1. mGlu5 receptor antagonists are neuroprotective against methamphetamine toxicity THDATGFAP Saline METH +MPEP +SIB-1893 Saline Methamphetamine (5 mg/kg x 3) Dopamine (ng/mg protein) 30 60 90 120 150 180 Saline MPEP, 10 mg/kg SIB-1893, 10 mg/kg LY379268, 1 mg/kg CPCCOEt, 10 mg/kg 0

2. Group-II mGlu receptors AC G i/o - ATP cAMP - Glutamate N and P/Q Ca 2+ channel  + MAPK PI-3-K AC-II mGlu2 - 872 aa Gene:Grm2/GRM2 mGlu3 – 877 aa Gene: Grm3/GRM3 LY354740 or LY379268 Backbone of orthosteric agonists

4. LY2144023 Phase II NCT00149292 28-day trial 40 mg bid LY vs. 15 mg olanzapine vs. placebo Patil et al. Nat. Med. 13, 1102, 2007 Orthosteric mGlu2/3 agonists Generalyzed anxiety disorder – Panic attacks – Schizophrenia Addiction (relapse) – Chronic pain - Neurodegeneration LY404039

5. Enhanced responsiveness to cocaine in mGlu2 KO mice (Morishima et al., PNAS, 2005)

6. Pharmacological activation of mGlu2/3 receptors reduces self-administration of nicotine and cocaine (Leichti et al., J. Neurosci., 2006; Adewale et al., JPET 2006)

7. Additive drugs VTA mGlu2/3 Activation of mGlu2/3 receptors precipitates the deficit in brain reward function associated with nicotine withdrawal (Kenny et al., JPET, 2003)

8. Cue-induced relapse Activation of mGlu2/3 receptors reduces priming- and context-induced drug reinstatement (Adewale et al., JPET, 2006; Leichti et al., J. Neurosci. 2006; ) Cue-induced nicotine relapse

9. Dysregulation of glutamate homeostasis in the N. Accumbens Core underlies relapse (Knackstedt et al., Biol. Psychiatry, 2009) PFCtx NAc Core Glut +

10. The XC - activator, N-acetylcysteine (NAC) restores synaptic plasticity in the NAc of cocaine- dependent rats by enabling the activation of mGlu2/3 receptors (Moussawi et al., Nat Neurosci., 2009)

11. Emerging drugs for the treatment of nicotine addiction (Kenny, Exp. Rev. Clin. Pharmacol. 23, 2009)

12. Chromatin regulation in drug addiction and depression Renthal and Nestler, Dialogues Clin Neurosci 11, 257,2010

13. Dnmt3 regulates cocaine reward and spine plasticity in the NAcc (LaPlant et al., Nat. Neurosci. 13, 9, 2010) GFP Dnmt3 HSV-GFP HSV-Dnmt3

14. 0 2.0 4.0 6.0 8.0 10 # * Control LY379268 (0.5 mg/kg) MET(750 mg/kg) MET + LY379268 BDNF promoter methylation 17 kD 42 kD β-actin Gadd45-β LY379268 (0.5 mg/kg) Controls 1234 Densitometric analysis of Gadd45b/β-actin (arbitrary units) 0 0.2 0.4 0.6 0.8 1.0 ControlsLY379268 VLP70 mg/kg CLZ 5 mg/kg HAL1.5mg/kg LY 0.5 mg/kg Ctrl Activation of mGlu2/3 receptors leads to gene promoter demethylayion Matriscano F. et al. Submitted

15. mGlu receptors as targets in addition 1.Acute reinforcing: mGlu2/3 agonists and mGlu5 NAMs Controversial role for mGlu1 receptors. mGlu4/7/8 receptors? 2.mGlu2/3 receptor antagonists improve the Reward impairment in drug withdrawal. mGlu5 NAMs are detrimental. mGlu2/3 agonists and mGlu5 NAM relieve physical symptoms of opioid withdrawal 3. Drug relapse after prolonged abstinence: Glu2/3 agonists and mGlu5 NAMs 4. mGlu2/3 agonists behave similarly to antistress hormones in the antireward/stress neuronal circuitry.

16. AMN082 Glutamate + mGlu7 Activation of mGlu7 receptors inhibits cocaine reinstatement via mGlu2/3 receptors (Li et al., J. Neurochem. 114, 1368, 2010)

17. Pathological cycling in addiction (Koob, Neuron, 2008)

20. Stress hormones (CRF, Vasopressin) enhance GABAergic transmission in the CeA Antistress hormones (Nociceptin, Oxytocin) reduces GABAergic transmission in the CeA Nie et al., Science, 2004; Huber et al., Science, 2005; Roberto and Siggins, PNAS, 2006; Koob, Neuron, 2008

21. Activation of mGlu2/3 receptors inhibits GABAergic transmission in the lateral portion of the CeA Swanson et al., 2004

22. Activation of mGlu2/3 receptors in the CeA attenuates the expression of incubation of cocaine craving (Lu et al., Biol. Psych. 2007)

23. Cocaine 0 -20 -10 -30 10 20 30 40 50 60 Ahmed et al., Nat. Neurosci. 2002 Hedonic allostasis with escalating cocaine use ICSS

24. Dnmt3 regulates cocaine reward and spine plasticity in the NAcc (LaPlant et al., Nat. Neurosci. 13, 9, 2010)

25. GFP Dnmt3a HSV-GFP HSV-Dnmt3a