Cocaine disposition in the brain after continuous or intermittent treatment and locomotor stimulation in mice

Intermittent s.c. and i.p. injections of cocaine (20 mg/kg; total 430 mg/kg for each animal) for 18 days resulted in locomotor stimulation of mice upon challenge with cocaine on the 25th or 26th day, compared with no locomotor stimulation in a saline-pretreated group. In contrast to the sensitization by intermittent cocaine administration, tolerance was found upon challenge after continuous administration of cocaine by minipumps (25 mg/kg/day; total 450 mg/kg for each animal) on a similar schedule. No differences were found between the sensitized and tolerant groups in the levels of cocaine and benzoylecgonine in plasma and brain 12 min after i.p. administration of a challenge dose of cocaine, suggesting that in these chronic experiments the changes in the locomotor response are not accounted for by dispositional effects. In contrast, in animals treated daily for 2 or 3 days i.p. with cocaine and challenged with cocaine 1 day later, there was both a greater locomotor stimulation and a higher level of brain cocaine than in saline-pretreated animals, suggesting a dispositional effect. Among individual animals there was a positive correlation between their locomotor stimulation by the challenge dose and their brain cocaine concentration.