# Presentation: 453541

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

**Kathryn A. Cunningham, Ph.D.**

**Notes:**
Thank you, Betsy for organizing this panel. 

## What isTranslational Research? 

**Notes:**
Thank you, Betsy for organizing this panel. 

**Science**
**Advances**

**Improved**
**Health**

## What isn’tTranslational Research? 

**Notes:**
Thank you, Betsy for organizing this panel. 

## What Happens in Vegas
Stays in Vegas

**What Happens in Vegas**
**Stays in Vegas**

**Notes:**
The ultimate aim is to overexpress 5-HT2AR in the VTA to establish whether this receptor controls expression of normal behavior in the adult rat and whether such overexpression is associated with enhanced responses to cocaine or other stimulants. 

## What happens in the lab stays in the lab

What happens in the clinic stays in the clinic

**What happens in the clinic stays in the clinic**

**What **_**isn’t **_**Translational Research?**

**Notes:**
The ultimate aim is to overexpress 5-HT2AR in the VTA to establish whether this receptor controls expression of normal behavior in the adult rat and whether such overexpression is associated with enhanced responses to cocaine or other stimulants. 

## 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**

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

**Notes:**
Thank you, Betsy for organizing this panel. 

## 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

**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?**

**Notes:**
The ultimate aim is to overexpress 5-HT2AR in the VTA to establish whether this receptor controls expression of normal behavior in the adult rat and whether such overexpression is associated with enhanced responses to cocaine or other stimulants. 

## Nature (genetics)

**Nature (genetics)**
**Nurture (environment)**

**Strengthen reinforcing effects of non-drug reinforcers**

**Strengthen inhibitory control**

**Block conditioned memories (craving)**

**Counteract stress  that leads to relapse**

**Adapted from Volkow 2005**

**Addiction as a Brain Disease:**
**Poslated Means to Prevent Relapse **

## Medications for Adjunctive Therapy in Addiction

| Alcoholism | Disulfiram (Antabuse)
Acamprosate (Campral)
Naltrexone (Revia)
Topiramate (Topamax) |
| --- | --- |
| Nicotine | Buproprion (Zyban)
Varencicline (Chantix) |
| Opiates | Buprenorphine (Suboxone)
Methadone |
| Stimulants | ?? |

## % Drug Misuse and Abuse ED Visits 2004

**% Drug Misuse and Abuse ED Visits 2004**

## Serotonin

**Nature (genetics)**
**Nurture (environment)**

**Strengthen reinforcing effects of non-drug reinforcers**

**Strengthen inhibitory control**

**Block conditioned memories (craving)**

**Counteract stress  that leads to relapse**

**Adapted from Volkow 2005**

**Serotonin**

**Addiction as a Brain Disease:**
**Poslated Means to Prevent Relapse **

## Cocaine: Inhibit Reuptake in vitroIC50 (M); Koe 1976

## Serotonin Receptor Subtypes

**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**

## 5-HT2 Receptor Signaling

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

## Preclinical Evidence Serotonin in Addictive Processes

**Notes:**
Thank you, Betsy for organizing this panel. 

## Prominent Rodent Addiction Models

| Assay | Measure of |
| --- | --- |
| Hyperactivity | Motor activity controlled by “reward circuit; easily measured |
| Drug discrimination  | Recognition, “subjective” effects; centrally mediated |
| Self administration | Reinforcing effects; motivation to take |
| Drug-evoked reinstatement | Drug-seeking; “relapse” |
| Cue-evoked reinstatement | Drug-seeking, “relapse” |
| Conditioned place preference | “Rewarding” effects; environmental cues under no-drug conditions |
| Conditioned locomotion  | Environmental cues under no-drug conditions |

**Prominent Rodent Addiction Models**

**Notes:**
A considerable amount of data has accumulated to suggest that manipulations of 5-HT2 receptors controls expression of stimulant induced behaviors.

## Systemic Administration of 5-HT2R Ligands: Rodent Addiction Models (Cocaine)

| Behavior | 5-HT2AR |  | 5-HT2CR |  |
| --- | --- | --- | --- | --- |
|  | Agonist | Antagonist | Agonist | Antagonist |
| Hyperactivity |  |  |  |  |
| Drug discrim. |  |  |  |  |
| Self-Admin |  | NE |  |  |
| Coc reinstate |  |  |  |  |
| Cue reinstate |  |  |  |  |
| CPP (acq, express) |  |  |  |  |
| Conditioned hyperactivity (expression) |  |  |  |  |

**From laboratories of Cunningham; Fletcher; Neisewander**

## 5-HT2AR Antagonist M100907 Blocks Cocaine Hyperactivity

**+ Cocaine ****(10 mg/kg)**

**Cocaine ****(10 mg/kg)**

**5-HT****2A****R Antagonist M100907 *****Blocks***** Cocaine Hyperactivity**

**Producer and Director: P. Frankel**

**Notes:**
Paul Frankel took these explanatory movies for me.

## Self-Administration: Animal Model of 

** ****Drug + Cues**

**Handling**
**Surgery**
**Recovery**

**Acquisition**
**Maintenance**
**“****Drug-Taking”**

**Reinstatement**
**no drug SA**
**“****Drug-Seeking”**

**Self-Administration: Animal Model of **
**Drug-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**

## Acquisition of Cocaine Self-Administration (0.75 mg/kg/0.1ml; n=16)

**Nic Dhonnchadha and Cunningham 2007**

## Extinction (n=16) of CocaineSelf-Administration (0.75 mg/kg/0.1 ml)

## 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**

## Cue-evoked Reinstatement:

**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**

## Doses of M100907 and MK 212: Few Effects on Basal Activity

## Therapeutic Potential:

| Block rat Behavior | Block human behavior? | Therapeutic
Utility? |
| --- | --- | --- |
| Hyperactivity stimulus effects | Intoxication, subjective effects | Block “euphoria”  |
| Self administration | Reinforcing effects | Block “reward”  |
| Cue-evoked reinstatement | Drug-seeking, “relapse” | Enhance control over relapse cues, craving  |

**Therapeutic Potential:**
**5-HT****2A****R Antagonist+5-HT****2C****R Agonist**

**Notes:**
A considerable amount of data has accumulated to suggest that manipulations of 5-HT2 receptors controls expression of stimulant induced behaviors.

## Nature (genetics)

**Nature (genetics)**
**Nurture (environment)**

**Strengthen reinforcing effects of non-drug reinforcers**

**Strengthen inhibitory control**

**Block conditioned memories (craving)**

**Counteract stress  that 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 Relapse **

## Selective 5-HT2AR Antagonist + 5-HT2CR Agonist

**Identify medication**

**Assess in clinical trials**

**Approval for indication**

**Improve lives**

**Use in clinical practice**

**Notes:**
The overall picture of protein signature discovery pathway. I will do step 1 and 2, step 3, 4 and 5 is my specific aim 3 in the proposal, but I may not be able to get to that point by Aug. 

## Clinical Potential for Selective 5-HT2R Ligands

| 5-HT2AR Antagonists | Phase | Indication |
| --- | --- | --- |
|     Sarpogrelate | Launched(Japan)  | Pain, brain injury, vascular disease |
|     Eplivanserin | Phase II | Anxiety, depression, psychosis |
|     M 100907 |  | Sleep disorders |
|     SUN C5147 | Phase II | Neurodegeneration |
| 5-HT2CR Agonists |  | Indication |
|    BVT 933 | Phase II | Obesity |
|    WAY 161503  | Pre-clinical | Anxiety, depression, neuroendocrine disorders, obesity   |

## 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**

## 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 with 5-HT****2C****R agonist ****(Cunningham, Grabowski, Moeller)**
**Alter reward/reinforcement**
**Enhance inhibitory control**
**Interfere with specific drug memories**

**Novel Drugs:**
**UTMB, UI, Wyeth**

**Preclinical:**
**UTMB**

**Translational Research:****5-HT****2****R Ligands in Stimulant Addiction**

**Clinical Trials:**
**UTHSC-H **
**UTMB**

**Notes:**
As previously mentioned, we want to identify these neuroadaptations by investigating mRNA changes 

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

**Communication**
**Integration of environments**
**Crossover technologies**
**Respect for individual strengths and weaknesses**

**Translational Research in Addiction Neurobiology**

**Notes:**
The ultimate aim is to overexpress 5-HT2AR in the VTA to establish whether this receptor controls expression of normal behavior in the adult rat and whether such overexpression is associated with enhanced responses to cocaine or other stimulants. 

## 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 **

## Citalopram Decreases Cocaine+ Urines in Outpatient Trials: Impulsive Endophenotype

**Citalopram is an**
**SSRI and 5-HT****2C****R Agonist**

**Project 1**

## 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**

## 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**

## Bivalent 5-HT2AR antagonist + 5-HT2CR 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 CHO cells *****in vitro***** (Herrick-Davis, 2006)**
**Heterodimer of two molecules with selectivity as 5-HT****2A****R antagonist plus 5-HT****2C****R agonist**

**Project 3**

## 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

**Need intellectual infrastructure**
**Address shared questions, issues **
**A selective 5-HT****2A****R antagonist/ 5-HT****2C****R agonist might provide therapeutic advantage**
**Translate this knowledge into new  strategies to enhance abstinence**

**Take Home Message**

**Notes:**
The ultimate aim is to overexpress 5-HT2AR in the VTA to establish whether this receptor controls expression of normal behavior in the adult rat and whether such overexpression is associated with enhanced responses to cocaine or other stimulants. 

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

_**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**

## Acknowledgements

**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**

**Supported by NIDA DA06511, DA13595, DA00260, DA07287**

_**UTMB Genomics and Bioinformatics**_
**Tom Wood**
**Michele Guineuax**
**Emily Welch**
**Bruce Luxon**
**Mala Sinha**

_**UTMB Proteomics**_
**Alex Kurosky**
**Kizhake Soman**