Translational Research in Addiction Neurobiology:

Lessons from the World of Serotonin

Kathryn A. Cunningham, Ph.D.

What isTranslational Research?

ScienceAdvances

ImprovedHealth

What isn’tTranslational Research?

What Happens in VegasStays in Vegas

What happens in the lab stays in the lab

What happens in the clinic stays in the clinic

What isn’t Translational Research?

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)

• 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?

Nature

(gen

etic

s)

Nature

(gen

etic

s)

Nurture

(envi

ronm

ent)

Nurture

(envi

ronm

ent)

Strengthen reinforcing effects of non-drug reinforcers

Strengthen reinforcing effects of non-drug reinforcers

Strengthen inhibitory control

Strengthen inhibitory control

Block conditioned memories (craving)

Block conditioned memories (craving)Counteract stress

that leads to relapse

Counteract stress that leads to

relapse

Addicted Brain

DriveDriveReward

Saliency

MemoryMemory

ControlControl

Adapted from Volkow 2005Adapted from Volkow 2005

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

SAMHSA, Drug Abuse Warning Network, 2006 (https://dawninfo.samhsa.gov/pubs/edpubs/)

% Drug Misuse and Abuse ED Visits 2004

Nature

(gen

etic

s)

Nature

(gen

etic

s)

Nurture

(envi

ronm

ent)

Nurture

(envi

ronm

ent)

Strengthen reinforcing effects of non-drug reinforcers

Strengthen reinforcing effects of non-drug reinforcers

Strengthen inhibitory control

Strengthen inhibitory control

Block conditioned memories (craving)

Block conditioned memories (craving)Counteract stress

that leads to relapse

Counteract stress that leads to

relapse

Addicted Brain

DriveDriveReward

Saliency

MemoryMemory

ControlControl

Adapted from Volkow 2005Adapted from Volkow 2005

Serotonin

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

Cocaine: Inhibit Reuptake in vitroIC50 (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 Activity in vivoED50 (mg/kg, iv)

Cunningham & Lakoski 1988;Einhorn et al. 1988; Pitt & Marwah 1987

Serotonin Receptor Subtypes

5-HT3

5-HT6

5-HT4

5-HT7

5-HT5A

5-HT1A

5-HT1B

5-HT5B

5-HT1D

5-HT1E

5-HT1F

5-HT2B

5-HT2C

5-HT2A

5-HT2 Receptor Signaling

Implicated in:–Addiction–Anorexia–Anxiety–Depression –Hallucinations

– Impulsivity–Movement–Psychosis–Stress sensitivity

Preclinical Evidence

Serotonin in Addictive Processes

Assay Measure ofHyperactivity 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

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

Behavior 5-HT2AR 5-HT2CRAgonist 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

M100907 (1 mg/kg)+ Cocaine (10 mg/kg)

Cocaine (10 mg/kg)

5-HT2AR Antagonist M100907 Blocks Cocaine Hyperactivity

Producer and Director: P. FrankelProducer and Director: P. Frankel

• Drug + Cues

HandlingSurgery

Recovery

AcquisitionMaintenance

“Drug-Taking”

Reinstatementno 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

Extinctionor

Withdrawal

• Lever press• No drug

Pix from Carrasquillo and Sweatt 2005

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

Training days

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Mea

n T

ota

l Lev

er

Pre

sses

/2 h

r (+

SE

M)

0

20

40

60

80

100

120

140

160

180

Mean

To

tal Infu

sion

s/2 hr (+

SE

M)0

20

40

60

80Active Lever PressesInactive Lever PressesInfusions

Nic

Dh

on

nch

adh

a an

d C

un

nin

gh

am 2

007

AcquisitionDrug + Cues

Extinction (n=16) of CocaineSelf-Administration (0.75 mg/kg/0.1 ml)

Extinction (Days)

0 2 4 6 8 10 12 14 16 18 20

Mea

n T

ota

l Lev

erP

ress

es/2

hr

(+ S

EM

)

0

20

40

60

80

100

120

Active Lever PressesInactive Lever Presses

Lever pressNo Drug

Cue-evoked Reinstatement:5-HT2AR Antagonist M100907 Suppresses

“Drug-Seeking”

Co

cain

e (0

.75

mg

/kg

/in

fusi

on

) A

fter

ext

inct

ion

Nic

Dh

on

nch

adh

a an

d C

un

nin

gh

am 2

007

ReinstatementCues Only

Cue-evoked Reinstatement:5-HT2CR Agonist MK 212 Suppresses

“Drug-Seeking”

Co

cain

e (0

.75

mg

/kg

/in

fusi

on

) A

fter

ext

inct

ion

Fo

x, N

ic D

ho

nn

chad

ha

and

Cu

nn

ing

ham

200

6

ReinstatementCues Only

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

0

150

300

450

600

MK0.1

VEH MK0.3

MK1

Ho

rizo

nta

l Dis

tan

ce T

rave

led

(cm

/60

min

)

5-HT2CR Agonist MK 212

MK2

*

0

150

300

450

600

M1000.02

VEH M1000.1

M1000.2

5-HT2AR Antagonist M 100907

MK0.1875

M1001

M1002

Block rat Behavior

Block human behavior?

TherapeuticUtility?

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-HT2AR Antagonist+5-HT2CR Agonist

Nature

(gen

etic

s)

Nature

(gen

etic

s)

Nurture

(envi

ronm

ent)

Nurture

(envi

ronm

ent)

Strengthen reinforcing effects of non-drug reinforcers

Strengthen reinforcing effects of non-drug reinforcers

Strengthen inhibitory control

Strengthen inhibitory control

Block conditioned memories (craving)

Block conditioned memories (craving)Counteract stress

that leads to relapse

Counteract stress that leads to

relapse

Addicted Brain

DriveDriveReward

Saliency

MemoryMemory

ControlControl

Adapted from Volkow 2005Adapted from Volkow 2005

5-HT2AR Antagonist+

5-HT2CR Agonist

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

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/reinforcementAlter reward/reinforcement– Enhance inhibitory controlEnhance inhibitory control– Interfere with specific drug memoriesInterfere with specific drug memories

Novel Drugs:UTMB, UI, Wyeth

Preclinical:UTMB

Translational Research:5-HT2R Ligands in Stimulant Addiction

Clinical Trials:UTHSC-H

UTMB

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

strengths and weaknesses

Translational Research in Addiction Neurobiology

Integrated Projects

Cellular & Molecular Biology Core BC.S. Watson, PI

J. A. Moron-Concepcion, Co-I

Project 1Clinical

Neurobiology of Serotonin and

AddictionF. G. Moeller, PI

Project 25-HT2R

Neurobiology in Animal Models of

Addictive BehaviorK. A. Cunningham, PI

Project 3Novel Probes for the

Study of 5-HT2R 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 anSSRI and 5-HT2CR Agonist

Pro

ject

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

Pro

ject

2

METH Self-Administration: Repeated Mirtazapine Suppresses Reinstatement

ME

TH

SA

(0

.1 m

g/k

g/in

fusi

on

; F

R5

Mir

taza

pin

e (5

mg

/kg

/day

fo

r 10

d

ays

)N

ap

ier,

Fo

x a

nd

Cu

nn

ing

ham

, 20

07

Pro

ject

2

Bivalent 5-HT2AR antagonist + 5-HT2CR Agonist

• 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

Pro

ject

3

• Translational research necessary• Need intellectual infrastructure• Address shared questions, issues • A selective 5-HTA selective 5-HT2A2AR antagonist/ 5-R antagonist/ 5-

HTHT2C2CR agonist might provide R agonist might provide

therapeutic advantagetherapeutic advantage• Translate this knowledge into new

strategies to enhance abstinence

Take Home Message

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

Graduate StudentsMarie Fe Lanfranco

Adriane dela Cruz

Erik Shank

TechniciansBob FoxSonja Stutz

Supported by NIDA DA06511, DA13595, DA00260, DA07287

AcknowledgementsCollaboratorsJohn Grabowski and F. Gerard

Moeller - UTHSC HoustonKelly Berg and Bill Clarke –

UTHSC San AntonioScott R. Gilbertson - UTMBMalgorzata Filip - Polish

Academy of PharmacologyAmar Natarjan – UTMBKenner Rice - NIDABryan Roth – Case WesternUmberto Spampinato -

University of Bordeaux

Supported by NIDA DA06511, DA13595, DA00260, DA07287

UTMB Genomics and BioinformaticsTom WoodMichele GuineuaxEmily WelchBruce LuxonMala Sinha

UTMB ProteomicsAlex KuroskyKizhake Soman