title: Cocaine Experience Enhances Thalamo-Accumbens N-Methyl-D-Aspartate Receptor Function.
abstract: Excitatory synaptic transmission in the nucleus accumbens (NAc) is a key biological substrate underlying behavioral responses to psychostimulants and susceptibility to relapse. Studies have demonstrated that cocaine induces changes in glutamatergic signaling at distinct inputs to the NAc. However, consequences of cocaine experience on synaptic transmission from the midline nuclei of the thalamus (mThal) to the NAc have yet to be reported.
  
  
  
  To examine synapses from specific NAc core inputs, we recorded light-evoked excitatory postsynaptic currents following viral-mediated expression of channelrhodopsin-2 in the mThal, prefrontal cortex (PFC), or basolateral amygdala from acute brain slices. To identify NAc medium spiny neuron subtypes, we used mice expressing tdTomato driven by the promoter for dopamine receptor subtype 1 (D1). We recorded N-methyl-D-aspartate receptor (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) properties to evaluate synaptic adaptations induced by cocaine experience, a 5-day cocaine exposure followed by 2 weeks of abstinence.
  
  
  
  Excitatory inputs to the NAc core displayed differential NMDAR properties, and cocaine experience uniquely altered AMPAR and NMDAR properties at mThal-D1(+), mThal-D1(-), and PFC-D1(+) synapses, but not at PFC-D1(-) synapses. Finally, at mThal-D1(+) synapses, cocaine enhanced GluN2C/D function and NMDAR-dependent synaptic plasticity.
  
  
  
  Our results identify contrasting cocaine-induced AMPAR and NMDAR modifications at mThal-NAc and PFC-NAc core synapses. These changes include an enhancement of NMDAR function and plasticity at mThal-D1(+) synapses. Incorporation of GluN2C/D-containing NMDARs most likely underlies these phenomena and represents a potential therapeutic target for psychostimulant use disorders.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Max E
authors.initials: ME
authors.lastname: Joffe
authors.affiliation: Department ofAnesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee; Department ofPsychiatry, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: brad.a.grueter@vanderbilt.edu.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Grueter
mesh_terms: D000818:Animals; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020644:Midline Thalamic Nuclei / Q000187:drug effects* / Q000502:physiology*; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology*; D062308:Optogenetics; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
chemical_list: C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D003042:Cocaine
keywords: Addiction; Cocaine; NMDAR; Nucleus accumbens; Prefrontal cortex; Thalamus