Metabotropic Glutamate 5 Receptors: Role in drug self-administration

and in regulating the activity of brain reward systems

Paul J. Kenny, Ph.DThe Scripps Research Institute

Jupiter, Florida

Structure of Group I metabotropic glutamate receptor with antagonist

Reid et al., (1997) Huang et al., (1997)

Cocaine Morphine

Drugs of abuse increase glutamate transmission:Role in drug reinforcement?

Glutamate receptors

Ionotropic Metabotropic

NR1 NR2A-D NR3A-B

NMDA AMPA

GluR1-4

Kainate

GluR5-7 KA1-2

Group I Group II Group III

mGlu1,5 mGlu2,3 mGlu4,6-8

Subtypes of glutamate receptors in the brain

Signaling cascades coupled to mGlu5 receptors

Kenny & Markou, Trends Pharmacol Sci, 2004

Distribution of mGlu5 receptors in the brain

Kenny & Markou, Trends Pharmacol Sci, 2004

(i)

Role for mGlu5 receptors in regulating drug intake

Chiamulera, Epping-Jordan et al., Nature Neuroscience, 2001

mGlu5 receptors regulate drug reinforcement: Genetic evidence

0

10

20

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40mGlu5+/+

Cocaine dose (mg/kg/injection)

saline 0.08 0.4 0.8 1.6 3.2

mGlu5-/-***

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Coc

aine

infu

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-25

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Control MPEP(30 mg/kg)

Morphine(10 mg/kg)

Morphine+ MPEP

(10 mg/kg)

Morphine+ MPEP

(30 mg/kg)

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Control MPEP(5 mg/kg)

Cocaine(15 mg/kg)

Cocaine+ MPEP(1 mg/kg)

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MPEP(20 mg/kg)

Cocaine+ MPEP(5 mg/kg)

Cocaine+ MPEP

(20 mg/kg)

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Pre

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nce

for

side

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with

coc

aine

(se

c)mGlu5 receptors regulate drug reinforcement:

Pharmacological evidence

Popik and Wrobel, (2002)McGeehan and Olive, (2003)

2-methyl-6-(phenylethylnyl)-pyridine (MPEP)

Intravenous drug self-administration procedure

Kenny et al., Psychopharmacology, 2005

Coc

aine

infu

sion

s (f

irst

hou

r)

1 4 7 10 13 16 19 220

5

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ShA (n=7)

LgA (n=7)

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Days of escalation

Extended daily access to cocaine self-administration escalates intake: compulsive-like drug intake

MPEP decreased cocaine intake similarly in escalated and non-escalated rats

0 3 6 910

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ShA (n=7)

LgA (n=7)

MPEP (mg/kg)

% B

asel

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coca

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ring

firs

t ho

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Kenny et al., Psychopharmacology, 2005

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*

0 1 3 6 90

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MPEP (mg/kg)

MPEP decreased cocaine intake similarly in escalated and non-escalated rats

Ch

an

ge

fro

m b

ase

line

co

cain

e in

fusi

on

s

Paterson et al., Psychopharmacology, 2003

MPEP decreased nicotine intake

0 3 6 9120

40

60

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120Nicotine: 0.01 mg/kg/infusionNicotine: 0.03 mg/kg/infusion

MPEP (mg/kg)

% B

asel

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coca

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****

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MPEP did not alter food responding

0 3 6 9120

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120Food: TO20 secFood: TO210 sec

MPEP (mg/kg)

% B

asel

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food

re

war

ds

Paterson et al., Psychopharmacology, 2003

•The effects of MPEP were similar in cocaine escalated and non-escalated rats, suggesting that mGlu5 receptors are not involved in the development of compulsive drug intake.

Summary:

•The mGlu5 receptor antagonist MPEP decreased cocaine and nicotine self-administration in rats.

•MPEP did not alter responding for food reinforcement in rats. This suggests that mGlu5 receptors are preferentially involved in drug reward.

(ii)

Role for mGlu5 receptors in regulating drug-inducedstimulation of brain reward systems

Why are drugs of abuse reinforcing?

Drug intake

One potential mechanism by which drugs induce their reinforcing effects is:

Activation of brain reward systems

Intracranial self-stimulation procedure

Reward threshold procedure developed by Kornetsky

The minimal stimulation currentthat maintains ICSS behavioris termed the reward threshold.

Lowering of thresholds = Increased reward activity.

Elevations of thresholds = Decreased reward activity.

MPEP decreased baseline reward sensitivity andattenuated cocaine-induced reward facilitation

Kenny et al., Psychopharmacology, 2005

R

ewar

d th

resh

olds

(%

)

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MPEP-Cocaine

MPEP (mg/kg)

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Vehicle - MPEP

Cocaine - MPEP

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-50

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60Nicotine - MPEP

Saline - MPEP

MPEP Dose (mg/kg)

R

ewa

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hre

shol

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(%)

**

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MPEP decreased baseline reward sensitivity andattenuated nicotine-induced reward facilitation

Harrison et al., Psychopharmacology, 2002

Summary:

•Doses of MPEP that decreased drug self-administration elevated baseline reward thresholds in rats, indicating blunted sensitivity of brain reward systems.

•This intrinsic inhibitory action of MPEP on brain reward systems countered thefacilitatory effects of cocaine and nicotine on brain reward systems.

•These data suggest that MPEP may decrease drug intake by inducing anegative affective state, thereby reducing the stimulatory effects of addictive drugs on brain reward systems.

(iii)

Potential mechanisms by which mGlu5 receptors regulate drug intake and sensitivity of brain reward systems

mGlu5 receptors in the nucleus accumbens are unlikely to regulate drug self-administration

Chiamulera, Epping-Jordan et al, 2001. Kenny, Boutrel, Specio, Koob and Markou, Unpublished observations.

% B

asel

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coca

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infu

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ns0.01 0.1 10

40

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MPEP (g/side)

MPEP infused directly into nucleus accumbens shell

c

0.1 10 0.5 2.5 5

-80

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Nicotine (0.03 mg/kg/infusion)FR5TO20 sec

LY235959 (mg/kg)

Cha

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(%)

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NMDA receptors regulate nicotine self-administration in rats

Kenny & Markou, under review.

*

v v** ** **

NMDA receptors in the ventral tegmental area (VTA) regulate nicotine self-administration

100 0.1 0.5 1 2mm above

-80

-60

-40

-20

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40Nicotine (0.03 mg/kg/infusionControl injection (1 ng/0.5 l; 2 mm above VTA)

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LY235959 (ng/0.5 l/side)

Ch

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z z

Kenny & Markou, under review.

v

v**

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NMDA receptors regulate nicotine-increased brain reward activity

0 0.5 1 2.5

-30

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Post-nicotine self-administration

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LY235959 (mg/kg)

R

ew

ard

th

resh

old

s (%

)

Kenny & Markou, under review.

•Potential cross-talk between mGlu5 and NMDA receptors in regulatingdrug self-administration and drug-enhanced brain reward sensitivity?

Sal-Sal Sal-LY MPEP-Sal MPEP-LY0

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LY: LY235959 (0.1 mg/kg)MPEP: MPEP (1 mg/kg)

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%)

Overall summary and conclusions:

•MPEP decreases drug self-administration and decreases baseline sensitivity of brain reward systems.

•The intrinsic inhibitory effects of MPEP on brain reward systems counter thestimulatory effects of cocaine and nicotine. MPEP likely decreases drug intake by inducing a negative affective state.

•mGlu5 receptors located in the nucleus accumbens are unlikely to participitatein regulating the effects of MPEP on drug intake.

•MPEP may reduce drug intake by decreasing the function of NMDA receptorsinvolved in regulating drug reinforcement.

Jupiter, Florida

Acknowledgements:

The Scripps Research Institute, La Jolla

Athina Markou, Ph.D.George Koob, Ph.D.Neil Paterson, M.D.Svetlana Semenova, Ph.D.Sheila Specio, M.S.

University of Lausanne, Switzerland

Benjamin Boutrel, Ph.D.

University of Leeds, UK

Amanda Harrison, Ph.D.

Novartis Pharma AG

Fabrizio Gasparini, Ph.D.

Ahmed, Kenny et al., Nature Neuroscience, 2002

Escalated cocaine intake

0 1 2 3 4 5 6 7 8 9 10 11 12 13 140

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20

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ShA (n=9)LgA (n=11)

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Escalation days

Coc

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infu

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s (f

irst

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