Abstract

The dopamine transporter (DAT) has been identified as the principal brain receptor site best correlated with the rewarding and euphoric properties of cocaine. Euphoric responses to rapid administration of cocaine can be much more prominent than those that follow slower rates of administration. In previous FYs, investigators in this Branch have found that activators of protein kinase C (PKC) modulate dopamine transport in transiently-expressing COS cells (Eur. J. Pharmacol., 268, 115-119). In this FY, we have begun to explore the extent to which direct phosphorylation of the DAT may produce the sorts of acute adaptations that could yield differing responses to rapid and slow rates of transporter occupancy. We have replicated effects of PKC activators in LLC-PK1 cells that stably express DAT, and used specific anti-DAT antisera developed in previous FYs to immunoprecipitate phosphor-DAT from striatal slice and stably transfected cell preparations. Initial evidence suggests that PKC activation does enhance levels of DAT phosphorylation, and thus increases evidence for phosphorylation as a candidate mechanism for rapid adaptations in dopaminergic systems relevant to cocaine-induced euphoria.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000076-04
Application #
5201642
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1995
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