Translational Research in Addiction Neurobiology: Lessons from the World of Serotonin

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Translational Research in Addiction Neurobiology
Lessons from the World of Serotonin

• Kathryn A. Cunningham, Ph.D.

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What isTranslational Research?
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Science Advances
Improved Health
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What isntTranslational Research?
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• What Happens in Vegas
• Stays in Vegas

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What isnt Translational Research?

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

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Google SearchTranslational 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

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

• 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

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Addiction as a Brain Disease Poslated Means to
Prevent Relapse
Strengthen reinforcing effects of non-drug
reinforcers
Strengthen inhibitory control
Nature (genetics) Nurture (environment)
Block conditioned memories (craving)
Counteract stress that leads to relapse
Adapted from Volkow 2005
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Medications for Adjunctive Therapy in Addiction
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Drug Misuse and Abuse ED Visits 2004
SAMHSA, Drug Abuse Warning Network, 2006
(https//dawninfo.samhsa.gov/pubs/edpubs/)
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Addiction as a Brain Disease Poslated Means to
Prevent Relapse
Strengthen reinforcing effects of non-drug
reinforcers
Strengthen inhibitory control
Nature (genetics) Nurture (environment)
Block conditioned memories (craving)
Serotonin
Counteract stress that leads to relapse
Adapted from Volkow 2005
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Cocaine Inhibit Reuptake in vitroIC50 (mM) Koe
1976
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Serotonin Receptor Subtypes
5-HT2B
5-HT5B
5-HT2A
5-HT6
5-HT4
5-HT5A
5-HT2C
5-HT1D
5-HT1A
5-HT1F
5-HT7
5-HT3
5-HT1B
5-HT1E
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5-HT2 Receptor Signaling

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

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Preclinical Evidence Serotonin in Addictive
Processes
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Prominent Rodent Addiction Models
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Systemic Administration of 5-HT2R Ligands Rodent
Addiction Models (Cocaine)
From laboratories of Cunningham Fletcher
Neisewander
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5-HT2AR Antagonist M100907 Blocks Cocaine
Hyperactivity
M100907 (1 mg/kg) Cocaine (10 mg/kg)
Cocaine (10 mg/kg)
Producer and Director P. Frankel
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Self-Administration Animal Model of Drug-Taking
and Drug-Seeking Behavior
Days 21-31
Days 0-7
Days 8-21
Days 32-42
Handling Surgery Recovery
Acquisition Maintenance Drug-Taking
Reinstatement no drug SA Drug-Seeking
Extinction or Withdrawal

• Priming
• Lever Press for Cues

• Drug Cues

• Lever press
• No drug

Pix from Carrasquillo and Sweatt 2005
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Acquisition of Cocaine Self-Administration (0.75
mg/kg/0.1ml n16)
Nic Dhonnchadha and Cunningham 2007
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Extinction (n16) of CocaineSelf-Administration
(0.75 mg/kg/0.1 ml)
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Cue-evoked Reinstatement 5-HT2AR Antagonist
M100907 Suppresses Drug-Seeking
Cocaine (0.75 mg/kg/infusion) After
extinction Nic Dhonnchadha and Cunningham 2007
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Cue-evoked Reinstatement 5-HT2CR Agonist MK 212
Suppresses Drug-Seeking
Cocaine (0.75 mg/kg/infusion) After
extinction Fox, Nic Dhonnchadha and Cunningham
2006
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Doses of M100907 and MK 212 Few Effects on Basal
Activity
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Therapeutic Potential 5-HT2AR Antagonist5-HT2CR
Agonist
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Addiction as a Brain Disease Poslated Means to
Prevent Relapse
Strengthen reinforcing effects of non-drug
reinforcers
5-HT2AR Antagonist 5-HT2CR Agonist
Strengthen inhibitory control
Nature (genetics) Nurture (environment)
Block conditioned memories (craving)
Counteract stress that leads to relapse
Adapted from Volkow 2005
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Selective 5-HT2AR Antagonist 5-HT2CR Agonist
Identify medication
Assess in clinical trials
Approval for indication
Use in clinical practice
Improve lives
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Clinical Potential for Selective 5-HT2R Ligands
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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

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Translational Research5-HT2R Ligands in
Stimulant Addiction

• Drug discovery and preclinical development for
  unique 5-HT2R ligands (Gilbertson, Cunningham,
  Johnson, Natarajan)
• Clinical trials with 5-HT2CR agonist (Cunningham,
  Grabowski, Moeller)
• Alter reward/reinforcement
• Enhance inhibitory control
• Interfere with specific drug memories

Clinical Trials UTHSC-H UTMB
Novel Drugs UTMB, UI, Wyeth
Preclinical UTMB
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Translational Research in Addiction Neurobiology

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

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Integrated Projects
Project 1 Clinical Neurobiology of Serotonin and
Addiction F. G. Moeller, PI
Project 2 5-HT2R Neurobiology in Animal Models of
Addictive Behavior K. A. Cunningham, PI
Project 3 Novel Probes for the Study of 5-HT2R
Neurobiology S. R. Gilbertson, PI
Cellular Molecular Biology Core B C.S. Watson,
PI J. A. Moron-Concepcion, Co-I
Industry Partnerships Acadia Pharmaceuticals
Organix, Inc., Omeros Corporation Wyeth Research
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Citalopram Decreases Cocaine Urines in
Outpatient Trials Impulsive Endophenotype
Project 1
Citalopram is an SSRI and 5-HT2CR Agonist
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Stimulant Self-Adminstration Model in Rat
Project 2

• 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

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METH Self-Administration Repeated Mirtazapine
Suppresses Reinstatement
Project 2
METH SA (0.1 mg/kg/infusion FR5 Mirtazapine (5
mg/kg/day for 10 days) Napier, Fox and
Cunningham, 2007
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Bivalent 5-HT2AR antagonist 5-HT2CR Agonist
Project 3

• Low doses of a 5-HT2CR agonist plus 5-HT2AR
  antagonist may provide novel therapeutic approach
• 5-HT2AR and 5-HT2CR heterodimerize in CHO cells
  in vitro (Herrick-Davis, 2006)
• Heterodimer of two molecules with selectivity as
  5-HT2AR antagonist plus 5-HT2CR agonist

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Take Home Message

• Translational research necessary
• Need intellectual infrastructure
• Address shared questions, issues
• A selective 5-HT2AR antagonist/ 5-HT2CR agonist
  might provide therapeutic advantage
• Translate this knowledge into new strategies to
  enhance abstinence

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• Co-Investigators
• Patsy Seitz, Ph.D.
• Marcy Bubar, Ph.D.
• Brid Nic Dhonnchadha, Ph.D.
• Erin Stoffel, Ph.D.

Graduate Students Marie Fe Lanfranco Adriane dela
Cruz Erik Shank
Technicians Bob Fox Sonja Stutz
Supported by NIDA DA06511, DA13595, DA00260,
DA07287
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Acknowledgements

• Collaborators
• John Grabowski and F. Gerard Moeller - UTHSC
  Houston
• Kelly Berg and Bill Clarke UTHSC San Antonio
• Scott R. Gilbertson - UTMB
• Malgorzata Filip - Polish Academy of Pharmacology
• Amar Natarjan UTMB
• Kenner Rice - NIDA
• Bryan Roth Case Western
• Umberto Spampinato - University of Bordeaux

UTMB Genomics and Bioinformatics Tom Wood Michele
Guineuax Emily Welch Bruce Luxon Mala Sinha
UTMB Proteomics Alex Kurosky Kizhake Soman
Supported by NIDA DA06511, DA13595, DA00260,
DA07287
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