title: Decreased plasma membrane targeting of NMDA-NR1 receptor subunit in dendrites of medial nucleus tractus solitarius neurons in rats self-administering morphine.
abstract: Opioid abuse is associated with repeated administration and escalation of dose that can result in profound adaptations in homeostatic processes. Potential cellular mechanisms and neural sites mediating opiate-dependent adaptations may involve NMDA-dependent synaptic plasticity within brain areas participating in behaviors related to consumption of natural reinforcers, as well as affective-autonomic integration, notably the medial nucleus tractus solitarius (mNTS). NMDA-dependent synaptic plasticity may be mediated by changes in the intracellular and surface targeting of NMDA receptors, particularly in postsynaptic sites including spines or small distal dendrites. High-resolution immunogold electron microscopic immunocytochemistry combined with morphometry were used to measure changes in targeting of the NMDA-NR1 (NR1) receptor subunit between intracellular and plasmalemmal sites in dendrites of neurons of the intermediate mNTS of rats self-administering escalating doses of morphine (EMSA). In control and EMSA rats, the density of plasmalemmal and cytosolic gold particles was inversely related to profile size. Collapsed across all NR1-labeled dendrites, rats self-administering morphine had a lower number of plasmalemmal gold particles per unit surface area (7.1 +/- 0.8 vs. 14.4 +/- 1 per 100 microm), but had a higher number of intracellular gold particles per unit cross-sectional area (169 +/- 6.1 vs. 148 +/- 5.1 per 100 microm2) compared to saline self-administering rats. Morphometric analysis showed that the decrease in plasma membrane labeling of NR1 was most robust in small dendritic profiles (<1 microm), where there was a reciprocal increase in the density of intracellular particles. These results indicate that the plasmalemmal distribution of the essential NR1 subunits in distal sites may prominently contribute to NMDA receptor-dependent modulation of neural circuitry regulating homeostatic processes, and targeting of these proteins can be prominently affected by morphine self-administration.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Glass
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kruzich
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Pickel
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000378:metabolism* / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011940:Receptor Aggregation / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D012646:Self Administration; D017552:Solitary Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: C409466:NR1 NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D009020:Morphine