This application for a NIDA Senior Scientist Award (K05) requests support for the candidate to pursue a multidisciplinary program focused on drug abuse research. The candidate's overall objectives are to investigate the molecular targets of psychostimulant drugs of abuse, the neuroadaptive mechanisms consequent to chronic drug exposure and to develop novel and effective medications for cocaine addiction. The dopamine transporter, a principal target of cocaine and amphetamine, is the major focus of the research. The research program is based on exciting leads generated over the previous project period and is supported by two grants from NIDA and two subcontracts. An ongoing objective is to investigate the therapeutic potential of novel cocaine agonists targeted to the dopamine transporter, with molecular, biochemical, behavioral and brain imaging techniques. Non-amines, and """"""""tropane horses"""""""" are a major focus of the medications development research. Non-amines bear no amine nitrogen in their structure yet retain the high affinity for the monoamine transporters and appropriate brain distribution, of their amine progenitors. """"""""Tropane horses"""""""" are a new class of compounds designed as cocaine antagonists. PET imaging of brain dopamine transporters will monitor dopamine transporter occupancy of candidate medications to establish drug doses that fully block access of cocaine to the transporter. Cell and molecular biology approaches will provide a mechanistic platform in support of our research. We will investigate the relevance of dopamine transporter gene polymorphisms to behavioral responses elicited by psychostimulants and the influence of polymorphisms on dopamine transporter density. Substrate or inhibitor induction of immediate early gene expression in cells transfected with the dopamine transporter will guide parallel investigation of neuroadaptive processes in pre-synaptic dopamine neurons. The research will be conducted in cell lines transfected with primate transporters and in non-human primates. This integrated research program will provide fundamental information on the neurobiological mechanisms underlying the behavioral effects of psychostimulants and candidate medications to treat cocaine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
5K05DA015305-02
Application #
6619351
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Hillery, Paul
Project Start
2002-08-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$116,251
Indirect Cost
Name
Harvard University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Madras, Bertha K; Compton, Wilson M; Avula, Deepa et al. (2009) Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later. Drug Alcohol Depend 99:280-95
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
Anderson, Carl M; Maas, Luis C; Frederick, Blaise deB et al. (2006) Cerebellar vermis involvement in cocaine-related behaviors. Neuropsychopharmacology 31:1318-26
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
Meltzer, Peter C; Butler, David; Deschamps, Jeffrey R et al. (2006) 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem 49:1420-32
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
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

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