Abstract

The dopamine transporter has been identified as the principal brain receptor site best correlated with the rewarding and euphoric properties of cocaine. We have continued studies using site-directed mutagenesis and molecular modelling and have pursued work with pharmacologic structure/activity studies. These joint strategies aim to identify specific amino acids within the dopamine transporter that are more important for cocaine analog binding than for dopamine uptake, and to identify compounds that could interact with these regions to provide dopamine-sparing cocaine antagonists. In this year we have further defined the nature of the interaction of cocaine with the dopamine transporter. We have used these data to define small molecule lead compounds that might interact with these transporter regions to provide dopamine-sparing cocaine antagonism. More complete understanding of the interactions of dopamine and cocaine with the dopamine transporter should lead to the elucidation of better pharmacological agents useful in the treatment of cocaine abuse.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000076-03
Application #
3752837
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Uchiumi, Osamu; Kasahara, Yoshiyuki; Fukui, Asami et al. (2013) Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine. Neuropharmacology 64:348-56
Seeman, Philip; Hall, Frank Scott; Uhl, George (2007) Increased dopamine D2High receptors in knockouts of the dopamine transporter and the vesicular monoamine transporter may contribute to spontaneous hyperactivity and dopamine supersensitivity. Synapse 61:573-6
Fukushima, Setsu; Shen, Haowei; Hata, Harumi et al. (2007) Methamphetamine-induced locomotor activity and sensitization in dopamine transporter and vesicular monoamine transporter 2 double mutant mice. Psychopharmacology (Berl) 193:55-62
Yamamoto, Hideko; Kamegaya, Etsuko; Hagino, Yoko et al. (2007) Genetic deletion of vesicular monoamine transporter-2 (VMAT2) reduces dopamine transporter activity in mesencephalic neurons in primary culture. Neurochem Int 51:237-44
Uhl, George (2007) Premature poking: impulsivity, cocaine and dopamine. Nat Med 13:413-4
Numachi, Yohtaro; Ohara, Arihisa; Yamashita, Motoyasu et al. (2007) Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters. Eur J Pharmacol 572:120-8
Dar, Dalit E; Metzger, Thomas G; Vandenbergh, David J et al. (2006) Dopamine uptake and cocaine binding mechanisms: the involvement of charged amino acids from the transmembrane domains of the human dopamine transporter. Eur J Pharmacol 538:43-7
Yamashita, Motoyasu; Fukushima, Setsu; Shen, Hao-wei et al. (2006) Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology 31:2132-9
Drgon, Tomas; Lin, Zhicheng; Wang, Gene-Jack et al. (2006) Common human 5' dopamine transporter (SLC6A3) haplotypes yield varying expression levels in vivo. Cell Mol Neurobiol 26:875-89
Dar, Dalit E; Mayo, Cheryl; Uhl, George R (2005) The interaction of methylphenidate and benztropine with the dopamine transporter is different than other substrates and ligands. Biochem Pharmacol 70:461-9

Showing the most recent 10 out of 21 publications