The proposed research has two objectives, to define the molecular targets of cocaine in human brain and to use positron emission tomography (PET) in the preclinical evaluation of potential cocaine substitutes. Our first goal is to systematically characterize [3H]cocaine binding sites in human brain regions including the nucleus accumbens, striatum, locus coeruleus, hippocampus, and amygdala. The research motivated by three preliminary findings that merit further investigation; (1) Using ex vivo autoradiography, we identified a number of regions in nonhuman primate brain that accumulate high levels of {3H}cocaine after i.v. administration of trace or pharmacologically relevant doses. We will characterize sites in these regions with a view to determining their functional significance. (2) In human post-mortem control striata, cocaine binding sites labeled by [3H]WIN 35, 428 were associated with the dopamine transporter. In Parkinson's diseased striata, [3H]WIN 35,428 binding sites differed from the dopamine transporter. We will compare sites labeled by [3H]WIN 35, 438 in these populations, with a view to assessing their relevance to the reinforcing properties of cocaine. (3) Preliminary data suggest that cocaine is metabolized more rapidly in the substantia nigra/ventral tegmental area of nonhuman primate brain than the striatum and we will extend these studies to human brain. Our second goal is focused on developing PET imaging techniques in nonhuman primate brain (Macaca fascicularis) to identify potential cocaine therapeutic agents. We will use positron emission tomography (PET) to image in vivo the direct (monoamine transporters) and indirect (D1 dopamine receptors) targets of cocaine in brain. Our objectives are to identify and to synthesize cocaine congeners with a view to developing high affinity long-acting cocaine substitutes. Their occupancy of the dopamine transporter will be measured by PET using [11C]WIN 35, 428 and occupancy of a broader spectrum of cocaine binding sites will be detected by the relatively non-selective cocaine congener [11C]CDCT. Candidate compounds will include high affinity long-acting dopamine transport inhibitors, novel cocaine congeners synthesized as a component of this program, and D1 dopamine receptor agonists. Occupancy of the D1 receptor will be measured by [11C]SCH 39166. We will evaluate dopamine transporter ligands (indirect dopamine agonists) and extend these studies to potent dopamine agonist drugs targeted to D1 dopamine receptors. This approach will provide fundamental information on [3H]cocaine binding sites in human brain tissue and utilize brain imaging techniques for identifying potential cocaine therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA009462-01
Application #
2122715
Study Section
Special Emphasis Panel (SRCD)
Project Start
1994-09-30
Project End
1999-08-31
Budget Start
1994-09-30
Budget End
1995-08-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Madras, Bertha K; Fahey, Michele A; Miller, Gregory M et al. (2003) Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors. Eur J Pharmacol 479:41-51
Meltzer, Peter C; Blundell, Paul; Zona, Thomas et al. (2003) A second-generation 99m technetium single photon emission computed tomography agent that provides in vivo images of the dopamine transporter in primate brain. J Med Chem 46:3483-96
Meschler, J P; Howlett, A C; Madras, B K (2001) Cannabinoid receptor agonist and antagonist effects on motor function in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated non-human primates. Psychopharmacology (Berl) 156:79-85
Miller, G M; Yatin, S M; De La Garza 2nd, R et al. (2001) Cloning of dopamine, norepinephrine and serotonin transporters from monkey brain: relevance to cocaine sensitivity. Brain Res Mol Brain Res 87:124-43
Goulet, M; Madras, B K (2000) D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated monkeys. J Pharmacol Exp Ther 292:714-24
Meltzer, P C; Blundell, P; Huang, H et al. (2000) 3-Aryl-2-carbomethoxybicyclo[3.2.1]oct-2-enes inhibit WIN 35,428 binding potently and selectively at the dopamine transporter. Bioorg Med Chem 8:581-90
De La Garza 2nd, R; Madras, B K (2000) [(3)H]PNU-101958, a D(4) dopamine receptor probe, accumulates in prefrontal cortex and hippocampus of non-human primate brain. Synapse 37:232-44
Morris, E D; Bonab, A A; Alpert, N M et al. (1999) Concentration of dopamine transporters: to Bmax or not to Bmax? Synapse 32:136-40
Seeman, P; Madras, B K (1998) Anti-hyperactivity medication: methylphenidate and amphetamine. Mol Psychiatry 3:386-96
Madras, B K; Gracz, L M; Meltzer, P C et al. (1998) Altropane, a SPECT or PET imaging probe for dopamine neurons: II. Distribution to dopamine-rich regions of primate brain. Synapse 29:105-15

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