From: Swanson et al. Nat Rev Drug Disc. 2005 Activation of mGlu2/3 receptors inhibits excitatory...
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Transcript of From: Swanson et al. Nat Rev Drug Disc. 2005 Activation of mGlu2/3 receptors inhibits excitatory...
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From: Swanson et al. Nat Rev Drug Disc. 2005
Activation of mGlu2/3 receptors inhibits excitatory synapticransmission with greater potency in the amygdala
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NMDA mGlu5
MEK
pERK
gene expression
MPEP blocks Nac ERK phosphorylation associated with alcohol reinstatement (Schroeder et al., Neuropharmacol. 2008)
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2. L’attivazione dei recettori NMDA dipende dalla presenza di unostimolo di rinforzo con carattere di associatività e cooperatività
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Il sistema dell’anti-reward (amigdala estesa) contribuisceal craving in astinenza e al relapse in risposta allo stress
Koob, Neuron, 2008
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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
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Difluorobenzaldazine (DFB)
mGlu1 enhancers
mGlu5 enhancer
mGlu2 enhancers
Positive allosteric modulators (enhancers) amplifyreceptor function in an activity-dependent manner
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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
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From: Swanson et al., Nat Rev Drug Discov. 2004
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Chronic cocaine reduces the function of mGlu2/3 receptorsin the NAc (Zheng-Xiong et al., JPET, 2002)
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Shell Core
Caudate
Infusion of MPEP in the NAc prevents contex-dependentrelapse to heroin seeking (Bossert et al., Neuropsychopharm., 2006)
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LTD LTP
Dynamic changes in dendritic spines in NAcc MSNs in response to cocaine (Russo et al., Trends Neurosci. 33, 2010)
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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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Kauer and Malenka, Nat. Rev. Neurosci. 2007
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Limbic motorsubcircuit
Dorsal-striatal motor subcircuit(motor habits)