title: Treatment of rats with an anti-(+)-methamphetamine monoclonal antibody shortens the duration of action of repeated (+)-methamphetamine challenges over a one month period.
abstract: This study assessed clinical scenarios of continuing monoclonal antibody (mAb) treatment for (+)-methamphetamine (METH) addiction, and the implications of missing or discontinuing this therapy. We hypothesized that chronic anti-METH mAb7F9 (METH KD=9 nM) treatment of rats could significantly decrease METH-induced behaviors; even with repeated METH challenges, use of METH doses in excess of mAb binding sites, and after discontinuing mAb treatment which results in a 10-fold reduction in mAb7F9 serum concentrations. Male Sprague Dawley rats (n=6/group) were treated with i.v. saline or a loading dose of mAb7F9 to achieve instant steady-state conditions followed by two weekly (141 mg/kg) doses ending on day 14. METH (0.56 mg/kg) was administered 4h and three days after each saline or mAb7F9 treatment, and on day 21. This produced locomotion and rearing behavior that lasted about 120 min in control rats. In mAb7F9 treated rats, METH-induced distance traveled was significantly reduced from 60 to 120 min (P<0.05) on days 0-21 and rearing was significantly reduced from 60 to 120 min on days 0-17. METH serum concentrations determined 5h after METH dosing was significantly increased in mAb7F9-treated rats after all METH challenges. On days 24 and 28 (the final day), the rats were administered a 3-fold higher METH dose (1.68 mg/kg). MAb7F9 treated rats showed a substantially earlier termination of the METH-induced locomotion on both days, even though the METH dose exceeded mAb7F9s binding capacity. METH brain concentrations determined 5h after METH on day 28 were also significantly decreased in mAb7F9-treated rats. In conclusion, over one month, mAb7F9 significantly and continuously bound METH and reduced METH-induced locomotor effects even after discontinuation of mAb treatment and challenge with higher METH doses.
authors.affiliation: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hambuchen
authors.affiliation: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rüedi-Bettschen
authors.affiliation: Department of Biostatistics, College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: D Keith
authors.initials: DK
authors.lastname: Williams
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Hendrickson
authors.affiliation: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: mowens@uams.edu.
authors.forename: S Michael
authors.initials: SM
authors.lastname: Owens
mesh_terms: D019969:Amphetamine-Related Disorders / Q000188:drug therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001666:Binding Sites, Antibody; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000097:blood* / Q000276:immunology; D009043:Motor Activity / Q000187:drug effects; D017207:Rats, Sprague-Dawley
chemical_list: D000911:Antibodies, Monoclonal; D008694:Methamphetamine
keywords: Chronic administration; Drug abuse; Methamphetamine; Monoclonal antibody; Preclinical studies; Rats