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  • 1. Translational Research in Addiction Neurobiology:Lessons from the World of Serotonin Kathryn A. Cunningham, Ph.D.

2. What is Translational Research? 3. Science Advances Improved Health 4. Whatisnt Translational Research? 5.

  • What Happens in Vegas
  • Stays in Vegas

6.

  • What happens in the lab stays in the lab
  • What happens in the clinic stays in the clinic

WhatisntTranslational Research? 7. Google Search: Translational Research

  • Clinical application of scientific research (bench to bedside)
  • Science required to develop clinical application from basic science discovery
  • Research to bring discovery directly from bench to applications in patients
  • Clinical research to apply basic research from genes, cells, or animals into diagnostic or therapeutic intervention

8. What is Translational Research in Addiction Neurobiology? Lessons from the World of Serotonin (from the perspective of a basic scientist) 9.

  • Infrastructure and environment
  • Facilitates complimentary, reciprocal, and synergistic interactions
  • Clinical research in human neurobiology, preclinical animal studies, molecular and cellular biology, and drug discovery initiatives
  • Facilitates training, career development
  • Exploits capabilities in multiple venues to directly examine question with the most appropriate procedures

What is Translational Research? 10. Nature (genetics) Nurture (environment) Strengthen reinforcing effects of non-drug reinforcers Strengthen inhibitory control Block conditioned memories (craving) Counteract stressthat leads to relapse Adapted from Volkow 2005 Addiction as a Brain Disease: Poslated Means to Prevent RelapseAddictedBrain Drive Reward Saliency Memory Control 11. Medications for Adjunctive Therapy in Addiction ?? Stimulants Buprenorphine (Suboxone) Methadone Opiates Buproprion (Zyban) Varencicline (Chantix) Nicotine Disulfiram (Antabuse) Acamprosate (Campral) Naltrexone (Revia) Topiramate (Topamax) Alcoholism 12. SAMHSA,Drug Abuse Warning Network , 2006 ( https:// dawninfo.samhsa.gov/pubs/edpubs / ) % Drug Misuse and Abuse ED Visits 2004 13. Nature (genetics) Nurture (environment) Strengthen reinforcing effects of non-drug reinforcers Strengthen inhibitory control Block conditioned memories (craving) Counteract stressthat leads to relapse Adapted from Volkow 2005 Serotonin Addiction as a Brain Disease: Poslated Means to Prevent RelapseAddictedBrain Drive Reward Saliency Memory Control 14. Cocaine: Inhibit Reuptakein vitro IC50 ( M); Koe 1976 NE DA 5-HT 0.27 1.7 0.85 NE DA 5-HT 0.5 2.2 0.6 Cocaine: Inhibition of Impulse Activityin vivo ED50 (mg/kg, iv) Cunningham & Lakoski 1988;Einhorn et al. 1988;Pitt & Marwah 1987 15. Serotonin Receptor Subtypes 5-HT 3 5-HT 6 5-HT 4 5-HT 7 5-HT 5A 5-HT 1A 5-HT 1B 5-HT 5B 5-HT 1D 5-HT 1E 5-HT 1F 5-HT 2B 5-HT 2C 5-HT 2A 16. 5-HT 2Receptor Signaling

  • Implicated in:
    • Addiction
    • Anorexia
    • Anxiety
    • Depression
    • Hallucinations
    • Impulsivity
    • Movement
    • Psychosis
    • Stress sensitivity

17. Preclinical EvidenceSerotonin in Addictive Processes 18. Prominent Rodent Addiction Models Environmental cues under no-drug conditions Conditioned locomotion Rewarding effects; environmental cues under no-drug conditions Conditioned place preference Drug-seeking; relapse Drug-evoked reinstatement Drug-seeking, relapse Cue-evoked reinstatement Reinforcing effects; motivation to take Self administration Recognition, subjective effects; centrally mediated Drug discriminationMotor activity controlled by reward circuit; easily measured Hyperactivity Measure of Assay 19. Systemic Administration of 5-HT 2 R Ligands: Rodent Addiction Models ( Cocaine ) From laboratories of Cunningham; Fletcher; Neisewander Conditioned hyperactivity(expression) Drug discrim. CPP(acq, express) Cue reinstate Coc reinstate Antagonist Agonist Antagonist Agonist NE Self-Admin Hyperactivity 5-HT 2C R 5-HT 2A R Behavior 20. M100907(1 mg/kg) + Cocaine(10 mg/kg) Cocaine(10 mg/kg) 5-HT 2A R Antagonist M100907BlocksCocaine Hyperactivity Producer and Director: P. Frankel 21.

  • Drug + Cues

Handling Surgery Recovery Acquisition Maintenance Drug-Taking Reinstatement no drug SA Drug-Seeking Self-Administration: Animal Model ofDrug-Taking and Drug-Seeking Behavior Days 0-7 Days 8-21 Days 32-42

  • Priming
  • Lever Press for Cues

Days 21-31 Extinction or Withdrawal

  • Lever press
  • No drug

Pix from Carrasquillo and Sweatt 2005 22. Acquisition of Cocaine Self-Administration (0.75 mg/kg/0.1ml; n=16) Nic Dhonnchadha and Cunningham 2007 Acquisition Drug + Cues 23. Extinction (n=16) of Cocaine Self-Administration (0.75 mg/kg/0.1 ml) Lever press No Drug 24. Cue-evoked Reinstatement: 5-HT 2A R Antagonist M100907 Suppresses Drug-Seeking Cocaine (0.75 mg/kg/infusion) After extinction Nic Dhonnchadha and Cunningham 2007 Reinstatement Cues Only 25. Cue-evoked Reinstatement: 5-HT 2C R Agonist MK 212 Suppresses Drug-Seeking Cocaine (0.75 mg/kg/infusion)After extinction Fox, Nic Dhonnchadha and Cunningham 2006 Reinstatement Cues Only 26. Doses of M100907 and MK 212: Few Effects on Basal Activity 27. Therapeutic Potential: 5-HT 2A R Antagonist+5-HT 2C R Agonist Enhance control over relapse cues, cravingBlock rewardBlock euphoriaTherapeutic Utility? Drug-seeking, relapse Cue-evoked reinstatement Reinforcing effects Self administration Intoxication, subjective effects Hyperactivity stimulus effects Block human behavior? Block rat Behavior 28. Nature (genetics) Nurture (environment) Strengthen reinforcing effects of non-drug reinforcers Strengthen inhibitory control Block conditioned memories (craving) Counteract stressthat leads to relapse Adapted from Volkow 2005 5-HT 2A R Antagonist + 5-HT 2C R Agonist Addiction as a Brain Disease: Poslated Means to Prevent RelapseAddictedBrain Drive Reward Saliency Memory Control 29. Selective 5-HT 2A R Antagonist + 5-HT 2C R Agonist Identify medication Assess in clinical trials Approval for indication Improve lives Use in clinical practice 30. Clinical Potential for Selective 5-HT 2 R Ligands Neurodegeneration Phase II SUN C5147 Pre-clinical Phase II Phase II Launched(Japan)Phase Anxiety, depression, psychosis Eplivanserin Anxiety, depression, neuroendocrine disorders, obesityWAY 161503Obesity BVT 933 Indication 5-HT 2C R Agonists Sleep disorders M 100907 Pain, brain injury, vascular disease Sarpogrelate Indication 5-HT 2A R Antagonists 31. Translational Research: Obstacles

  • No medication with appropriate profile
  • Need animal models that more directly model human condition
  • Addiction is an orphan disease
    • Industry not interested
  • Clinical research very expensive
  • How to establish proof of concept
  • Linkages with clinical scientists
  • Linkages with chemical biologists

32.

  • Drug discovery and preclinical development for unique 5-HT 2 R ligands(Gilbertson, Cunningham, Johnson, Natarajan)
  • Clinical trials with 5-HT 2C R agonist(Cunningham, Grabowski, Moeller)
    • Alter reward/reinforcement
    • Enhance inhibitory control
    • Interfere with specific drug memories

Translational Research: 5-HT 2 R Ligands in Stimulant Addiction Novel Drugs: UTMB, UI, Wyeth Preclinical: UTMB Clinical Trials: UTHSC-HUTMB 33.

  • New common language
  • Communication
  • Integration of environments
  • Crossover technologies
  • Respect for individual strengths and weaknesses

Translational Research in Addiction Neurobiology 34. Integrated Projects Cellular & Molecular Biology Core B C.S. Watson, PI J. A. Moron-Concepcion, Co-I Project 1 Clinical Neurobiology of Serotonin and Addiction F. G. Moeller, PI Project 2 5-HT 2 R Neurobiology in Animal Models of Addictive Behavior K. A. Cunningham, PI Project 3 Novel Probes for the Study of 5-HT 2 R Neurobiology S. R. Gilbertson, PI Industry Partnerships: Acadia Pharmaceuticals; Organix, Inc., Omeros Corporation; Wyeth Research 35. Citalopram Decreases Cocaine+ Urines in Outpatient Trials:Impulsive Endophenotype Citalopram is an SSRI and 5-HT 2C R Agonist Project 1 36. Stimulant Self-Adminstration Model in Rat

  • History of chronic stimulant SA
  • Withdrawal (forced abstinence)
  • Window during which reinstatement phenomena prominent (Shaham)
    • Cue-elicited drug-seeking (cue reactivity)
  • Reacquisition of drug-taking

Project 2 37. METH Self-Administration: Repeated Mirtazapine Suppresses Reinstatement METH SA (0.1 mg/kg/infusion; FR5 Mirtazapine (5 mg/kg/day for 10 days) Napier, Fox and Cunningham, 2007 Project 2 38. Bivalent 5-HT 2A R antagonist + 5-HT 2C R Agonist

  • Low doses of a 5-HT 2C R agonist plus 5-HT 2A R antagonist may provide novel therapeutic approach
  • 5-HT 2A R and 5-HT 2C R heterodimerize in C

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