Tags

Type your tag names separated by a space and hit enter

Preference for distinct functional conformations of the dopamine transporter alters the relationship between subjective effects of cocaine and stimulation of mesolimbic dopamine.
Biol Psychiatry. 2014 Nov 15; 76(10):802-9.BP

Abstract

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.

Authors+Show Affiliations

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.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.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.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.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.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.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.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.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

24853388

Citation

Kohut, Stephen J., et al. "Preference for Distinct Functional Conformations of the Dopamine Transporter Alters the Relationship Between Subjective Effects of Cocaine and Stimulation of Mesolimbic Dopamine." Biological Psychiatry, vol. 76, no. 10, 2014, pp. 802-9.
Kohut SJ, Hiranita T, Hong SK, et al. Preference for distinct functional conformations of the dopamine transporter alters the relationship between subjective effects of cocaine and stimulation of mesolimbic dopamine. Biol Psychiatry. 2014;76(10):802-9.
Kohut, S. J., Hiranita, T., Hong, S. K., Ebbs, A. L., Tronci, V., Green, J., Garcés-Ramírez, L., Chun, L. E., Mereu, M., Newman, A. H., Katz, J. L., & Tanda, G. (2014). Preference for distinct functional conformations of the dopamine transporter alters the relationship between subjective effects of cocaine and stimulation of mesolimbic dopamine. Biological Psychiatry, 76(10), 802-9. https://doi.org/10.1016/j.biopsych.2014.03.031
Kohut SJ, et al. Preference for Distinct Functional Conformations of the Dopamine Transporter Alters the Relationship Between Subjective Effects of Cocaine and Stimulation of Mesolimbic Dopamine. Biol Psychiatry. 2014 Nov 15;76(10):802-9. PubMed PMID: 24853388.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preference for distinct functional conformations of the dopamine transporter alters the relationship between subjective effects of cocaine and stimulation of mesolimbic dopamine. AU - Kohut,Stephen J, AU - Hiranita,Takato, AU - Hong,Soo-Kyung, AU - Ebbs,Aaron L, AU - Tronci,Valeria, AU - Green,Jennifer, AU - Garcés-Ramírez,Linda, AU - Chun,Lauren E, AU - Mereu,Maddalena, AU - Newman,Amy H, AU - Katz,Jonathan L, AU - Tanda,Gianluigi, Y1 - 2014/04/19/ PY - 2013/08/07/received PY - 2014/03/08/revised PY - 2014/03/13/accepted PY - 2014/5/24/entrez PY - 2014/5/24/pubmed PY - 2015/7/28/medline KW - ADHD KW - benztropine analogs KW - cocaine discrimination KW - dopamine microdialysis KW - drug abuse and addiction KW - nucleus accumbens shell SP - 802 EP - 9 JF - Biological psychiatry JO - Biol. Psychiatry VL - 76 IS - 10 N2 - 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. SN - 1873-2402 UR - https://www.unboundmedicine.com/medline/citation/24853388/Preference_for_distinct_functional_conformations_of_the_dopamine_transporter_alters_the_relationship_between_subjective_effects_of_cocaine_and_stimulation_of_mesolimbic_dopamine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(14)00266-2 DB - PRIME DP - Unbound Medicine ER -