The Pharmacokinetic Determinants of the Frequency and Pattern of Intravenous Cocaine Self-administration in Rats by Pharmacokinetic Modeling

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Abstract
We investigated the pharmacokinetic determinants of the frequency of intravenous cocaine self-administration in 2.5-h sessions. Two groups of rats were implanted with dual catheters that permitted cocaine infusion and blood sampling via the femoral and jugular vein catheters, respectively. Half of the animals in each group self-administered one of the two cocaine unit doses (0.5 and 1 mg/kg/infusion) by pressing a lever under a continuous schedule of reinforcement. To monitor serum cocaine concentrations, the remaining animals received concurrent, response-independent infusions whenever the matched animals self-administered cocaine infusions. Multiple concentration-time data in two successive self-administrations were determined to monitor the extent of fluctuation in concentrations by pharmacokinetic modeling. Behavioral analyses revealed the higher unit dose (1 mg/kg) resulted in less frequent cocaine self-administration, and a longer interinfusion interval, whereas the total doses were similar for the two groups (24.5–27.0 mg/kg/2.5 h). Cocaine decayed biexponentially. Both the values of clearance and terminal elimination rate constant for the self-administration paradigm were significantly greater than those after the bolus cocaine dosing series (0.5 and 1 mg/kg, separated by 3 days). The regularity in cocaine self-administration produced relatively stable serum cocaine concentrations that oscillated between maximum (Cmax) and minimum (Cmin) values regardless of dose size and interinfusion interval. Although the Cmaxfor the 1-mg/kg unit dose (1.47 μg/ml) was significantly higher than that for the 0.5-mg/kg dose (0.82 μg/ml), theCmin values between the groups approximated each other (0.28, and 0.34 μg/ml, respectively). Hence, theCmin is the determinant of the initiation of the next drug-taking behavior.