Evaluation of a pharmacokinetic hypothesis for reduced locomotor stimulation from methamphetamine and cocaine in adolescent versus adult male C57BL/6J mice

Abstract

Rationale: Adolescent mice display reduced locomotor stimulation to cocaine and amphetamine compared to adults, but the mechanisms are not known.

Objectives: The primary aim of the current study is to test a possible pharmacokinetic explanation for the attenuated locomotor stimulation seen in adolescents. A secondary aim is to extend the current literature for acute methamphetamine in adolescents.

Materials and methods: Male, adolescent (PN 30-35) and adult (PN 69-74) C57BL/6J mice were administered an intraperitoneal injection of cocaine (5, 15, 30 mg/kg) or methamphetamine (1, 2, 4 mg/kg) and euthanized 5, 10, 15, 30, 60, 120, or 240 min later. Home cage locomotor activity was recorded by video tracking, and drug concentration levels in brain and blood from the infraorbital sinus were measured using liquid chromatography combined with mass spectroscopy.

Results: Both methamphetamine and cocaine increased locomotor activity in a dose-response fashion, but the magnitude of the increase was less in adolescents than adults. Concentration of methamphetamine in the brain was similar between ages across time points. Concentration of cocaine in the brain was significantly higher in adolescents than adults at 5 min, but similar at all other time points.

Conclusions: Results suggest pharmacokinetics may make a small contribution to differential stimulation between adolescents and adult mice, but are unlikely the only factor. Developmental differences within the brain that effect pharmacodynamic properties of psychostimulants (e.g., number of receptor or transporters) represent alternatives.