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

Reid et al., (1997) Huang et al., (1997) Cocaine Morphine Drugs of abuse increase glutamate transmission: Role in drug reinforcement?

Glutamate receptors Ionotropic Metabotropic NR1NR2A-DNR3A-B NMDAAMPA GluR1-4 Kainate GluR5-7KA1-2 Group IGroup 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 Cocaine infusions per hour

Control MPEP (30 mg/kg) Morphine (10 mg/kg) Morphine + MPEP (10 mg/kg) Morphine + MPEP (30 mg/kg) ** Preference for side paired with morphine (sec) 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) * Preference for side paired with cocaine (sec) 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 Cocaine infusions (first hour) Extended daily access to cocaine self-administration escalates intake: compulsive-like drug intake

MPEP decreased cocaine intake similarly in escalated and non-escalated rats % Baseline cocaine infusions during first hour ** Kenny et al., Psychopharmacology, 2005 ** *

Collapsed groups MPEP (mg/kg) MPEP decreased cocaine intake similarly in escalated and non-escalated rats Change from baseline cocaine infusions

Paterson et al., Psychopharmacology, 2003 MPEP decreased nicotine intake % Baseline cocaine infusions **

MPEP did not alter food responding % Baseline food rewards 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-induced stimulation 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 current that maintains ICSS behavior is termed the reward threshold. Lowering of thresholds = Increased reward activity. Elevations of thresholds = Decreased reward activity.

MPEP decreased baseline reward sensitivity and attenuated cocaine-induced reward facilitation Kenny et al., Psychopharmacology, 2005  Reward thresholds (%) ** Vehicle - MPEP Cocaine - MPEP

 Reward thresholds (%) ** MPEP decreased baseline reward sensitivity and attenuated 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 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.

(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, Kenny, Boutrel, Specio, Koob and Markou, Unpublished observations. % Baseline cocaine infusions MPEP infused directly into nucleus accumbens shell c

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 z z Kenny & Markou, under review. v v ** *

NMDA receptors regulate nicotine-increased brain reward activity Kenny & Markou, under review.

Potential cross-talk between mGlu5 and NMDA receptors in regulating drug self-administration and drug-enhanced brain reward sensitivity? Sal-SalSal-LYMPEP-SalMPEP-LY LY: LY (0.1 mg/kg) MPEP: MPEP (1 mg/kg) Change from baseline nicotine infusions (%)

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.

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 Cocaine infusions (first hour)