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Dysregulation of glutamate homeostasis in the NAc core
underlies relapse (Knackstedt et al., Biol. Psychiatry, 2009)
Activation of mGlu2/3 receptors attenuates both stress
and cue ethanol seeking (Zhao et al., J. Neurosci. 2006)
Orthosteric ligands of mGlu receptors
DHPG
CHPG
(mGlu1/5 ago) (mGlu5 ago)
2R,4R-APDC
(mGlu2/3 ago)
L-AP4
LY354740
(mGlu2/3 ago)
AIDA
LY367385
(mGlu1 antag) (mGlu1 antag)
LY379268
(mGlu2/3 ago)
L-phosphoserine
(R,S)-PPG
(mGlu4/6/7/8 agonists)
EGlu
(mGlu2/3 antag)
LY341495
(pan-antag.; preferential mGlu2/3)
Group-III mGlu receptors (except mGlu6)
N and P/Q
Ca2+channel Glutamate
-
Gi/o
-
mGlu4 912 aa
mGlu7a 915 aa
mGlu7b
mGlu8a 908 aa
mGlu8b
mGlu8c
AC
cAMP
ATP
Presynaptic
+
mGlu2/3 AC
PI-3-K
Gi
Postsynaptic
mGlu4/7/8
PLC
Gq
mGlu1/5
p-Akt
Gi
GSK-3ß
AC
L-Glu
iGluRs
Gi
mGlu2
mGlu5 receptor antagonists do not affect METH-induced DA
release, but prevent the production of ROS induced by METH
Salycilic acid (5 mM, added to perfusion fluid) +
hydroxyl radicals = 2,3-dyhydroxybenzoic acid
350
Saline
2,3DHBA in the perfusate (% basal)
Dopamine in the perfusate (% basal)
200
MPEP, 10 mg/kg
180
160
140
120
100
80
Saline
MPEP, 10 mg/kg
300
250
200
*
150
*
*
100
50
0
20
40
60
80
100
120
140
160
180
200
220
0
20
40
60
80
100 120 140 160 180 200 220
Time (min)
Time (min)
MPEP (10 mg/kg, i.p.)
MPEP (10 mg/kg, i.p.)
METH (5 mg/kg, i.p.)
METH (5 mg/kg, i.p.)
Negative allosteric modulators inhibit receptor
function independently of the concentrations of
ambient glutamate
mGlu1 negative modulators
Fenobam
mGlu5 negative modulators
ADX100159
Activation of mGlu2/3 receptors in the NAc reduces
context-dependent heroin relapse
(Bossert et al., Neuropsychopharmacol., 2006)
LY379268
3. mGlu5 stimulates gliotransmission in the NAc
(D’Ascenzo et al., PNAS 2000)
mGlu2
mGlu2/3
mGlu4/7/8
Glut NR2A
i
mGlu3
NR2B
mGlu3
mGlu3
Glut
Glia
mGlu5
Glia
mGlu5
DNA methylation and histone acetylation are two critical epigenetic
mechanisms controlling chromatin structure and function
in mammalian neurons
Or methylation
Korzus Nat. Neurosc. 13,405,2010
Renthal and Nestler
Dialog. Clin Neurosci 11, 2009
Class C G-protein coupled receptors
Metabotropic Glu (mGlu1-8) - GABAB – Ca2+ sensing – pheromone –
Taste receptors: T1R1/T1R3 (umami) – T1R2/T1R3 (sweet)
Antagonist
Venus Fly Trap
Agonist
Changes in synaptic plasticity in
medium spiny neurons of NAcc
associated with drug addiction