A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to d-amfetamine, methylphenidate and modafinil

•Discriminative and reinforcing effects of lisdexamfetamine (LDX) determined in rats.•LDX's unusual pharmacokinetics influence its ability to generalise to d-amfetamine.•LDX does not serve as a positive reinforcer in cocaine-trained rats.•LDX profiled against d-amfetamine, methylphenidate and modafinil.

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.