Effects of murine-derived anti-methamphetamine monoclonal antibodies on (+)-methamphetamine self-administration in the rat.
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-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) = 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.
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72204, USA. DEMcMillan@uams.edu
D E
DE
McMillan
W C
WC
Hardwick
M
M
Li
M G
MG
Gunnell
F I
FI
Carroll
P
P
Abraham
S M
SM
Owens
D018663:Adrenergic Agents / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration
D018663:Adrenergic Agents; D000911:Antibodies, Monoclonal; D008694:Methamphetamine