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Vol. 302, Issue 1, 119-126, July 2002
Department of Pharmacology and Toxicology, College of Medicine,
University of Arkansas for Medical Sciences, Little Rock, Arkansas
These studies tested the hypothesis that a single dose of
high-affinity anti-phencyclidine monoclonal antibody (anti-PCP mAb) provides long-term protection against behavioral effects of repeated PCP administration in rats. Rats were treated with saline, nonspecific bovine IgG (NS-IgG), or anti-PCP mAb (1.0 g/kg). The next morning, the
rats were challenged with escalating i.v. doses of PCP (0.32, 0.56, and
1.0 mg/kg) at 90-min intervals. This regimen was repeated every 3 days
for 2 weeks. In the saline and NS-IgG control groups, PCP yielded
reproducible and linear dose-dependent effects that remained constant
during the experiment. In contrast, the anti-PCP mAb treatment blocked
PCP effects on day 1, and sustained significant (P < 0.05) reductions in drug effects for the entire 2-week experiment. Brain PCP concentrations (determined at study termination) were reduced
by ~55%, whereas serum concentrations were increased over 4000%
compared with controls. Thus, a single dose of antibody medication
provided long-term reductions in drug effects and brain concentrations,
beyond the expected capacity of the drug-antibody interaction. These
data challenge current concepts about in vivo dose dependence and
unimolecular interaction between antibody binding sites and small
molecules and establish that neuroprotection by mAbs may have an unique
mechanism of action.