Two murine-derived anti-methamphetamine monoclonal antibodies were studied as potential pharmacokinetic antagonists of (ϩ)-methamphetamine self-administration by rats. Intravenous administration of a 1 g/kg dose of the lower affinity [antibody equilibrium dissociation constant (K d ) ϭ 250 nM] monoclonal antibody (mAb) designated mAb6H8, 1 day before the start of several daily 2-h self-administration sessions produced effects that depended on the dose of (ϩ)-methamphetamine. mAb6H8 increased the rate of self-administration of a unit dose of 0.06 mg/kg (ϩ)-methamphetamine, had little effect on the rate of self-administration of a unit dose of 0.03 mg/kg (ϩ)-methamphetamine, and lowered the rate of self-administration of a unit dose of 0.01 mg/kg (ϩ)-methamphetamine to a level similar to that after saline substitution. mAb-induced changes in rates of self-administration occurred very early in self-administration sessions and lasted for 3 to 7 days. Intravenous administration of a 1 or a 0.6 g/kg dose of a higher affinity (K d ϭ 11 nM) mAb designated mAb6H4, 24 h before the first of several self-administration sessions, produced very similar effects to the lower affinity mAb, despite the more than 20-fold greater affinity for (ϩ)-methamphetamine. It is proposed that these anti-methamphetamine antibodies bind some of the self-administered (ϩ)-methamphetamine before it can penetrate into brain, thereby reducing the amount of free drug available to function as a reinforcer. Although neither of these mAb medications are optimal antibodies for treating (ϩ)-methamphetamine abuse, the experiments demonstrate that anti-(ϩ)-methamphetamine monoclonal antibodies can attenuate the self-administration of the drug and suggest the potential of using monoclonal antibodies as pharmacokinetic antagonists of (ϩ)-methamphetamine.
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