title: A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to D-amfetamine, methylphenidate and modafinil.
abstract: Lisdexamfetamine dimesylate, which consists of L-lysine covalently bound to D-amfetamine, is the first prodrug for treating ADHD. Its metabolic conversion to yield D-amfetamine by rate-limited, enzymatic hydrolysis is unusual because it is performed by peptidases associated with red blood cells. Other stimulants shown to be effective in managing ADHD include D-amfetamine, methylphenidate and modafinil. All have the potential for misuse or recreational abuse. The discriminative and reinforcing effects of these compounds were determined in rats using a 2-choice, D-amfetamine (0.5 mg/kg, i.p.)-cued drug-discrimination test, and by substitution for intravenous cocaine in self-administration. Lisdexamfetamine (0.5-1.5 mg/kg [D-amfetamine base], p.o.) generalised to saline when tested 15 min post-dosing, but dose-dependently generalised to d-amfetamine at 60 min. At 120 min, its D-amfetamine-like effects were substantially diminished. At 15 min, methylphenidate (3.0-10 mg/kg, p.o.) and D-amfetamine (0.1-1.5 mg/kg, p.o.) dose-dependently generalised to the intraperitoneal D-amfetamine cue. Switching to the intraperitoneal route reduced the interval required for lisdexamfetamine to be recognised as D-amfetamine-like, but did not alter its potency. Switching to intraperitoneal injection increased the potency of methylphenidate and D-amfetamine by 3.4× and 2.2×, respectively. Modafinil (50-200 mg/kg, i.p.) generalised partially, but not fully, to d-amfetamine. Methylphenidate (0.1, 0.3, 1.0 mg/kg/injection, i.v.) maintained robust self-administration at the 2 highest doses. Neither lisdexamfetamine (0.05, 0.15 or 0.5 mg/kg/injection [D-amfetamine base], i.v.) nor modafinil (0.166, 0.498 or 1.66 mg/kg/injection, i.v.) served as reinforcers. The results reveal important differences between the profiles of these stimulants. Lisdexamfetamine did not serve as a positive reinforcer in cocaine-trained rats, and although it generalised fully to D-amfetamine, its discriminative effects were markedly influenced by its unusual pharmacokinetics.
authors.affiliation: RenaSci Ltd, BioCity Nottingham, Pennyfoot Street, Nottingham NG1 1GF, UK. david.heal@renasci.co.uk
authors.forename: David J
authors.initials: DJ
authors.lastname: Heal
authors.forename: Niki W
authors.initials: NW
authors.lastname: Buckley
authors.forename: Jane
authors.initials: J
authors.lastname: Gosden
authors.forename: Nigel
authors.initials: N
authors.lastname: Slater
authors.forename: Charles P
authors.initials: CP
authors.lastname: France
authors.forename: David
authors.initials: D
authors.lastname: Hackett
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D000069478:Lisdexamfetamine Dimesylate; D008774:Methylphenidate / Q000494:pharmacology*; D000077408:Modafinil; D051381:Rats; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D001559:Benzhydryl Compounds; D008774:Methylphenidate; D003042:Cocaine; D000077408:Modafinil; D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine
keywords: ADHD; AMF; C(max); C-II; C-IV; CD; DAT; Discriminative effects; Drug discrimination; FR; IACUC; IR; Institutional Animal Care and Use Committee; Lisdexamfetamine; Methylphenidate; Modafinil; PET; PFC; Reinforcer; SAL; SR; Schedule 2 Controlled Drug; Schedule 4 Controlled Drug; Self-administration; amfetamine; attention deficit hyperactivity disorder; controlled drug; d-Amfetamine; dopamine reuptake transporter; fixed ratio; i.p.; i.v.; immediate release; intraperitoneal; intravenous; maximum plasma drug concentration; p.o.; per os (oral); positron emission tomography; prefrontal cortex; saline; sustained release; t(max); time to reach maximum plasma drug concentration