The predominantly human sequence, high-affinity anticocaine monoclonal antibody (mAb) 2E2 was cleared slowly from mouse blood by a first-order process with an elimination t 1/2 of 8.1 days. Infused 2E2 also produced a dramatic dose-dependent increase in plasma cocaine concentrations and a concomitant decrease in the brain cocaine concentrations produced by an i.v. injection of cocaine HCl (0.56 mg/kg). At the highest dose of 2E2 tested (3:1, mAb/drug), cocaine was not detectable in the brain. Pharmacokinetic studies showed that the normal disappearance of cocaine from plasma was described by a two-compartment pharmacokinetic model with distribution t 1/2␣ and terminal elimination t 1/2 values of 1.9 and 26.1 min, respectively. In the presence of an equimolar dose of mAb 2E2, there was a 26-fold increase in the area under the plasma cocaine concentration-time curve (AUC) relative to the AUC in the absence of 2E2. Consequently, 2E2 decreased the volume of distribution of cocaine from 6.0 to 0.20 l/kg, which approximated that of 2E2 (0.28 l/kg). However, cocaine was still rapidly cleared from plasma, and its elimination was now described by a single-compartment model with an elimination t 1/2 of 17 min. Importantly, 2E2 also produced a 4.5-fold (78%) decrease in the cocaine AUC in the brain. Therefore, the effect of 2E2 on plasma and brain cocaine concentrations was predominantly caused by a change in the distribution of cocaine with negligible effects on its rate of clearance. These data support the concept of immunotherapy for drug abuse.Despite decades of basic and clinical research there is still no approved pharmacotherapy for the prevention of relapse in cocaine abusers (Vocci and Ling, 2005). The drug-induced reinstatement (priming) of drug self-administration behavior represents an animal model of relapse (DeWitt and Stewart, 1981) with the concentration of cocaine in the body a critical determinant of the probability of reinstating cocaine selfadministration (Norman et al., 1999(Norman et al., , 2002. Because the site of action of cocaine is presumably in the brain, decreasing the concentrations reaching the brain would be expected to decrease the probability of relapse. Antibodies with high affinity and specificity for cocaine would be expected to act as pharmacokinetic antagonists by sequestering cocaine in the peripheral circulation and preventing its entry to the brain. Indeed, active immunization of animals with hapten-carrier conjugates can elicit the production of polyclonal anticocaine antibodies with sufficient levels and affinity for cocaine that they can reduce the amount of cocaine entering the brain (Fox et al., 1996). Active immunization has also been shown to attenuate the behavioral effects (Carrera et al., 1995;Fox et al., 1996;Ettinger et al., 1997) and the priming effect (Carrera et al., 2000) of systemically administered cocaine in rats. Furthermore, the ability of active immunization to produce levels of polyclonal anticocaine antibodies in humans (Kosten et al., 2002) that we...
The predominantly human sequence anti-cocaine monoclonal antibody (mAb), 2E2, has high affinity and specificity for cocaine and antagonizes cocaine distribution to the brain in mice. To determine whether 2E2 can alter the self-administration of cocaine in rats, both cocaine-induced reinstatement (priming) of self-administration, and the rates of cocaine consumption were assessed during daily sessions. After self-administration training, the rats' cocaine priming threshold values were stable over a 2-week baseline period. Furthermore, the rates of cocaine consumption at unit doses of 0.3 and 3.0 mol/kg were steady within sessions and stable between sessions. Then, 2E2 (120 mg/kg i.v.) or an equivalent dose of nonspecific human polyclonal IgG (control) was infused and daily sessions continued. 2E2 produced an initial, approximately 3-fold, increase in the cocaine priming threshold that declined toward baseline values over the subsequent 3 weeks, with an effect t 1/2 of approximately 4 days. In contrast to the substantial increase in the cocaine priming threshold, 2E2 produced only modest dose-dependent increases (42 and 18%) in the cocaine consumption rates, and these also gradually declined toward baseline values. There was no significant effect of the control IgG on the priming threshold or rates of consumption of cocaine. After infusion, antibody blood concentrations declined over time, and a two-compartment pharmacokinetic model generated values for the distribution and elimination half-lives of 0.5 and 11.6 days for 2E2 and 0.4 and 6.0 days for control IgG. 2E2 had a long-lasting effect on cocaine-induced priming, which may predict its efficacy as an immunotherapy for cocaine abuse.The drug-induced reinstatement (priming) of drug selfadministration behavior represents an animal model of some aspects of the relapse process (de Wit and Stewart, 1981;Shalev et al., 2002) in addicts. The cumulative concentration of cocaine is a critical determinant of the probability of reinstating cocaine self-administration in rats (Norman et al., , 2002. Because the site of action for cocaine is presumably in the brain, decreasing the drug concentrations reaching the brain would be expected to decrease the probability of relapse. Antibodies with high affinity and specificity for cocaine are hypothesized to sequester cocaine in the peripheral circulation and reduce its entry to the brain (Kosten and Owens, 2005). Pharmacokinetic antagonism is defined as a decrease in the concentration of an agonist at its site of action. Typically, the mechanism by which this is achieved is by increasing the rate of agonist clearance (Rang et al., 2007). Although this may occur with antibody Fab fragments targeting slowly cleared drugs such as digoxin (Bateman, 2004), this would not occur with monoclonal antibodies (mAb) targeting rapidly cleared drugs such as cocaine or nicotine (Keyler et al., 2005). Antibodies generally act as chemical antagonists by binding to and thereby reversibly inactivating drugs. As a consequence, anti-drug an...
Summary Competitive dopamine receptor antagonists increase the rate of cocaine self-administration. As the rate of self-administration at a particular unit dose is determined by the satiety threshold and the elimination half-life (t1/2) of cocaine, we investigated whether dopamine receptor antagonists altered these parameters. The plasma cocaine concentration at the time of each self-administration was constant during a session demonstrating that this satiety threshold concentration represents an equiactive cocaine concentration. The plasma cocaine concentration at the time of self-administration was increased by SCH23390, consistent with pharmacological theory. In rats trained to reliably self-administer cocaine, SCH23390 had no effect on the plasma steady-state cocaine concentration produced by constant infusions of cocaine. Therefore, this antagonist had no effect on cocaine t1/2 at a dose that accelerated cocaine self-administration. A continuous cocaine infusion at a rate that maintained steady state concentrations above the satiety threshold stopped self-administration. SCH23390, or the D2 dopamine receptor antagonist (−) eticlopride, reinstated self-administration in the presence of the constant cocaine infusion. This is consistent with SCH23390 and eticlopride raising the satiety threshold above the steady state level produced by the constant cocaine infusion. It is concluded that the antagonist-induced acceleration of cocaine self-administration is the result of a pharmacokinetic/pharmacodynamic interaction whereby the rate of cocaine elimination is faster at the higher concentrations, as dictated by first-order kinetics, so that cocaine levels decline more rapidly to the elevated satiety threshold. This results in the decreased inter-injection intervals.
Competitive dopamine receptor antagonists accelerate psychomotor stimulant self-administration. According to pharmacological theory of competitive antagonism antagonists raise the equiactive agonist concentration. In the self-administration paradigm this is assumed to be the satiety threshold or Cmin. The magnitude of the proportional increase in satiety threshold (agonist concentration ratio) as a function of antagonist dose should reflect the antagonist pharmacodynamic potency. The time course of this effect should reflect the rate of change of antagonist occupancy of receptors and, therefore, antagonist concentration i.e. pharmacokinetics. Rats self-administered apomorphine or cocaine at a stable rate and were then injected i.v. with one of four competitive D1–like or D2–like dopamine receptor antagonists and the session continued. The agonist concentrations at the time of each self-administration (satiety thresholds) were calculated during the session. The antagonists accelerated self-administration of both agonists with a concomitant increase in the calculated satiety thresholds. The maximum agonist concentration ratio was proportional to the dose of antagonist. The time courses of the changes in agonist concentration ratio were independent of the agonist and of the dose of antagonist. Schild analysis of the maximum agonist concentration ratio as a function of the antagonist dose allowed apparent pA2 (or Kdose) to be measured. Antagonist Kdose values should provide a quantitative basis for receptor identification in behavioral pharmacology. The assay system may also measure the pharmacokinetics of antagonist elimination from the brain. Agonist self-administration represents a sensitive in vivo pharmacological assay system that provides information useful for pharmacokinetic/pharmacodynamic modeling of antagonist effects.
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