Pathological cycling in addiction (Koob, Neuron, 2008)
Drugs of abuse increase synaptic DA in the Nucleus Accumbens
(Di Chiara and Imperato, Proc. Natl. Acad. Sci., 1988)
ethanol
nicotine
Limbic motor
subcircuit
Dorsal-striatal
motor subcircuit
(motor habits)
Glutamate release associated with addiction
(You et al., J. Neurosci., 2007; LaLumiere and Kalivas, J. Neurosci. 2008)
Cocaine self-administration
Nac core
heroin
Glutamate Receptor Families
AMPA
Kainate
NMDA
Metabotropic
Go
Gi, Gq
GluR1
GluR2
GluR3
GluR4
GluR5
GluR6
GluR7
KA1
KA2
NMDAR1
NMDAR2A
NMDAR2B
NMDAR2C
NMDAR2D
NMDAR3
mGluR1
mGluR5
mGluR2
mGluR3
mGluR4
mGluR6
mGluR7
mGluR8
LTP and LTD of excitatory synaptic transmission as a
substrate for associative learning
Control
LTP
Drugs of abuse induce LTP
at excitatory synapses on
DAergic neurons in the VTA
(Kauer and Malenka,
Nat. Rev. Neurosci. 8, 844, 2007)
Bidirectional loss of synaptic plasticity at the PFC/NAc core
synapses following chronic cocaine
(Mussawi et al., Nat. Neurosci., 2009)
NAc
LTP
LTD
Transiction to addiction is associated with a persistent
impairment in NMDA-dependent LTD in the NAcc core
Kasanetz F., Deroche-Gemonet V., Berson N., Balado E., Lafourcade M.,
Manzoni O., Piazza P.V. Science 328, 1709, 2010
The “perfect” drug:
1. inhibits the reinforcing properties of drugs and associated
cues
2. reinstates the mechanisms of control by the PFC over
the VTA-NAc
3. interferes with maladaptive mechanisms leading to hedonic
allostasis
4. relieves physical and motivational withdrawal symptoms
5. prevents relapse in response to drug priming, context,
and stress
6. has an impact on the negative reinforcement generated by
the stress neural circuit (extended amygdala)
mGlu2
mGlu3
mGlu1
mGlu5
mGlu4
mGlu6
mGlu7
mGlu8
mGlu5 receptors: potential targets for
The treatment of addiction
GS
MAPK, PI-3-K
Negative allosteric modulators of mGlu5 receptors:
Fragile X, GERD, migraine, nicotine addiction,
Parkinson’s disease/L-DOPA-induced dyskinesias
Fenobam
AFQ056
ADX10059
ADX48621
STX107
AZD2516
Reinforcing effects of cocaine are absent in mGlu5 knockout
mice (Chiamulera et al., Nature, 2001)
Activation of mGlu5 receptors is required for incentive
motivation for the reinforcer (Markou, Biol. Psych. 2007)
1. Amplification of PF/VTA
excitatory synapses by mGlu5
receptors
Extinction training after cocaine self-administration lowers
surface mGlu5 receptors in the Nacc core to inhibit drug seeking
mGlu5
Knackstedt et al., J. Neurosci. 30, 2010
mGlu5 receptor blockade reduces
methamphetamine reinforcement
and reimstatement
(Gass et al., Neuropsychopharm. 34, 2008)
mGlu5 receptor blockade
is protective against
Methamphetamine
(“Shabu”)
toxicity
Lewy bodies in the substantia nigra
of a Parkinsonian patient
Intracytoplasmic inclusions after
methamphetamine injection
Forno et al., 1996
Fornai et al., 2003
Ubiquitin
a-Synuclein
Saline
Parkin
Methamphetamine
Fornai et al., 2003