Fluctuation of the dopamine uptake inhibition potency of cocaine, but not amphetamine, at mammalian cells expressing the dopamine transporter.
Cocaine, amphetamines and other psychostimulants inhibit synaptic dopamine uptake by interfering with dopamine transporter (DAT) function. The resultant potentiation of dopaminergic neurotransmission is associated with psychostimulant addiction. Fluctuations in dopamine uptake inhibition potency (DUIP) were observed for classical DAT blockers including cocaine, mazindol, methylphenidate (Ritalintrade mark) and benztropine in CHO cells expressing wild type DAT; cocaine potency also decreased in DAT-expressing non-neuronal COS-7 cells and neuronal N2A neuroblastoma cells. In contrast, the DAT substrate (+)-amphetamine did not display this DUIP fluctuation. In parallel experiments, no fluctuation was observed for the apparent binding affinities of these 5 drugs. The DUIP decrease appeared to correlate with an increase in cell surface DAT expression level, as measured by B(max) values and confocal microscopy. The fact that the DUIP profile of amphetamine diverged from that of the classical DAT blockers is consistent with the idea of fundamental differences between the mechanisms of abused psychostimulant DAT substrates and inhibitors. Identification of the cellular factors that underlie the DAT inhibitor DUIP fluctuation phenomenon may be relevant to anti-psychostimulant drug discovery efforts.
Ukairo
Okechukwu T
OT
Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Mellon Hall, Room 453, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
Ramanujapuram
Suneetha
S
Surratt
Christopher K
CK
D000661:Amphetamine / Q000494:pharmacology*; D019969:Amphetamine-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001590:Benztropine / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D016466:CHO Cells; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008454:Mazindol / Q000494:pharmacology; D008774:Methylphenidate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D001590:Benztropine; D008774:Methylphenidate; D008454:Mazindol; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine