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

1
Activation of mGlu2/3 receptors inhibits
excitatory synaptic ransmission with greater
potency in the amygdala
From Swanson et al. Nat Rev Drug Disc. 2005
2
MPEP blocks Nac ERK phosphorylation associated
with alcohol reinstatement (Schroeder et al.,
Neuropharmacol. 2008)
NMDA mGlu5
MEK pERK gene expression
3
2. Lattivazione dei recettori NMDA dipende dalla
presenza di uno stimolo di rinforzo con carattere
di associatività e cooperatività
4
Il sistema dellanti-reward (amigdala estesa)
contribuisce al craving in astinenza e al relapse
in risposta allo stress Koob, Neuron, 2008
5
Group-I mGlu receptors
mGlu1a long (1194 aa) mGlu1b short
C-term mGlu1c short C-term mGlu1d short
C-term mGlu1e extracellular Gene Grm1 or
GRM1 mGlu5a long C-term mGlu5b long
C-term Gene Grm5 or GRM5
GS
MAPK, PI-3-K
mGlu1a, mGlu5a, mGlu5b constitutively active
6
Positive allosteric modulators (enhancers)
amplify receptor function in an
activity-dependent manner

mGlu1 enhancers
mGlu5 enhancer
Difluorobenzaldazine (DFB)
mGlu2 enhancers
7
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
8
From Swanson et al., Nat Rev Drug Discov. 2004
9
Chronic cocaine reduces the function of mGlu2/3
receptors in the NAc (Zheng-Xiong et al., JPET,
2002)
10
Infusion of MPEP in the NAc prevents
contex-dependent relapse to heroin seeking
(Bossert et al., Neuropsychopharm., 2006)
Caudate
Shell
Core
11
Dynamic changes in dendritic spines in NAcc MSNs
in response to cocaine (Russo et al., Trends
Neurosci. 33, 2010)
LTD LTP
12
mGluR ligands in the clinic
mGluR5 NAMs Fenobam (NPL-2009) Neuropharm/FRAXA Fr
agile X STX107 Seaside Therapeutics Fragile
X AFQ056 Novartis Fragile X,
PD/D-Dys, Nicotine addiction ADX48621 Addex
PD/D-Dys AZD2516 Astra Zeneca PD/D-Dys ADX100
159 Addex GERD, migraine AZD2066 Astra
Zeneca 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 Parkinsons Disease
D-Dys (L-DOPA-induced dyskinesias GERD
gastroesophageal reflux disorder AD
Alzheimers disease
13
Kauer and Malenka, Nat. Rev. Neurosci. 2007
14
Limbic motor subcircuit Dorsal-striatal
motor subcircuit (motor habits)