Preference for distinct functional conformations of the dopamine transporter alters the relationship between subjective effects of cocaine and stimulation of mesolimbic dopamine.
BACKGROUND
Subjective effects of cocaine are mediated primarily by dopamine (DA) transporter (DAT) blockade. The present study assessed the hypothesis that different DAT conformational equilibria regulate differences in cocaine-like subjective effects and extracellular DA induced by diverse DA-uptake inhibitors (DUIs).


METHODS
The relationship between cocaine-like subjective effects and stimulation of mesolimbic DA levels by standard DUIs (cocaine, methylphenidate, WIN35,428) and atypical DUIs (benztropine analogs: AHN1-055, AHN2-005, JHW007) was investigated using cocaine discrimination and DA microdialysis procedures in rats.


RESULTS
All drugs stimulated DA levels with different maxima and time courses. Standard DUIs, which preferentially bind outward-facing DAT conformations, fully substituted for cocaine, consistently producing cocaine-like subjective effects at DA levels of 100-125% over basal values, regardless of dose or pretreatment time. The atypical DUIs, with DAT binding minimally affected by DAT conformation, produced inconsistent cocaine-like subjective effects. Full effects were obtained, if at all, only at a few doses and pretreatment times and at DA levels 600-700% greater than basal values. Importantly, the linear, time-independent, relationship between cocaine-like subjective effects and DA stimulation obtained with standard DUIs was not obtained with the atypical DUIs.


CONCLUSIONS
These results suggest a time-related desensitization process underlying the reduced cocaine subjective effects of atypical DUIs that may be differentially induced by the binding modalities identified using molecular approaches. Since the DAT is the target of several drugs for treating neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder, these results help to identify safe and effective medications with minimal cocaine-like subjective effects that contribute to abuse liability.
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland.
Stephen J
SJ
Kohut
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland.
Takato
T
Hiranita
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Soo-Kyung
SK
Hong
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland.
Aaron L
AL
Ebbs
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland.
Valeria
V
Tronci
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland.
Jennifer
J
Green
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland; Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, México.
Linda
L
Garcés-Ramírez
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland.
Lauren E
LE
Chun
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland.
Maddalena
M
Mereu
Medicinal Chemistry Sections, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland; Medications Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland.
Amy H
AH
Newman
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland.
Jonathan L
JL
Katz
Psychobiology, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland; Medications Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland. Electronic address: gtanda@mail.nih.gov.
Gianluigi
G
Tanda
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine; D004298:Dopamine
ADHD; benztropine analogs; cocaine discrimination; dopamine microdialysis; drug abuse and addiction; nucleus accumbens shell