Effects of Murine-Derived Anti-Methamphetamine Monoclonal Antibodies on (+)-Methamphetamine Self-Administration in the Rat

摘要

Two murine-derived anti-methamphetamine monoclonal antibodies were studied as potential pharmacokinetic antagonists of (+)-methamphetamine self-administration by rats.Intravenous administration of a 1 g/kg dose of the lower affinity [antibody equilibrium dissociation constant (K_d)=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 (+)-methamphetamine.mAb6H8 increased the rate of self-administration of a unit dose of 0.06 mg/kg (+)-methamphetamine,had little effect on the rate of self-administration of a unit dose of 0.03 mg/kg (+)-methamphetamine,and lowered the rate of self-administration of a unit dose of 0.01 mg/kg (+)-methamphetamine to a level similar to that after saline substitution.mAb-induced changes in rates of self-administration occurred very early in self-adminis-tration 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=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 (+)-methamphetamine.It is proposed that these anti-methamphetamine antibodies bind some of the self-administered (+)-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 (+)-methamphetamine abuse,the experiments demonstrate that anti-(+)-methamphetamine monoclonal antibodies can attenuate the self-administration of the drug and suggest the potential of using monoclonal antibodies as pharmacokinetic antagonists of (+)-methamphetamine.