ALTERATION OF CATALEPTIC RESPONSES INDUCED BY DOPAMINE-RECEPTOR ANTAGONISTS AFTER CHRONIC COCAINE ADMINISTRATION IN MICE

The influence of chronic treatment of mice with cocaine, an indirect d opamine receptor agonist, on the cataleptic effects of ,-tetrahydro-3- methyl-5-phenyl-1H-3-benzazepin-7ol hydrochloride (SCH23390), a dopami ne D-1 receptor antagonist, or haloperidol, mainly a dopamine D, recep tor antagonist, was investigated. Mice were given cocaine (10 mg/kg s. c.) once every other day for 7 (4 injections), 15 (8 injections) or 21 (11 injections) days. The cataleptic effects of SCH23390 (0.3 mg/kg i .p.) were significantly reduced when it was given 1-7 days after the l ast dose of a 7- or 15-day pretreatment course of cocaine. When SCH233 90 was given 14-21 days after the cocaine the cataleptic effect was in creased in the 15-day, but not the 7-day, cocaine-pretreated mice. How ever, after a 21-day treatment with cocaine, a challenge dose of SCH23 390 given 1-3 days thereafter produced a decreased cataleptic response , but as increased response after 7-21 days. The cataleptic effects of haloperidol (0.3 mg/kg i.p.) were reduced when it was given 1-7 days after the last dose of a 7-day pretreatment, but increased 1-3 days af ter that of a 15-day pretreatment with cocaine (10 mg/kg s.c.). The pr etreatment with cocaine for 21 days did not affect the haloperidol cat alepsy during a 1- to 3-day withdrawal period. However, haloperidol ca talepsy was decreased only 7 days, then reversed 14 days and gradually increased 21 days after the last injection of a 15- or 21-day pretrea tment course of cocaine. These results suggest that chronic treatment with the indirect dopamine receptor agonist, cocaine, caused supersens itivity of dopamine D-1 receptors (a decrease in SCH23390 catalepsy) d uring the early withdrawal period and subsensitivity (an increase in S CH23390 catalepsy) after a longer period of withdrawal. It was apparen t that the longer the period and the higher the dose of pretreatment w ith cocaine, the less were the alterations in initial responses and th e greater were the alterations in subsequent responses to the dopamine D-1 receptor antagonists.