Metabotropic Glutamate 5 Receptors: Role in drug self-administration

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? Morphine Cocaine 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

4. Signaling cascades coupled to mGlu5 receptors Kenny & Markou, Trends Pharmacol Sci, 2004

5. Distribution of mGlu5 receptors in the brain Kenny & Markou, Trends Pharmacol Sci, 2004

6. (i) Role for mGlu5 receptors in regulating drug intake

7. Cocaine infusions per hour mGlu5 receptors regulate drug reinforcement: Genetic evidence Chiamulera, Epping-Jordan et al., Nature Neuroscience, 2001

8. 1000 200 800 175 150 600 125 Preference for side paired * with cocaine (sec) 100 400 Preference for side paired with morphine (sec) ** 75 * 200 50 25 0 0 Control MPEP Morphine Morphine Morphine -200 -25 (30 mg/kg) (10 mg/kg) + MPEP + MPEP Control MPEP MPEP Cocaine Cocaine Cocaine Cocaine (10 mg/kg) (30 mg/kg) (5 mg/kg) (20 mg/kg) (15 mg/kg) + MPEP + MPEP + MPEP (1 mg/kg) (5 mg/kg) (20 mg/kg) mGlu5 receptors regulate drug reinforcement: Pharmacological evidence 2-methyl-6-(phenylethylnyl)-pyridine (MPEP) McGeehan and Olive, (2003) Popik and Wrobel, (2002)

9. Intravenous drug self-administration procedure

10. Cocaine infusions (first hour) Extended daily access to cocaine self-administration escalates intake: compulsive-like drug intake Kenny et al., Psychopharmacology, 2005

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

12. Collapsed groups 120 100 80 60 40 20 0 0 1 3 6 9 MPEP (mg/kg) MPEP decreased cocaine intake similarly in escalated and non-escalated rats Change from baseline cocaine infusions

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

14. % Baseline food rewards MPEP did not alter food responding Paterson et al., Psychopharmacology, 2003

15. 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.

16. (ii) Role for mGlu5 receptors in regulating drug-induced stimulation of brain reward systems

17. Why are drugs of abuse reinforcing? One potential mechanism by which drugs induce their reinforcing effects is: Drug intake Activation of brain reward systems

18. Intracranial self-stimulation procedure

19. Reward threshold procedure developed by Kornetsky Lowering ofthresholds = Increased reward activity. Elevations ofthresholds = Decreased reward activity. The minimal stimulation current that maintains ICSS behavior is termed the reward threshold.

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

21. ** ** Reward thresholds (%) MPEP decreased baseline reward sensitivity and attenuated nicotine-induced reward facilitation Harrison et al., Psychopharmacology, 2002

22. 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.

23. (iii) Potential mechanisms by which mGlu5 receptors regulate drug intake and sensitivity of brain reward systems

24. MPEP infused directly into nucleus accumbens shell % Baseline cocaine infusions Kenny, Boutrel, Specio, Koob and Markou, Unpublished observations. mGlu5 receptors in the nucleus accumbens are unlikely to regulate drug self-administration c Chiamulera, Epping-Jordan et al, 2001.

25. NMDA receptors regulate nicotine self-administration in rats * ** v ** v ** Kenny & Markou, under review.

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

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

28. LY: LY235959 (0.1 mg/kg) MPEP: MPEP (1 mg/kg) 120 100 80 Change from baseline nicotine infusions (%) 60 40 20 0 Sal-Sal Sal-LY MPEP-Sal MPEP-LY • Potential cross-talk between mGlu5 and NMDA receptors in regulating drug self-administration and drug-enhanced brain reward sensitivity?

29. 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.

30. 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. Jupiter, Florida

31. Cocaine infusions (first hour) Escalated cocaine intake Ahmed, Kenny et al., Nature Neuroscience, 2002