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Activation of mGlu2/3 receptors inhibits excitatory synaptic ransmission with greater potency in the amygdala From: Swanson et al. Nat Rev Drug Disc. 2005 MPEP blocks Nac ERK phosphorylation associated with alcohol reinstatement (Schroeder et al., Neuropharmacol. 2008) NMDA mGlu5 MEK pERK gene expression 2. L’attivazione dei recettori NMDA dipende dalla presenza di uno stimolo di rinforzo con carattere di associatività e cooperatività Il sistema dell’anti-reward (amigdala estesa) contribuisce al craving in astinenza e al relapse in risposta allo stress Koob, Neuron, 2008 Group-I mGlu receptors GS MAPK, PI-3-K mGlu1a mGlu1b mGlu1c mGlu1d mGlu1e long (1194 aa) short C-term short C-term short C-term extracellular Gene: Grm1 or GRM1 mGlu5a long C-term mGlu5b long C-term Gene: Grm5 or GRM5 mGlu1a, mGlu5a, mGlu5b constitutively active Positive allosteric modulators (enhancers) amplify receptor function in an activity-dependent manner mGlu1 enhancers mGlu5 enhancer Difluorobenzaldazine (DFB) mGlu2 enhancers The mGlu1 receptor PAM, Ro 67-7476 (4 mg/kg, i.p.) reverses AMPA receptor distribution and sensitization induced by cocaine (Bellone and Luscher, Nat. Neurosci., 2006) VTA 1 Additive Drugs From: Swanson et al., Nat Rev Drug Discov. 2004 Chronic cocaine reduces the function of mGlu2/3 receptors in the NAc (Zheng-Xiong et al., JPET, 2002) Infusion of MPEP in the NAc prevents contex-dependent relapse to heroin seeking (Bossert et al., Neuropsychopharm., 2006) Caudate Shell Core Dynamic changes in dendritic spines in NAcc MSNs in response to cocaine (Russo et al., Trends Neurosci. 33, 2010) LTD LTP mGluR ligands in the clinic mGluR5 NAMs Fenobam (NPL-2009) STX107 AFQ056 Neuropharm/FRAXA Seaside Therapeutics Novartis ADX48621 AZD2516 ADX100159 AZD2066 Addex Astra Zeneca Addex Astra Zeneca Fragile X Fragile X Fragile X, PD/D-Dys, Nicotine addiction PD/D-Dys PD/D-Dys GERD, migraine GERD, Neuropathic pain mGlu2/3 Agonists LY2144023/LY404039 Eli Lilly Schizophrenia mGlu2 PAMs ADX71149 Addex Schizophrenia, Anxiety, Depression, AD NAM and PAM = negative and positive allosteric modulators PD = Parkinson’s Disease; D-Dys (L-DOPA-induced dyskinesias; GERD = gastroesophageal reflux disorder; AD = Alzheimer’s disease Kauer and Malenka, Nat. Rev. Neurosci. 2007 Limbic motor subcircuit Dorsal-striatal motor subcircuit (motor habits)
