Resilient GluN2B-containing NMDARs contribute to dysfunctional synaptic plasticity associated with chronic cocaine intake

Abstract

Learning and memory mechanisms that are normally related to natural rewards, such as long-term potentiation (LTP) and depression (LTD), may be usurped by the voluntary intake of drugs of abuse. The maladaptive behaviour that characterizes addiction is thought to arise from persistent changes in excitatory synaptic function in brain reward circuits. The oval region of the dorsal bed nucleus of the stria terminalis (ovBST) is one such region susceptible to drug-induced synaptic remodeling and is implicated in drug-driven behaviors, reinforcement and stress-induced relapse to drug-seeking. Using whole-cell voltage clamp recordings of ovBST neurons in brain slices prepared from adult Long-Evans rats, we demonstrated an unrestrained increase in AMPAR-mediated excitatory transmission with maintenance of cocaine self-administration. This is unlike self-administration of a natural reward, in which we observed an enhancement and then decline of AMPAR-mediated transmission with continued intake. Additionally, we demonstrate impairment in NMDAR-mediated LTD in ovBST neurons with cocaine self-administration. This impairment may be due to resilient GluN2B-containing NMDARs, as application of a GluN2B-antagonist rescued impaired LTD. Based on models of NMDAR-mediated bidirectional plasticity we suggest that a drug-induced de-regulation between GluN2A and GluN2B subunits impairs LTD, which may underlie the enhancement AMPAR-mediated transmission.