Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression.
Drugs of abuse induce long-lasting changes in neural circuits that may underlie core components of addiction. Here we focus on glutamatergic synapses onto dopamine (DA) neurons of the ventral tegmental area (VTA). Using an 'ex vivo' approach in mice, we show that a single injection of cocaine caused strong rectification and conferred sensitivity to the polyamine Joro spider toxin (JST) of AMPAR-mediated excitatory postsynaptic currents (AMPAR EPSCs), indicating the recruitment of receptors that lack GluR2. This qualitative change in transmission was paralleled by an increase in the AMPAR:NMDAR ratio and was prevented by interfering with the protein interacting with C kinase-1 (PICK1) in vivo. Activation of metabotropic glutamate receptors (mGluR1s) by intraperitoneal injection of a positive modulator depotentiated synapses and abolished rectification in slices of cocaine-treated mice, revealing a mechanism to reverse cocaine-induced synaptic plasticity in vivo.
Department of Basic Neurosciences, University of Geneva, 1 Michel Servet, CH-1211 Geneva, Switzerland.
Camilla
C
Bellone
Christian
C
Lüscher
D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000494:pharmacology; D018797:Cell Cycle Proteins; D003042:Cocaine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D009687:Nuclear Proteins / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D018091:Receptors, AMPA / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D018709:Statistics, Nonparametric; D009435:Synaptic Transmission / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000166:cytology
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; C091822:Prkcabp protein, mouse; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D008734:Methoxyhydroxyphenylglycol; D003042:Cocaine; C010117:3,4-dihydroxyphenylglycol