title: Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection.
abstract: Exposure to cocaine induces addiction-associated behaviors partially through remodeling neurocircuits in the nucleus accumbens (NAc). The paraventricular nucleus of thalamus (PVT), which projects to the NAc monosynaptically, is activated by cocaine exposure and has been implicated in several cocaine-induced emotional and motivational states. Here we show that disrupting synaptic transmission of select PVT neurons with tetanus toxin activated via retrograde trans-synaptic transport of cre from NAc efferents decreased cocaine self-administration in rats. This projection underwent complex adaptations after self-administration of cocaine (0.75 mg/kg/infusion; 2 h/d × 5 d, 1d overnight training). Specifically, 1d after cocaine self-administration, we observed increased levels of AMPA receptor (AMPAR)-silent glutamatergic synapses in this projection, accompanied by a decreased ratio of AMPAR-to-NMDA receptor (NMDAR)-mediated EPSCs. Furthermore, the decay kinetics of NMDAR EPSCs was significantly prolonged, suggesting insertion of new GluN2B-containing NMDARs to PVT-to-NAc synapses. After 45-d withdrawal, silent synapses within this projection returned to the basal levels, accompanied by a return of the AMPAR/NMDAR ratio and NMDAR decay kinetics to the basal levels. In amygdala and infralimbic prefrontal cortical projections to the NAc, a portion of cocaine-generated silent synapses becomes unsilenced by recruiting calcium-permeable AMPARs (CP-AMPARs) after drug withdrawal. However, the sensitivity of PVT-to-NAc synapses to CP-AMPAR-selective antagonists was not changed after withdrawal, suggesting that CP-AMPAR trafficking is not involved in the evolution of cocaine-generated silent synapses within this projection. Meanwhile, the release probability of PVT-to-NAc synapses was increased after short- and long-term cocaine withdrawal. These results reveal complex and profound alterations at PVT-to-NAc synapses after cocaine exposure and withdrawal.
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Neumann
authors.affiliation: The Second Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Yicun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Masago
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: The Second Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Ranji
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yanhua H
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Sesack
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Schlüter
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant; D008297:Male; D020644:Midline Thalamic Nuclei / Q000187:drug effects* / Q000502:physiology*; D009434:Neural Pathways; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D003042:Cocaine