Cocaine sensitization in the mouse using a cumulative dosing regime.

Many rodent models of cocaine sensitization use intermittent high doses of cocaine pretreatment followed by testing with a single moderate cocaine dose. The aim of the present study was to investigate the rate and extent of sensitization to the locomotor-stimulant effects of cocaine using multiple cocaine doses (5-40 mg/kg). Eight groups of male Swiss-Webster mice were pretreated with either single doses of cocaine (40 mg/kg) or saline in the home cage, or multiple doses in the test environment, for 4 days. On the fifth day they were tested for locomotor activity, following a single dose of saline and cumulative doses of cocaine (5-40 mg/kg at 10-minute intervals). All eight groups of mice developed context-dependent sensitization to the locomotor stimulant effects of cocaine. Subsequent testing, at 10-day intervals, revealed that sensitization was maximal after five test sessions of cumulative cocaine dosing, regardless of the pretreatment regime. The main determinant of the rate at which sensitization occurred was the frequency of cumulative cocaine dosing. However, both the potency and efficacy of cocaine were altered by different pretreatments associated with exposure to the locomotor activity chambers. This robust context-dependent sensitization was long lasting, and not abolished by a 5-day extinction procedure involving cumulative saline dosing in the locomotor activity chambers. In conclusion, cumulative dosing and its inherent handling, in combination with cocaine, induced marked sensitization not produced by cocaine alone.