Stopping Cocaine Before It Gets to the Brain: New Frontiers in Treatment

Stopping cocaine before it gets to the brain: new frontiers in treatment

CELAC Symposium “Progress and Challenges in Scientific Research on Treatments, Pharmacological Strategies and Vaccines against Drug Addiction” Marilyn E. Carroll 1

Collaborators: Stephen Brimijoin 2, Yang Gao 2, Robin Parks 3, Natalie E. Zlebnik 1, Justin J. Anker 1

1Department of Psychiatry, University of Minnesota, Minneapolis, MN

2Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN

3Regenerative Medicine Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada

NIDA Tested Medications for Treatment of Cocaine Dependence

 Amantadine  Disulfiram  Lofexidine  Propanolol  Lys-dex  Divalproex  Lobeline  Reboxetine amphetamine  Dronabinol  LY544344  Risperidone  Aripriprazole*  Fluoxetine*  Mecamylamine  RTI compounds  Atomoxetine  Gabapentin  Memantine  Selegiline  Baclofen  GBR12909  Methamphetamine  Sertraline  Buprenorphine  GCP44352  Methylphenidate  Tiagabine  Bup/naloxone  Gammavinyl GABA  Methadone  Topiramate  Bupropion  Hydromorphone  Modafinil  Vigagatrin  Buspirone  LAAM  N-acetyl-aspartate  Venlafaxine  Clonidine  L-Dopa/Carbidopa  Naltrexone x 2  Yohimbine  DHEA  L-tryptophan  Olanzapine  … and More  Desipramine  Pergolide  d-Amphetamine  Progesterone  Dextrometorphan 3 studies of cocaine hydrolase (CocH) treatment to acutely block:

1. Cocaine self-administration (progressive ratio)

2. Cocaine escalation

3. Cocaine reinstatement

3 studies of CocH viral vector (VEC) treatment to chronically block:

1. Cocaine reinstatement

2. Cocaine-induced locomotor sensitization with cocaine vaccine (VAC)

3. Cocaine self-administration (VEC + VAC) 3 studies of cocaine hydrolase (CocH) treatment to acutely block:

1. Cocaine self-administration (progressive ratio)

2. Cocaine escalation

3. Cocaine reinstatement

3 studies of CocH viral vector (VEC) treatment to chronically block:

1. Cocaine reinstatement

2. Cocaine-induced locomotor sensitization with cocaine vaccine (VAC)

3. Cocaine self-administration (VEC + VAC) BChE - cocaine hydrolase (CocH) - genetically engineered from human BChE

A199S/F227A/S287G/A328W/Y332G

10000 F227AS/S287G/A328W/Y332A CocH

1000 cat A199S/S287G/A328W/Y332G 100

cocaine k cocaine A328W/Y332A 10

wild type BChE 1 1 2 3 4 5 (2002) (2003) (2004) (2008) Successive Mutation Generations Molecular interception by enzyme (“Pac-man model”) CocH drastically accelerates cocaine metabolism in rats unprotected subject

brain 2500 blood 2000 control rats

cocaine 1500 enzyme- 1000 enzyme-treated subject pretreated

500 plasmacocaine brain 0 0 30 60 90 120 blood

cocaine

Gao et al, Chemico-Biol. Interact. 2010 Brimijoin et al. Neuropsychopharmacol 33: 2715-2725, 2008 CocH rescues rats from cocaine-induced seizures

Brimijoin et al. Neuropsychopharmacol 33: 2715-2725, 2008

Locomotor activity apparatus

CocH prevents cocaine-induced locomotor activity in mice

40 No BChE Wildtype 30 CocH No Cocaine 20

Beam Crossings Beam 10

0 0 10 20 30 40 50 60 70 Time (min)

Brimijoin et al. Neuropsychopharmacol 33: 2715-2725, 2008 Cocaine hydrolase treatment requires enzyme activity to suppress cocaine-stimulation in mice Cholinesterase inhibitor, iso-OMPA, blocked enzyme activity inhibitor restores stimulation inhibitor alone - no effect in presence of enzyme

** ** 500 **

400 ** ** **

Distance 300 traveled

200 distance distance traveled 100

0 saline CocH CocH + control iso-OMPA iso-OMPA

cocaine Carroll et al., 2012 IV drug self-administration apparatus Phases of Drug Abuse Process

= 3 studies

Acquisition Short vs. Long Access Extinction Reinstatement

Drugs

Responding Sal

Operant Responding Operant Short Access

Time (~ 2 - 3 months)

Modified from de Vries (1998) and Ahmed and Koob (1998) Cocaine self-administration during short access (2 h) under a progressive-ratio (PR) schedule to assess motivation ** 15 b ** ** CocH enzyme (vs saline) ++ reduced PR performance ++ 12 ++ for 1 session

3 Mean Mean Infusions (±SEM)

0 0 (Sal) 2 1 4 Albu-CocH Dose (mg/kg) B D A B D A B D A Before, During, After CocH

Carroll et al. Psychopharmacology, 2011 Escalation of cocaine self-administration during long access (6 h) d

Saline or enzyme treatment 700 For first 7 days 2 mg/kg CocH 600 Saline # 500 ** # ** CocH enzyme (vs saline) increased 400 cocaine infusions for first 4 (of 7) days

300 # #

200 Mean Mean (±SEM) Infusions

100

0 0 3 6 9 12 15 18 21 Days

Carroll et al. Psychopharmacology, 2011 (S) Saline pretreatment (A) amphetamine priming injection priming amphetamine(A) pretreatment Saline (S) injection priming cocaine (C) pretreatmentEnzyme (E)

Mean (± SEM) Responses responseswith Reinstatement (relapse) enzymeCocH blocked acutely reinst. CocH

Brimijoin al. Neuropsychopharmacologyet 2008 after CocH after on reinst. on no effectno 4 days

3 studies of cocaine hydrolase (CocH) treatment to acutely block:

1. Cocaine self-administration (progressive ratio)

2. Cocaine escalation

3. Cocaine reinstatement

3 studies of CocH viral vector (VEC) treatment to chronically block:

1. Cocaine reinstatement

2. Cocaine-induced locomotor sensitization with cocaine vaccine (VAC)

3. Cocaine self-administration (VEC + VAC) Adenoviral gene delivery for long-term actions Hydrolase transduction raises cocaine-hydrolase activity in plasma up to 1,000,000-fold

10000 4500 units

1000

100

.1 CocE activityCocE (mU/ml)

.01 0.0045 units .001 1x 3x 5x 10x 5x Control CocE AME359 Year-long generation of CocH with helper-dependent

adenoviral vector (hdAD) by gene transfer

10 0 0 hdAD

10 0

10 (mU/ml) 1 first-generation vector

0. 1 injected enzyme cocaine hydrolase activity hydrolase cocaine

0. 0 1 0 10 0 20 0 30 0 40 0

days after injection

Ottawa, Mayo Gao and Brimijoin J Pharmacol Exp Ther 330:449-457, 2009 Gene transfer of hydrolase blocks fosB induction in neostriatum in rats given repeated cocaine treatment

MW 134 FosB 82

41 32

AME + C S + S E + C S + C CocH

0 saline onlysaline AME empty cocaine induction

Gao and Brimijoin J Pharmacol Exp Ther 330:449-457, 2009 Cocaine clearance in blood plasma in rats treated

2 weeks earlier with CocH vector or saline controls

Plasma cocaine minimal in CocH

vector-treated group Plasma cocaine (uM) cocaine Plasma

Anker et al., Biol. Psychiatry, 2011 CocH vector reinstatement procedure

1 injection of CocH vector or saline 1 day before extinction

P hase ACQ MAINT EXT Reinstatement (8) Protracted Reinstatement (days) (~10) (~10) (14) S C S C S C S A S C S C S C S C S C S C S C S C S A Dose C 0.4 mg/kg, i.v. C (5, 10, 15 ); A (2) C (10) C (10); A (2) (mg/kg, i.p.) Weeks N/A N/A 3 5 6 7 8 12 16 20 24 post vector

Blood draws for CocH levels weekly then monthly

Anker et al., Biol. Psychiatry, 2011 Maintenance Extinction

Males

Females

Anker et al. Biol. Psychiatry, 2011 Reinstatement after CocH vector (week 3) by cocaine priming dose

15 16 17 18 19 20 21 22 23 24 Days post CocH vector injection

Anker et al., Biol. Psychiatry, 2011 Reinstatement responding after CocH vector (weeks 5 - 8)

Control > CocH vector

Minimal responding on days of saline (S) or no priming injections (1-5)

Anker et al., Biol. Psychiatry, 2011 Active lever reinstatement responding

# * group differences (0.01, 0.05)

Anker et al., Biol. Psychiatry, 2011

Active lever reinstatement responding

# * group differences (0.01, 0.05)

CocH blood levels

(no differences across weeks)

SEM)

Mean ( Mean

CocH Vmax(mU/ml) CocH

Anker et al., Biol. Psychiatry, 2011 Active lever reinstatement responding Inactive lever responding - control for general # * group differences behavioral suppression

no group differences

Anker et al., Biol. Psychiatry, 2011 Active lever responding first 3 days after return to operant chamber for monthly reinstatement testing

* Day 1 > Days 2 and 3 no group differences

Anker et al., Biol. Psychiatry, 2011 Spontaneous locomotor behavior during 3 45 min sessions - - CocH vector vs control (no cocaine administered)

no group differences

CocH vector did not suppress locomotor activity.

Anker et al., Biol. Psychiatry, 2011 3 studies of cocaine hydrolase (CocH) treatment to acutely block:

1. cocaine self-administration (progressive ratio)

2. cocaine escalation

3. cocaine reinstatement

3 studies of CocH viral vector (VEC) treatment to chronically block:

1. cocaine reinstatement

2. cocaine-induced locomotor sensitization with cocaine vaccine (VAC)

3. Cocaine self-administration (VEC + VAC)

Enhanced interception with Enzyme & Vaccine brain unprotected subject blood

cocaine brain enzyme-treated blood

cocaine brain antibody-treated blood

cocaine brain enzyme plus antibody blood

cocaine

Locomotor activity apparatus

Each session = Saline - locomotor chamber (45 min) then cocaine (10 mg/kg) - locomotor chamber (45 min)

Day 8

Locomotor activity Sensitization Coc > Sal > V+V Day 1 vs 8

Control Yes Yes Yes

VAC Yes Yes blocked

VEC Yes Yes Yes

V + V blocked blocked

Carroll et al., 2012 Mean beam breaks over 45 min following cocaine injections across the 8 days of cocaine treatment

V + V > VAC, VEC, and Control in reducing locomotor behavior

Carroll et al., 2012 Challenge = saline or cocaine injected 15 days after the 8 treatment days

Day 24 Locomotor activity Sensitization Coc > Sal < Control Day 1 vs 23

Control Yes Yes

VAC Yes Yes blocked

VEC Yes Yes Yes

V + V Yes blocked Yes

Carroll et al., 2012 High dose cocaine in mice and VEC + VAC combinations Effect on locomotor behavior

100 mg/kg cocaine 120 mg/kg, divided (60) 10 min apart

CocH + VAC (AB) > VAC, CocH, SAL and Control in reducing locomotor behavior

Carroll et al., 2012 VEC + VAC effects on cocaine (0.4 mg/kg) self-administration during 2-hr sessions

NO TX VEC

Zlebnik et al., 2012 VEC + VAC effects on cocaine (0.4 mg/kg) self-administration during 2-hr sessions

NO NO TX VEC TX VEC VAC

Zlebnik et al., 2012

Summary

Cocaine abuse treatment model Treatment effect

Acute (repeated pre-session CocH) 2-hr self-administration PR schedule reduction 6-hr escalation FR 1 increase reinstatement reduction

Chronic (CocH vector - 1 injection) reinstatement 6-month reduction 2-hr self-administration FR 1 increase

VAC + CocH vector (V + V) Reduction up to 1 month locomotor activity V + V > VAC = VEC > Control locomotor sensitization V + V > VAC = VEC > Control 2-hr self-administration FR 1 VAC improved VEC treatment

Advantages - Disadvantages of CocH-based Treatments

CocH enzyme Advantages: Rescue for OD in ER Reduces motivation to take cocaine Blocks relapse

Disadvantages: Increases long-access self-administration 2-fold Blocks relapse to cocaine but not other drugs

Vector-delivered CocH enzyme Advantages: Blocks relapse 6 months or more Reduces cocaine sensitization which may be related to cocaine self-administration Adds to effects of VAC on sensitization and self-administration during short access FR 1

Disadvantage: Increases short-access self-administration Acknowledgements

Faculty collaborators: Thomas R. Kosten Baylor College of Medicine

Postdoctoral associates: Liyi Geng Mayo Clinic Justin Anker University of Minnesota

Undergraduate students: Alex Claxton University of Minnesota Seth Johnson “ Amy Saykao “

Enzyme development and biochemistry Liyi Geng, Molecular Pharmacology, Mayo Clinic, Rochester MN hdAD-Vector development Robin Parks, Ottawa Hospital Research Inst., Ottawa CN

Cocaine vaccine and antibody Frank Orson, VA Med Center, Houston TX Tom Kosten, Baylor College of Medicine, Houston TX Berma Kinsey, Baylor College of Medicine, Houston TX

This research was supported by NIDA Avant-Garde Award DP1 DA031340, Minnesota Partnership for Biotechnology and Medical Genomics, R01 DA023979, R01 DA023979S1 (SB; MEC-subcontractor) and K05 DA015267 (MEC). Additive effect of atomoxetine and wheel running access on cocaine-primed reinstatement in LoI > HiI rats

NO TX ATO only LoI > HiI

QuickTime™ and a decompressor are needed to see this picture. Wheel only Wheel + ATO

(Zlebnik and Carroll, in progress) Additive effect of wheel access + progesterone Males > females Cocaine Females Males ** * * * 25 ** ** & 20

10 &

Mean (± SEM) Responses SEM) (± Mean 0 LW W LW+P W+P LW W LW+P W+P

QuickTime™ and a decompressor are needed to see this picture. (Zlebnik and Carroll, in progress) Next Frontier…..

Deep Brain Stimulation (DBS) for Cocaine Addiction

Kenneth B. Baker1, Marilyn E. Carroll2

Wallin Foundation Grant, 2011 - 2012

1Department of Neurology, University of Minnesota, Minneapolis, MN 2Department of Psychiatry, University of Minnesota, Minneapolis, MN

Left and right DBS leads implanted in the region of the NA superimposed on MRI. VTAs are shown in orange

A schematic of the scaled DBS lead with 4 contacts Results of DBS with drug-rewarded behavior in rats

Target Drug reinforcer - Task Effect Authors NAcc shell vs Cocaine Shell: reinstatement Vassoler et al. 2008 dorsal striatum Reinstatement

NAcc shell vs core Cocaine Shell: reinstatement Vassoler et al. 2008 Reinstatement Core: no effect

NAcc shell vs core Alcohol Shell and core: Knapp et al. 2009 consumption Consumption

NAcc core- unilateral Morphine (CPP) 75% reduction in Liu et al. 2008 morphine preference

Lateral habenula Cocaine Reinstatement Friedman et al. 2010 reinstatement

Med forebrain bundle Cocaine, sucrose Reinstatement Levy et al. 2007 Prefrontal cortex Progressive ratio

Subthalamic nucleii Cocaine Break point for cocaine Rouaud et al. 2010 progressive ratio (motivation for reward) (Baunez) Break point food Results of DBS with drug-rewarded behavior in humans (case studies) Target Addictive Behavior Effect Authors Subthalamic Abuse of dopamine Witjas et al. 2005 Nucleii replacement therapy

Abuse of DA drug Subthalamic Gambling Ardouin et al. 2006 Nucleii Hypersexuality

STN for movement Smoking Cessation Kuhn et al. 2009 disorder

STN for movement Smoking Cessation Mantione et al. 2010 disorder Weight loss

NAcc Heroin drug use, craving Valencia Alfonso et al. 2012

NAcc Heroin drug use Zhou et al. 2011

NAcc Alcohol Abstinence Muller et al. 2009 * Quality of life Craving

Cue related Craving Heinze et al. 2009