The overall goals of this project are to develop effective medications to treat cocaine addiction while concurrently investigating the biological basis for individual primate responses to candidate medications. The dopamine transporter, a principal target of cocaine, and transport inhibitors are the central focus of the research. With molecular, biochemical, behavioral and brain imaging techniques, we will assess the therapeutic potential of dopamine transport inhibitors. The research is based on exciting leads generated over the previous project period that evolved into four aims: 1. In pursuit of a cocaine antagonist, we developed a """"""""tropane horse"""""""", designed to react covalently with the dopamine transporter (DAT), block cocaine access to the transporter but spare dopamine transport. We will investigate this class of compounds and cocaine replacements in vitro and in behavioral paradigms to identify promising, leads. 2. In support of this goal, we will conduct PET imaging procedures to identify effective cocaine replacements and antagonists. PET imaging of the DAT with [11C]altropane will identify compounds that fully occupy the dopamine transporter (cocaine replacements) and others that block cocaine access to the DAT but do not modify extracellular dopamine levels (cocaine antagonist). 3. Monkeys display strikingly different responses to dopamine transport inhibitors that are inversely correlated with baseline levels of activity. PET imaging of the dopamine transporter and gencityping of the dopamine transporter gene will clarify the association between transporter density, activity levels, and polymorphisms in the dopamine transporter gene. 4. As pre-synaptic neuroadaption elicited by cocaine may contribute to the addictive process, the effects of chronic administration of select candidate medications on transporter density and dopamine release will be monitored by PET imaging and in post-mortem tissue. This integrated research pro-ram will further the development of candidate medications to treat cocaine addiction and provide fundamental information on the neurobiological mechanisms underlying the behavioral effects of psychostimulants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011558-07
Application #
6612882
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Kline, Richard
Project Start
1997-09-30
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
7
Fiscal Year
2003
Total Cost
$374,943
Indirect Cost
Name
Harvard University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Verrico, Christopher D; Lynch, Laurie; Fahey, Michele A et al. (2008) MDMA-induced impairment in primates: antagonism by a selective norepinephrine or serotonin, but not by a dopamine/norepinephrine transport inhibitor. J Psychopharmacol 22:187-202
Verrico, Christopher D; Miller, Gregory M; Madras, Bertha K (2007) MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology (Berl) 189:489-503
Jassen, Amy K; Yang, Hong; Miller, Gregory M et al. (2006) Receptor regulation of gene expression of axon guidance molecules: implications for adaptation. Mol Pharmacol 70:71-7
Xiao, Danqing; Miller, Gregory M; Jassen, Amy et al. (2006) Ephrin/Eph receptor expression in brain of adult nonhuman primates: implications for neuroadaptation. Brain Res 1067:67-77
Madras, Bertha K; Fahey, Michele A; Goulet, Martin et al. (2006) Dopamine transporter (DAT) inhibitors alleviate specific parkinsonian deficits in monkeys: association with DAT occupancy in vivo. J Pharmacol Exp Ther 319:570-85
Madras, Bertha K; Xie, Zhihua; Lin, Zhicheng et al. (2006) Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther 319:561-9
Jassen, Amy K; Brown, Jeffrey M; Panas, Helen N et al. (2005) Variants of the primate vesicular monoamine transporter-2. Brain Res Mol Brain Res 139:251-7
Madras, Bertha K; Miller, Gregory M; Fischman, Alan J (2005) The dopamine transporter and attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1397-409
Yatin, Servet M; Miller, Gregory M; Madras, Bertha K (2005) Dopamine and norepinephrine transporter-dependent c-Fos production in vitro: relevance to neuroadaptation. J Neurosci Methods 143:69-78
Meltzer, Peter C; Pham-Huu, Duy-Phong; Madras, Bertha K (2004) Synthesis of 8-thiabicyclo[3.2.1]oct-2-enes and their binding affinity for the dopamine and serotonin transporters. Bioorg Med Chem Lett 14:6007-10

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