title: Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure.
abstract: BACKGROUND
  Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment's efficacy in decreasing cocaine consumption is unknown.
  
  
  METHODS
  This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure.
  
  
  RESULTS
  In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0-0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32-3.2mg/kg/day, i.m.) or d-amphetamine (0.032-0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine.
  
  
  CONCLUSIONS
  Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine's efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA (Drs Banks, Hutsell, Negus, and Mr Poklis); Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA (Drs Banks and Negus); Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC (Dr Blough) mbanks7@vcu.edu.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA (Drs Banks, Hutsell, Negus, and Mr Poklis); Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA (Drs Banks and Negus); Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC (Dr Blough).
authors.forename: Blake A
authors.initials: BA
authors.lastname: Hutsell
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA (Drs Banks, Hutsell, Negus, and Mr Poklis); Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA (Drs Banks and Negus); Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC (Dr Blough).
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA (Drs Banks, Hutsell, Negus, and Mr Poklis); Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA (Drs Banks and Negus); Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC (Dr Blough).
authors.forename: Justin L
authors.initials: JL
authors.lastname: Poklis
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA (Drs Banks, Hutsell, Negus, and Mr Poklis); Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA (Drs Banks and Negus); Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC (Dr Blough).
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003216:Conditioning, Operant / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005518:Food Preferences / Q000187:drug effects; D000069478:Lisdexamfetamine Dimesylate / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D012646:Self Administration; D013997:Time Factors
chemical_list: D018765:Dopamine Uptake Inhibitors; D003042:Cocaine; D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine
keywords: Lisdexamfetamine effects in rhesus monkeys; addiction; choice; cocaine; lisdexamfetamine; rhesus monkey