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National Institute on Drug Abuse

1 Z01 DA000119-16 CBRB
Mechanisms Of Action Of Cocaine

Principal Investigator: Richard B Rothman, MD, PhD (CP, NIDA)
NIH Collaborators: Jean Lud Cadet, MD (MNB, NIDA)
Michael H Baumann, BS, MS, PhD (PP, NIDA)
Christina M Dersch, BS, MS (PP, NIDA)
John S Partilla, BS (PP, NIDA)
Kenner C Rice, PhD (NIDA)
Xiaoying Wang, PhD (PP, NIDA)
Extramural Collaborators: Bruce E Blough, PhD (Chemistry and Life Sciences, Research Triangle Institute International)
Nancy Mello, PhD (Alcohol and Drug Abuse Center, McLean Hospital/Harvard University)
Steve Negus, PhD (Alcohol and Drug Abuse Center, McLean Hospital/Harvard University)
Bryan Roth, M.D., Ph.D. (Department of Pharmacoogy, University of North Carolina Chapel Hill Medical School)
Dean F Wong, MD, PhD (Department of Radiology and Radiological Science, Johns Hopkins Hospital)
 from October 01, 2006 to September 30, 2007
Human subject research: Neither Human Subjects nor Human Tissues
Total Staff Years:0.3
Keywords:cocaine, phentermine, fenfluramine, addiction, ligand binding, drug devleopment, HIV, AIDS
Goals and Objectives:The overarching goal of this project is to study the effects of stimulant drugs (cocaine, methamphetamine, MDMA) on brain, and, using this knowledge, to help develop new medications to treat stimulant addiction. Towards this end, we are developing novel non-amphetamine drugs that release neuronal dopamine and serotonin. These dual DA/5-HT releasing agents have are non-stimulants, yet decrease drug self-administration.
Summary:The Clinical Psychopharmacology Section conducts preclinical and clinical research into the mechanisms of action of cocaine. A major component of this project, conducted in collaboration with investigators at NIDDK is the synthesis and evaluation of potential treatment medications for cocaine addiction. The strong association of high risk behaviors related to the spread of HIV with cocaine addiction makes the effort to develop cocaine treatment medications highly related to the fight against AIDS. In this fiscal year we continued the effort to develop analogs of GBR12909 as putative cocaine antagonists or cocaine substitution- type medications. Previous studies in Rhesus monkeys showed that daily administration of GBR12909 and a long-acting ester derivative of GBR12909 1-2-Bis(4-fluorophenyl)methoxyethyl-4- (3-hydroxy-3-phenylpropyl)piperaziny decanoate suppresses cocaine self-administration without the development of tolerance. A single administration of this agent almost eliminated cocaine self-administration in Rhesus monkeys for one month. Other efforts demonstrated that the clinically available dopamine releaser, phentermine, decreased cocaine self-administration in Rhesus monkeys. A particularly important study demonstrated that administration of medications which increase both synaptic DA and 5-HT have no abuse liability yet decrease cocaine self- administration. Other efforts involve antagonists of the serotonin 4 receptor (5-HT4) as potential treatments of cocaine- induced cardiac arrhythmia. An important study demonstrated that a high affinity ligand for all three biogenic amine transporters blocks the ability of methamphetamine to release DA, 5-HT and NE. Clinical and laboratory experiments continued to demonstrate robust changes in the serotonergic systems during cocaine withdrawal. These results support the hypothesis that cocaine withdrawal is associated with a dual deficit of dopamine and serotonin and provide a strong rationale for the treatment of cocaine addiction with medications which affect both neurotransmitters.
Publications generated by this research:
  1. Baumann MH, Wang X, Rothman RB (2007) 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings. Psychopharmacology (Berl) 189:407-24. PubMed -- Full Text (PubMed Central)
  2. Boos TL, Greiner E, Calhoun WJ, Prisinzano TE, Nightingale B, Dersch CM, Rothman RB, Jacobson AE, Rice KC (2006) Structure-activity relationships of substituted N-benzyl piperidines in the GBR series: Synthesis of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piperidine, an allosteric modulator of the serotonin transporter. Bioorg Med Chem 14:3967-73. PubMed
  3. Ghitza UE, Rothman RB, Gorelick DA, Henningfield JE, Baumann MH (2007) Serotonergic responsiveness in human cocaine users. Drug Alcohol Depend 86:207-13. PubMed
  4. Gilbert KM, Boos TL, Dersch CM, Greiner E, Jacobson AE, Lewis D, Matecka D, Prisinzano TE, Zhang Y, Rothman RB, Rice KC, Venanzi CA (2007) DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods. Bioorg Med Chem 15:1146-59. PubMed
  5. Gilbert KM, Boos TL, Dersch CM, Greiner E, Jacobson AE, Lewis D, Matecka D, Prisinzano TE, Zhang Y, Rothman RB, Rice KC, Venanzi CC (2007) DAT SERT selectivity of flexible GBR 12909 analogs modeled sing 3D-QSAR methods. Bioorg. Med. Chem. 15:1146-1159.
  6. Greiner E, Boos TL, Prisinzano TE, De Martino MG, Zeglis B, Dersch CM, Marcus J, Partilla JS, Rothman RB, Jacobson AE, Rice KC (2006) Design and synthesis of promiscuous high-affinity monoamine transporter ligands: unraveling transporter selectivity. J Med Chem 49:1766-72. PubMed
  7. Halladay AK, Wagner GC, Sekowski A, Rothman RB, Baumann MH, Fisher H (2006) Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan. Synapse 59:277-89. PubMed
  8. Hiebel A, Partilla JS, Rothman RB, Jacobson AE, Rice KC (2006) Synthesis of 3H4-Ethyl2,5,6-trimethyl-7-(2,4,6,-trimethylphenyl)pyrrolo2,3-dpyrimidin-4-ylaminobutanol: a high affinity radioligand for the corticotropin-releasing hormone type 1 receptor. J. Labeled Comp. and Radiopharmaceuticals 49:635-40.
  9. Kulkarni SS, Nightingale B, Dersch CM, Rothman RB, Newman AH (2006) Design and synthesis of noncompetitive metabotropic glutamate receptor subtype 5 antagonists. Bioorg Med Chem Lett 16:3371-5. PubMed
  10. Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB (2007) Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate agonist medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. J Pharmacol Exp Ther 320:627-36. PubMed
  11. Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, Rothman RB (2006) Interaction of amphetamines and related compounds at the vesicular monoamine transporter. J Pharmacol Exp Ther 319:237-46. PubMed
  12. Rothman RB, Baumann MH (2006) Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs. Ann N Y Acad Sci 1074:245-60. PubMed
  13. Rothman RB, Baumann MH (2006) Therapeutic potential of monoamine transporter substrates. Curr Top Med Chem 6:1845-59. PubMed
  14. Rothman RB, Blough BE, Baumann MH (2006) Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction. Trends Pharmacol Sci 27:612-8. PubMed
  15. Rothman RB, Blough BE, Baumann MH (2007) Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions. AAPS J 9:E1-10. PubMed
  16. Wang X, Baumann MH, Dersch CM, Rothman RB (2007) Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT depletion by the administration of l-5-hydroxytryptophan. Neuroscience 148:212-20. PubMed
  17. Young R, Rothman RB, Rangisetty JB, Partilla JS, Dukat M, Glennon RA (2006) TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo4,5-gisoquinoline) inhibits the consumption of snacks in mice. Pharmacol Biochem Behav 84:74-83. PubMed
  18. Zolkowska D, Rothman RB, Baumann MH (2006) Amphetamine analogs increase plasma serotonin: implications for cardiac and pulmonary disease. J Pharmacol Exp Ther 318:604-10. PubMed

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