From: Swanson et al. Nat Rev Drug Disc. 2005

Activation of mGlu2/3 receptors inhibits excitatory synapticransmission with greater potency in the amygdala

NMDA mGlu5

MEK

pERK

gene expression

MPEP blocks Nac ERK phosphorylation associated with alcohol reinstatement (Schroeder et al., Neuropharmacol. 2008)

2. L’attivazione dei recettori NMDA dipende dalla presenza di unostimolo di rinforzo con carattere di associatività e cooperatività

Il sistema dell’anti-reward (amigdala estesa) contribuisceal craving in astinenza e al relapse in risposta allo stress

Koob, Neuron, 2008

Group-I mGlu receptors

mGlu1a long (1194 aa)mGlu1b short C-termmGlu1c short C-termmGlu1d short C-termmGlu1e extracellularGene: Grm1 or GRM1

mGlu5a long C-termmGlu5b long C-termGene: Grm5 or GRM5

mGlu1a, mGlu5a, mGlu5bconstitutively active

MAPK, PI-3-K

GS

Difluorobenzaldazine (DFB)

mGlu1 enhancers

mGlu5 enhancer

mGlu2 enhancers

Positive allosteric modulators (enhancers) amplifyreceptor function in an activity-dependent manner

1

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

AdditiveDrugs

From: Swanson et al., Nat Rev Drug Discov. 2004

Chronic cocaine reduces the function of mGlu2/3 receptorsin the NAc (Zheng-Xiong et al., JPET, 2002)

Shell Core

Caudate

Infusion of MPEP in the NAc prevents contex-dependentrelapse to heroin seeking (Bossert et al., Neuropsychopharm., 2006)

LTD LTP

Dynamic changes in dendritic spines in NAcc MSNs in response to cocaine (Russo et al., Trends Neurosci. 33, 2010)

mGluR5 NAMsFenobam (NPL-2009) Neuropharm/FRAXA Fragile XSTX107 Seaside Therapeutics Fragile XAFQ056 Novartis Fragile X, PD/D-Dys,

Nicotine addictionADX48621 Addex PD/D-DysAZD2516 Astra Zeneca PD/D-DysADX100159 Addex GERD, migraineAZD2066 Astra Zeneca GERD, Neuropathic pain

mGlu2/3 AgonistsLY2144023/LY404039 Eli Lilly Schizophrenia

mGlu2 PAMsADX71149 Addex Schizophrenia, Anxiety,

Depression, AD

NAM and PAM = negative and positive allosteric modulatorsPD = Parkinson’s Disease; D-Dys (L-DOPA-induced dyskinesias;GERD = gastroesophageal reflux disorder; AD = Alzheimer’s disease

mGluR ligands in the clinic

Kauer and Malenka, Nat. Rev. Neurosci. 2007

Limbic motorsubcircuit

Dorsal-striatal motor subcircuit(motor habits)