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 dopamine receptor agonist, on the cataleptic effects of R-(+)-chloro-2,3,4,5,-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7ol hydrochloride (SCH23390), a dopamine D-1 receptor antagonist, or haloperidol, mainly a dopamine D, receptor 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 last dose of a 7- or 15-day pretreatment course of cocaine. When SCH23390 was given 14-21 days after the cocaine the cataleptic effect was increased in the 15-day, but not the 7-day, cocaine-pretreated mice. However, after a 21-day treatment with cocaine, a challenge dose of SCH23390 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 after that of a 15-day pretreatment with cocaine (10 mg/kg s.c.). The pretreatment with cocaine for 21 days did not affect the haloperidol catalepsy during a 1- to 3-day withdrawal period. However, haloperidol catalepsy was decreased only 7 days, then reversed 14 days and gradually increased 21 days after the last injection of a 15- or 21-day pretreatment course of cocaine. These results suggest that chronic treatment with the indirect dopamine receptor agonist, cocaine, caused supersensitivity of dopamine D-1 receptors (a decrease in SCH23390 catalepsy) during the early withdrawal period and subsensitivity (an increase in SCH23390 catalepsy) after a longer period of withdrawal. It was apparent that the longer the period and the higher the dose of pretreatment with cocaine, the less were the alterations in initial responses and the greater were the alterations in subsequent responses to the dopamine D-1 receptor antagonists.