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mGlu5 receptor antagonists are neuroprotective against
methamphetamine toxicity
Saline
MPEP, 10 mg/kg
SIB-1893 , 10 mg/kg
LY379268, 1 mg/kg
150
*
*
90
60
+MPEP
120
METH
CPCCOEt, 10 mg/kg
+SIB-1893
Dopamine (ng/mg protein)
180
Saline
TH
30
0
Saline
Methamphetamine
(5 mg/kg x 3)
DAT
GFAP
Group-II mGlu receptors
N and P/Q
Ca2+channel Glutamate
mGlu2 - 872 aa
Gene:Grm2/GRM2
-
Gi/o
-
mGlu3 – 877 aa
AC
cAMP
Gene: Grm3/GRM3
ATP
bg
Backbone of orthosteric agonists
+
MAPK
PI-3-K
AC-II
LY354740 or LY379268
Orthosteric mGlu2/3 agonists
Generalyzed anxiety disorder – Panic attacks – Schizophrenia
Addiction (relapse) – Chronic pain - Neurodegeneration
LY2144023
LY404039
Phase II NCT00149292 28-day trial
40 mg bid LY vs. 15 mg olanzapine
vs. placebo
Patil et al. Nat. Med. 13, 1102, 2007
Enhanced responsiveness to cocaine in mGlu2 KO mice
(Morishima et al., PNAS, 2005)
Pharmacological activation of mGlu2/3 receptors reduces
self-administration of nicotine and cocaine
(Leichti et al., J. Neurosci., 2006; Adewale et al., JPET 2006)
Activation of mGlu2/3 receptors
precipitates the deficit in brain
reward function associated with
nicotine withdrawal
mGlu2/3
(Kenny et al., JPET, 2003)
Additive
drugs
VTA
Activation of mGlu2/3 receptors reduces priming- and
context-induced drug reinstatement
(Adewale et al., JPET, 2006; Leichti et al., J. Neurosci. 2006; )
Cue-induced nicotine relapse
Cue-induced
relapse
Dysregulation of glutamate homeostasis in the N. Accumbens
Core underlies relapse (Knackstedt et al., Biol. Psychiatry, 2009)
PFCtx
Glut
+
NAc
Core
The XC- activator,
N-acetylcysteine (NAC)
restores synaptic plasticity
in the NAc of cocainedependent rats by enabling
the activation of mGlu2/3
receptors
(Moussawi et al.,
Nat Neurosci., 2009)
Emerging drugs for the treatment of nicotine addiction
(Kenny, Exp. Rev. Clin. Pharmacol. 23, 2009)
Chromatin regulation in drug addiction and depression
Renthal and Nestler, Dialogues Clin Neurosci 11, 257,2010
Dnmt3 regulates cocaine reward and spine plasticity
in the NAcc (LaPlant et al., Nat. Neurosci. 13, 9, 2010)
GFP Dnmt3
HSV-GFP
HSV-Dnmt3
Activation of mGlu2/3 receptors
leads to gene promoter
demethylayion
Matriscano F. et al. Submitted
Ctrl
VLP70 mg/kg
CLZ 5 mg/kg
Control
LY379268 (0.5 mg/kg)
MET(750 mg/kg)
10
8.0
4.0
#
2.0
0
*
17 kD
β-actin
42 kD
1
MET + LY379268
6.0
Gadd45-β
Densitometric analysis of
Gadd45b/β-actin (arbitrary units)
BDNF promoter methylation
HAL1.5mg/kg
LY 0.5 mg/kg
2
Controls
3
4
LY379268
(0.5 mg/kg)
1.0
0.8
0.6
0.4
0.2
0
Controls
LY379268
mGlu receptors as targets in addition
1. Acute reinforcing: mGlu2/3 agonists and mGlu5 NAMs
Controversial role for mGlu1 receptors. mGlu4/7/8 receptors?
2. mGlu2/3 receptor antagonists improve the
Reward impairment in drug withdrawal.
mGlu5 NAMs are detrimental.
mGlu2/3 agonists and mGlu5 NAM relieve physical
symptoms of opioid withdrawal
3. Drug relapse after prolonged abstinence: Glu2/3 agonists
and mGlu5 NAMs
4. mGlu2/3 agonists behave similarly to antistress hormones in
the antireward/stress neuronal circuitry.
Activation of mGlu7 receptors inhibits cocaine reinstatement
via mGlu2/3 receptors (Li et al., J. Neurochem. 114, 1368, 2010)
Glutamate
mGlu7
+
AMN082
Pathological cycling in addiction (Koob, Neuron, 2008)
Stress hormones (CRF, Vasopressin) enhance
GABAergic transmission in the CeA
Antistress hormones (Nociceptin, Oxytocin) reduces
GABAergic transmission in the CeA
Nie et al., Science, 2004; Huber et al., Science, 2005;
Roberto and Siggins, PNAS, 2006; Koob, Neuron, 2008
Activation of mGlu2/3 receptors
inhibits GABAergic transmission in
the lateral portion of the CeA
Swanson et al., 2004
Activation of mGlu2/3 receptors in the CeA attenuates
the expression of incubation of cocaine craving
(Lu et al., Biol. Psych. 2007)
ICSS
60
50
40
30
20
10
0
-10
-20
-30
Hedonic allostasis with escalating cocaine use
Cocaine
Cocaine
Cocaine
Ahmed et al., Nat. Neurosci. 2002
Dnmt3 regulates cocaine reward and spine plasticity
in the NAcc (LaPlant et al., Nat. Neurosci. 13, 9, 2010)
GFP Dnmt3a
HSV-GFP
HSV-Dnmt3a