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
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
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