Translational Research in Addiction Neurobiology:
description
Transcript of Translational Research in Addiction Neurobiology:
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