Decreased plasma membrane targeting of NMDA‐NR1 receptor subunit in dendrites of medial nucleus tractus solitarius neurons in rats self‐administering morphine

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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 μm), but had a higher number of intracellular gold particles per unit cross‐sectional area (169 ± 6.1 vs. 148 ± 5.1 per 100 μm2) 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 μm), 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. Synapse 53:191–201, 2004.