title: Vaccination protects rats from methamphetamine-induced impairment of behavioral responding for food.
abstract: (+)-Methamphetamine (METH) addiction is a chronic disease that interferes with fundamental brain-mediated behaviors and biological functions like eating. These studies present preclinical efficacy and safety profiles for a METH conjugate vaccine (IC(KLH)-SMO9) designed to treat METH abuse. ICKLH-SMO9 efficacy and safety were assessed over a 16-week period by monitoring general health and stability of responding in a food maintained behavioral paradigm. Male Sprague-Dawley rats were trained to lever press for food reinforcers until stable behavior was established. Rats (n=9/group) were then immunized with 100 μg of a control antigenic carrier protein (IC(KLH)-Cys) or IC(KLH)-SMO9 in Alhydrogel adjuvant, with booster immunizations at 4, 8 and 12 weeks. Health, immunization site and behavior were assessed daily. No adverse effects were found. During weeks 14-16, when antibody titers and METH affinity (K(d)=13.9 ± 1.7 nM) were maximal, all rats received progressively higher METH doses (0.3-3.0 mg/kg) every 3-4 days, followed by behavioral testing. Even though the lower METH doses from 0.3 to 1.0 mg/kg produced no impairment in food maintained behavior, 3.0-mg/kg in control rats showed significantly (p<0.05) reduced response rates and number of reinforcers earned, as well as reduced food intake. In sharp contrast, the IC(KLH)-SMO9 group showed no changes in food maintained behavior at any METH dose, even though METH serum concentrations showed profound increases due to anti-METH antibody binding. These findings suggest the IC(KLH)-SMO9 vaccine is effective and safe at reducing adverse METH-induced effects, even at high 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: Daniela
authors.initials: D
authors.lastname: Rüedi-Bettschen
authors.forename: Sherri L
authors.initials: SL
authors.lastname: Wood
authors.forename: Melinda G
authors.initials: MG
authors.lastname: Gunnell
authors.forename: C Michael
authors.initials: CM
authors.lastname: West
authors.forename: Rama R
authors.initials: RR
authors.lastname: Pidaparthi
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: S Michael
authors.initials: SM
authors.lastname: Owens
mesh_terms: D000818:Animals; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019966:Substance-Related Disorders / Q000517:prevention & control*; D016896:Treatment Outcome; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D018074:Vaccines, Conjugate; D008694:Methamphetamine
keywords: (+)-[2′,6′-(3)H(n)]-methamphetamine; (+)-amphetamine; (+)-methamphetamine; AMP; Cys; Drug abuse; FI; FR; HSMO9; Hapten; IC(KLH); IC(KLH)-Cys; IC(KLH)-SMO9; K(d); KLH; L-cysteine; LC–MS/MS; MCV; METH; METH-conjugate vaccine; Methamphetamine; Preclinical studies; RED; Rats; Vaccine; [(3)H]-METH; equilibrium dissociation constant; fixed-interval schedule of behavioral reinforcement; fixed-ratio schedule of behavioral reinforcement; immunocyanin monomers derived from native KLH; keyhole limpet hemocyanin; liquid chromatography coupled to tandem mass spectrometry; mAb; maleimide activated immunocyanin end capped with cysteine; monoclonal antibody; rapid equilibrium dialysis; the METH-conjugate vaccine; the METH-like hapten (S)-N-(2-(mercaptoethyl)-6-(3-(2-(methylamino)propyl)phenoxy)hexanamide
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