Daily Monitoring of Dopamine Efflux Reveals a Short-Lasting Occlusion of the Dopamine Agonist Properties ofd-Amphetamine by Dopamine Transporter Blockers GBR 12909 and Methylphenidate

Abstract

In vivo brain microdialysis was used in conjunction with "reverse-dialysis" of the dopamine-transporter (DAT) blockers GBR 12909 and methylphenidate (MPH) to observe the temporal course of their effects on d-amphetamine (d-AMPH)-induced increases in dopamine (DA) efflux in the rat nucleus accumbens (NAc). Reverse-dialysis of d-AMPH (10 μM) for 30 min resulted in a 2000-2500% increase in DA efflux. Pretreatment with GBR 12909 or MPH (20, 100 μM) for 90 min, which on their own elevated DA levels ∼2000-3000% above baseline values, dose-dependently occluded d-AMPH-evoked DA efflux. In GBR 12909-treated rats, basal levels of DA remained dramatically elevated at 24, 48, and 72 h following treatment, while levels in the MPH group returned back toward pretreatment values. Despite this contrast in basal DA efflux, the magnitudes of DA efflux evoked by a second exposure to d-AMPH were comparable in the two treatment groups. Together, these data support the development of DAT blockers as potential pharmacological interventions for the control of psychostimulant abuse. Furthermore, our data implicate DAT as a common site of action for both GBR 12909 and MPH, as well as d-AMPH.