N-Acetylcysteine reverses cocaine-induced metaplasticity.
Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.
Moussawi
Khaled
K
Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue BSB410, Charleston, South Carolina, USA.
Pacchioni
Alejandra
A
Moran
Megan
M
Olive
M Foster
MF
Gass
Justin T
JT
Lavin
Antonieta
A
Kalivas
Peter W
PW
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology; D055502:Secondary Prevention; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine; D000111:Acetylcysteine