Metabotropic Glutamate 5 Receptors: Role in drug selfadministration

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 Research
Institute Jupiter, Florida
Structure of Group I metabotropic glutamate
receptor with antagonist
2
Drugs of abuse increase glutamate
transmission Role in drug reinforcement?
Cocaine
Morphine
Reid et al., (1997)
Huang et al., (1997)
3
Subtypes of glutamate receptors in the brain
Glutamate receptors
Ionotropic
Metabotropic
Kainate
Group III
NMDA
AMPA
Group I
Group II
GluR5-7
KA1-2
mGlu4,6-8
NR1
NR2A-D
NR3A-B
GluR1-4
mGlu1,5
mGlu2,3
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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
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mGlu5 receptors regulate drug reinforcement
Genetic evidence
Chiamulera, Epping-Jordan et al., Nature
Neuroscience, 2001
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mGlu5 receptors regulate drug reinforcement
Pharmacological evidence
2-methyl-6-(phenylethylnyl)-pyridine (MPEP)
Popik and Wrobel, (2002)
McGeehan and Olive, (2003)
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Intravenous drug self-administration procedure
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Extended daily access to cocaine
self-administration escalates intake
compulsive-like drug intake
Kenny et al., Psychopharmacology, 2005
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MPEP decreased cocaine intake similarly in
escalated and non-escalated rats



Kenny et al., Psychopharmacology, 2005
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MPEP decreased cocaine intake similarly in
escalated and non-escalated rats
Change from baseline cocaine infusions
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MPEP decreased nicotine intake
Paterson et al., Psychopharmacology, 2003
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MPEP did not alter food responding
Paterson et al., Psychopharmacology, 2003
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Summary

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

• 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.

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

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(ii) Role for mGlu5 receptors in regulating
drug-induced stimulation of brain reward systems
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Why are drugs of abuse reinforcing?
One potential mechanism by which drugs induce
their reinforcing effects is
Drug intake
Activation of brain reward systems
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Intracranial self-stimulation procedure
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Reward threshold procedure developed by Kornetsky
Lowering of thresholds Increased reward
activity.
Elevations of thresholds Decreased reward
activity.
The minimal stimulation current that maintains
ICSS behavior is termed the reward threshold.
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MPEP decreased baseline reward sensitivity
and attenuated cocaine-induced reward facilitation


Vehicle - MPEP
Cocaine - MPEP
Kenny et al., Psychopharmacology, 2005
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MPEP decreased baseline reward sensitivity
and attenuated 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 the
• facilitatory effects of cocaine and nicotine on
  brain reward systems.

• These data suggest that MPEP may decrease drug
  intake by inducing a
• negative 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
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mGlu5 receptors in the nucleus accumbens are
unlikely to regulate drug self-administration
c
Chiamulera, Epping-Jordan et al, 2001.
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NMDA receptors regulate nicotine
self-administration in rats


v
v


Kenny Markou, under review.
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NMDA receptors in the ventral tegmental area
(VTA) regulate nicotine self-administration
v


v
Kenny Markou, under review.
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NMDA receptors regulate nicotine-increased brain
reward activity
Kenny Markou, under review.
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• Potential cross-talk between mGlu5 and NMDA
  receptors in regulating
• drug self-administration and drug-enhanced brain
  reward sensitivity?

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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 the
• stimulatory 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 participitate
• in regulating the effects of MPEP on drug intake.

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

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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 Benjami
n Boutrel, Ph.D. University of Leeds, UK Amanda
Harrison, Ph.D. Novartis Pharma AG Fabrizio
Gasparini, Ph.D.
Jupiter, Florida
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Escalated cocaine intake
Ahmed, Kenny et al., Nature Neuroscience, 2002