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

Abstract

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 selfadministrations 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 (C max ) and minimum (C min ) values regardless of dose size and interinfusion interval. Although the C max for the 1-mg/kg unit dose (1.47 g/ml) was significantly higher than that for the 0.5-mg/kg dose (0.82 g/ml), the C min values between the groups approximated each other (0.28, and 0.34 g/ml, respectively). Hence, the C min is the determinant of the initiation of the next drug-taking behavior.Intravenous cocaine self-administration was first demonstrated in rats in 1968 (Pickens andThompson, 1968). In that study, rats implanted with i.v. cannulas were placed in operant chambers where each lever-press response (i.e., fixed ratio 1 schedule) produced an infusion of a fixed dose of cocaine (e.g., 1 mg/kg/infusion). The resulting self-infusion behavior was viewed as an example of operant conditioning, in which the drug infusion served as a reinforcer for responses leading to its presentation. The results indicated that the number of infusions varied inversely in an almost linear manner with the size of the unit dose. That is, as the unit dose was increased, the number of infusions decreased and the interinfusion interval increased. As a result, the total self-administered drug dose remained relatively similar across different unit doses. The inverse relationship between the frequency of drug self-administration and unit dose also has been shown in studies of cocaine and other drugs of abuse (e.g., morphine, amphetamine) by using various schedules of reinforcement in mice (David et al., 2001), rats (Carroll et al., 1981;Caine et al., 1999), monkeys (Goldberg et al., 1971;Wilson et al., 19...

The Roles of Dopamine and α1-Adrenergic Receptors in Cocaine Preferences in Female and Male Rats

“…Individuals with the most attenuated amphetamine-induced DA were more likely to choose cocaine over alternative monetary rewards (Martinez et al, 2007), which is strikingly consistent with the neurochemistry and choice behavior of CP rats. While others have reported reduced DA responses following cocaine self-administration (Ferris et al, 2011;Gerrits et al, 2002), the longitudinal nature of our experiment revealed that the attenuation occurred after cocaine preferences developed, which may contribute to the increased cocaine intake of CP rats (Guillem et al, 2013;Lau and Sun, 2002;Wise et al, 1995). Our data from PP rats suggest that cocaine exposure itself does not attenuate cocaine-induced DA in the NAc, which is consistent with other studies linking escalation (but not intake) to changes in DA neurotransmission (Willuhn et al, 2014).…”

Variability of drug self-administration in rats

“…1 at the time a self-infusion was initiated. Procedures for estimating drug levels similar to the one used here have provided lawful and relevant data in recent studies (Tsibulsky and Norman 1999;Nicola and Deadwyler 2000), and direct measures of cocaine levels confirm that such monoexponential decay functions can adequately describe the pharmacokinetics of cocaine (Lau and Sun 2002). However, drug levels in tissue were not directly measured here, and it is possible that whole-body drug levels may not correlate perfectly with levels of drug effect in specific brain sites.…”

“…4D). Lau and Sun (2002) recently compared post-infusion drug levels reached with 500 and 1000 mg/kg unit doses of cocaine and also concluded that post-infusion levels do not appear to limit intake. In addition, it is known that rats will self-administer unit doses of cocaine that produce higher whole-body drug levels than the maximum observed here [e.g.…”

A Chimeric Human/Murine Anticocaine Monoclonal Antibody Inhibits the Distribution of Cocaine to the Brain in Mice

“…This result is similar to that which has previously been reported for i.v. injected cocaine in several species, including rats (Booze et al, 1997;Lau and Sun, 2002), nonhuman primates (Misra et al, 1977;Evans and Foltin, 2004), and for i.p. injected cocaine in mice (Benuck et al, 1987).…”