e. 2. A challenge dose of SCH23390 exhibited enhanced catalepsy when g iven 15 days, but not at 24 h, after the last pretreatment dose of SCH 23390 (0.1-1.0 mg/kg s.c.). In contrast, haloperidol catalepsy was not affected by the SCH23390 pretreatment. 3. However, in animals chronic ally pretreated with haloperidol (0.1-1.0 mg/kg s.c.), a challenge dos e of SCH23390 as well as haloperidol exhibited attenuated cataleptic e ffects at 24 h and normal cataleptic responses at 15 days after the la st dose of the pretreatment regimen. 4. Challenge doses of haloperidol or SCH23390 given to mice 24 h after chronic cocaine pretreatment pro duced enhanced and attenuated cataleptic responses, respectively; howe ver, these responses were no longer produced when haloperidol or SCH23 390 was given to mice pretreated chronically with a combination of coc aine and either haloperidol or SCH23390. 5. The enhanced catalepsy pro duced by a challenge dose of SCH23390 (15-60 days after chronic cocain e) was further potentiated when it was administered to animals that ha d been pretreated chronically with a combination of SCH23390 and cocai ne, but was antagonized in animals pretreated chronically with haloper idol and cocaine. In contrast, the degree of enhanced cataleptic respo nses produced by a challenge dose of haloperidol 30-60 days after pret reatment chronically with a combination of cocaine + SCH23390 was simi lar to that seen after chronic cocaine alone. However, this enhanced r esponse was antagonized in animals that had been pretreated chronicall y with the combination of cocaine+haloperidol. 6. The results suggest that the coadministration of SCH23390 with cocaine was able to block i ndirectly dopamine D2 receptor inhibition (subsensitivity) induced dur ing the early withdrawal period from chronic cocaine, despite the fact that by itself SCH23390 did not have an effect on haloperidol catalep sy. Accordingly, the stimulatory effects of dopamine D2 receptors by a single administration of cocaine may be mediated mainly by an indirec t stimulation of dopamine D2 receptor function via its D1 receptor sti mulating action. 7. The coadministration of SCH23390 with cocaine rath er aggravate the subsensitive effect of dopamine D1 receptors (increas ed SCH23390 catalepsy) produced during long-term withdrawal period fro m 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 resul t suggest that a single administration of SCH23390 or haloperidol afte r long-term withdrawal periods from chronic cocaine may not be effecti ve as antipsychotic drugs because of further aggravation of suppressiv e behaviors. These results also provide evidence that Dr receptor anta gonists may be more effective as antipsychotic drugs than dopamine D1 receptor antagonist, since the coadministration of haloperidol with co caine normalized the abnormal behaviors seen during early and long-ter m withdrawal periods from chronic cocaine.