Pathological cycling in addiction (Koob, Neuron, 2008)

DA release (% of basal) 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)

Cocaine self-administration heroin Glutamate release associated with addiction (You et al., J. Neurosci., 2007; LaLumiere and Kalivas, J. Neurosci. 2008) Nac core

Glutamate Receptor Families AMPAKainateNMDAMetabotropic GluR1 GluR2 GluR3 GluR4 GluR5 GluR6 GluR7 KA1 KA2 NMDAR1 NMDAR2A NMDAR2B NMDAR2C NMDAR2D mGluR1 mGluR5 mGluR2 mGluR3 mGluR4 mGluR6 mGluR7 mGluR8 Go Gi, Gq NMDAR3

Control LTP LTP and LTD of excitatory synaptic transmission as a substrate for associative learning

Drugs of abuse induce LTP at excitatory synapses on DAergic neurons in the VTA (Kauer and Malenka, Nat. Rev. Neurosci. 8, 844, 2007)

NAc Bidirectional loss of synaptic plasticity at the PFC/NAc core synapses following chronic cocaine (Mussawi et al., Nat. Neurosci., 2009) 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)

mGlu1 mGlu5 mGlu2 mGlu3 mGlu4 mGlu6 mGlu7 mGlu8

mGlu5 receptors: potential targets for The treatment of addiction MAPK, PI-3-K GSGS

Fenobam ADX10059 ADX48621 STX107 AZD2516 AFQ056 Negative allosteric modulators of mGlu5 receptors: Fragile X, GERD, migraine, nicotine addiction, Parkinson’s disease/L-DOPA-induced dyskinesias

Reinforcing effects of cocaine are absent in mGlu5 knockout mice (Chiamulera et al., Nature, 2001)

1. Amplification of PF/VTA excitatory synapses by mGlu5 receptors Activation of mGlu5 receptors is required for incentive motivation for the reinforcer (Markou, Biol. Psych. 2007)

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 Saline Methamphetamine Ubiquitin  -Synuclein Parkin Fornai et al., 2003