Fluctuation of the dopamine uptake inhibition potency of cocaine, but not amphetamine, in CHO cells stably transfected with the dopamine transporter

Cocaine, amphetamines and other psychostimulants inhibit synaptic dopamine (DA) uptake by interfering with dopamine transporter (DAT) function. The resultant potentiation of dopaminergic neurotransmission is associated with psychostimulant addiction. We previously reported fluctuations in dopamine uptake inhibition potency (DUIP) at different cell passages (“low”, “medium” and “high”) of wild type (WT) DAT CHO cells for classical DAT blockers including cocaine and methylphenidate. In the present study, the DAT substrate D‐amphetamine did not display this DUIP fluctuation. For all drugs tested, no significant differences were observed in binding affinities at WT DAT (via displacement of [ 3 H]‐WIN 35,428) as a function of cell passage. DAT expression (reported by B max values) was subtly altered by cell passage, but DA turnover number was unaffected. It is currently unclear why DUIPs, but not apparent binding affinities, fluctuate for the classic DAT blockers, or why D‐amphetamine does not exhibit this fluctuation. The fact that amphetamine diverges from this DAT blocker pharmacologic profile is consistent with the idea of fundamental differences between the mechanisms of abused psychostimulant DAT substrates and inhibitors. Funding was provided by NIDA grants DA16604 and DA16604‐01S1 (to C.K.S)