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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. - PowerPoint PPT Presentation
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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 stressand cue ethanol seeking (Zhao et al., J. Neurosci. 2006)
Orthosteric ligands of mGlu receptors
DHPG CHPG AIDA LY367385 (mGlu1/5 ago) (mGlu5 ago) (mGlu1 antag) (mGlu1 antag)
2R,4R-APDC LY354740 LY379268 EGlu(mGlu2/3 ago) (mGlu2/3 ago) (mGlu2/3 ago) (mGlu2/3 antag)
L-AP4 L-phosphoserine (R,S)-PPG LY341495 (mGlu4/6/7/8 agonists) (pan-antag.; preferential mGlu2/3)
Group-III mGlu receptors (except mGlu6)
ACGi/o -ATP
cAMP-
GlutamateN and P/Q
Ca2+channel mGlu4 912 aamGlu7a 915 aamGlu7bmGlu8a 908 aamGlu8bmGlu8c
+
PI-3-K
p-Akt GSK-3ß
Postsynaptic
L-GluiGluRs
mGlu1/5Gq
GimGlu4/7/8
mGlu2/3
Gi
Presynaptic
PLC
AC
AC
GimGlu2
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
Time (min)
0 20 40 60 80 100 120 140 160 180 200 220
Do
pam
ine
in t
he
per
fusa
te (
% b
asal
)
80
100
120
140
160
180
200
MPEP (10 mg/kg, i.p.)
METH (5 mg/kg, i.p.)
MPEP, 10 mg/kg
Saline
Time (min)
0 20 40 60 80 100 120 140 160 180 200 220
2,3D
HB
A i
n t
he
per
fusa
te (
% b
asal
)50
100
150
200
250
300
350
MPEP (10 mg/kg, i.p.)METH (5 mg/kg, i.p.)
*
**
MPEP, 10 mg/kg
Saline
Fenobam
mGlu5 negative modulators
mGlu1 negative modulators
Negative allosteric modulators inhibit receptorfunction independently of the concentrations of
ambient glutamate
ADX100159
LY379268
Activation of mGlu2/3 receptors in the NAc reduces context-dependent heroin relapse
(Bossert et al., Neuropsychopharmacol., 2006)
3. mGlu5 stimulates gliotransmission in the NAc (D’Ascenzo et al., PNAS 2000)
mGlu2
Glia
mGlu3
mGlu3
mGlu4/7/8mGlu2/3
i
mGlu3
mGlu5
Glut
Glut
mGlu5
Glia
NR2B
NR2A
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 NestlerDialog. 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)
Venus Fly Trap AgonistAntagonist
Changes in synaptic plasticity in medium spiny neurons of NAccassociated with drug addiction
