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![Page 1: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/1.jpg)
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
![Page 2: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/2.jpg)
Reid et al., (1997) Huang et al., (1997)
Cocaine Morphine
Drugs of abuse increase glutamate transmission:Role in drug reinforcement?
![Page 3: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/3.jpg)
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
![Page 4: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/4.jpg)
Signaling cascades coupled to mGlu5 receptors
Kenny & Markou, Trends Pharmacol Sci, 2004
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Distribution of mGlu5 receptors in the brain
Kenny & Markou, Trends Pharmacol Sci, 2004
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(i)
Role for mGlu5 receptors in regulating drug intake
![Page 7: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/7.jpg)
Chiamulera, Epping-Jordan et al., Nature Neuroscience, 2001
mGlu5 receptors regulate drug reinforcement: Genetic evidence
0
10
20
30
40mGlu5+/+
Cocaine dose (mg/kg/injection)
saline 0.08 0.4 0.8 1.6 3.2
mGlu5-/-***
**
*
Coc
aine
infu
sion
s pe
r ho
ur
![Page 8: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/8.jpg)
-25
0
25
50
75
100
125
150
175
200
Control MPEP(30 mg/kg)
Morphine(10 mg/kg)
Morphine+ MPEP
(10 mg/kg)
Morphine+ MPEP
(30 mg/kg)
**
Pre
fere
nce
for
side
pai
red
with
mor
phin
e (s
ec)
-200
0
200
400
600
800
1000
Control MPEP(5 mg/kg)
Cocaine(15 mg/kg)
Cocaine+ MPEP(1 mg/kg)
*
MPEP(20 mg/kg)
Cocaine+ MPEP(5 mg/kg)
Cocaine+ MPEP
(20 mg/kg)
*
Pre
fere
nce
for
side
pai
red
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)
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Intravenous drug self-administration procedure
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Kenny et al., Psychopharmacology, 2005
Coc
aine
infu
sion
s (f
irst
hou
r)
1 4 7 10 13 16 19 220
5
10
15
20
25
30
35
ShA (n=7)
LgA (n=7)
***
Days of escalation
Extended daily access to cocaine self-administration escalates intake: compulsive-like drug intake
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MPEP decreased cocaine intake similarly in escalated and non-escalated rats
0 3 6 910
20
40
60
80
100
120
140
ShA (n=7)
LgA (n=7)
MPEP (mg/kg)
% B
asel
ine
coca
ine
infu
sio
nsdu
ring
firs
t ho
ur
****
**
Kenny et al., Psychopharmacology, 2005
****
*
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0 1 3 6 90
20
40
60
80
100
120 Collapsed groups
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
![Page 13: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/13.jpg)
Paterson et al., Psychopharmacology, 2003
MPEP decreased nicotine intake
0 3 6 9120
40
60
80
100
120Nicotine: 0.01 mg/kg/infusionNicotine: 0.03 mg/kg/infusion
MPEP (mg/kg)
% B
asel
ine
coca
ine
infu
sio
ns
****
**
![Page 14: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/14.jpg)
MPEP did not alter food responding
0 3 6 9120
40
60
80
100
120Food: TO20 secFood: TO210 sec
MPEP (mg/kg)
% B
asel
ine
food
re
war
ds
Paterson et al., Psychopharmacology, 2003
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•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.
![Page 16: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/16.jpg)
(ii)
Role for mGlu5 receptors in regulating drug-inducedstimulation of brain reward systems
![Page 17: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/17.jpg)
Why are drugs of abuse reinforcing?
Drug intake
One potential mechanism by which drugs induce their reinforcing effects is:
Activation of brain reward systems
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Intracranial self-stimulation procedure
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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.
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MPEP decreased baseline reward sensitivity andattenuated cocaine-induced reward facilitation
Kenny et al., Psychopharmacology, 2005
R
ewar
d th
resh
olds
(%
)
0 3 6 91-50
-40
-30
-20
-10
0
10
20
30MPEP-Vehicle
***
MPEP-Cocaine
MPEP (mg/kg)
****
Vehicle - MPEP
Cocaine - MPEP
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0 1 3 9
-50
-40
-30
-20
-10
0
10
20
30
40
50
60Nicotine - MPEP
Saline - MPEP
MPEP Dose (mg/kg)
R
ewa
rd t
hre
shol
ds
(%)
**
**
MPEP decreased baseline reward sensitivity andattenuated nicotine-induced reward facilitation
Harrison et al., Psychopharmacology, 2002
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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.
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(iii)
Potential mechanisms by which mGlu5 receptors regulate drug intake and sensitivity of brain reward systems
![Page 24: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/24.jpg)
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
ine
coca
ine
infu
sio
ns0.01 0.1 10
40
60
80
100
120
140
MPEP (g/side)
MPEP infused directly into nucleus accumbens shell
c
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0.1 10 0.5 2.5 5
-80
-60
-40
-20
0
20
40
Nicotine (0.03 mg/kg/infusion)FR5TO20 sec
LY235959 (mg/kg)
Cha
nge
from
bas
elin
en
ico
tine
infu
sio
ns
(%)
*** ** **
NMDA receptors regulate nicotine self-administration in rats
Kenny & Markou, under review.
*
v v** ** **
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NMDA receptors in the ventral tegmental area (VTA) regulate nicotine self-administration
100 0.1 0.5 1 2mm above
-80
-60
-40
-20
0
20
40Nicotine (0.03 mg/kg/infusionControl injection (1 ng/0.5 l; 2 mm above VTA)
*
**
LY235959 (ng/0.5 l/side)
Ch
an
ge fr
om
bas
elin
en
ico
tine
infu
sio
ns
(%)
z z
Kenny & Markou, under review.
v
v**
*
![Page 27: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/27.jpg)
NMDA receptors regulate nicotine-increased brain reward activity
0 0.5 1 2.5
-30
-20
-10
0
10
20
Post-nicotine self-administration
###
##
LY235959 (mg/kg)
R
ew
ard
th
resh
old
s (%
)
Kenny & Markou, under review.
![Page 28: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/28.jpg)
•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
20
40
60
80
100
120
LY: LY235959 (0.1 mg/kg)MPEP: MPEP (1 mg/kg)
Cha
nge
from
bas
elin
e
nico
tine
infu
sion
s (
%)
![Page 29: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/29.jpg)
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.
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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.
![Page 31: Metabotropic Glutamate 5 Receptors: Role in drug self-administration and in regulating the activity of brain reward systems Paul J. Kenny, Ph.D The Scripps.](https://reader036.fdocuments.net/reader036/viewer/2022062314/56649f225503460f94c3a9f4/html5/thumbnails/31.jpg)
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
10
20
30
ShA (n=9)LgA (n=11)
***
Escalation days
Coc
aine
infu
sion
s (f
irst
hou
r)