dysregulation of glutamate homeostasis in the nac core underlies relapse (knackstedt et al., biol....
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Dysregulation of glutamate homeostasis in the NAc core underlies relapse (Knackstedt et al., Biol. Psychiatry, 2009)
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Activation of mGlu2/3 receptors attenuates both stressand cue ethanol seeking (Zhao et al., J. Neurosci. 2006)
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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)
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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
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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
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Fenobam
mGlu5 negative modulators
mGlu1 negative modulators
Negative allosteric modulators inhibit receptorfunction independently of the concentrations of
ambient glutamate
ADX100159
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LY379268
Activation of mGlu2/3 receptors in the NAc reduces context-dependent heroin relapse
(Bossert et al., Neuropsychopharmacol., 2006)
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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
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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
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Renthal and NestlerDialog. Clin Neurosci 11, 2009
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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
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Changes in synaptic plasticity in medium spiny neurons of NAccassociated with drug addiction
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