title: GluN2B-containing NMDA receptors blockade rescues bidirectional synaptic plasticity in the bed nucleus of the stria terminalis of cocaine self-administering rats.
abstract: Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA-dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self-administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA-mediated potentiation of AMPA receptors in this region may be part of the neural circuits of drug relapse.
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: Julian
authors.initials: J
authors.lastname: deBacker
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Hawken
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Normandeau
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Jones
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Di Prospero
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: Elysia
authors.initials: E
authors.lastname: Mechefske
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Gardner Gregory
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hayton
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: Éric C
authors.initials: ÉC
authors.lastname: Dumont
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000503:physiopathology; D019422:Dietary Sucrose / Q000008:administration & dosage; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011897:Random Allocation; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012646:Self Administration; D012686:Septal Nuclei / Q000187:drug effects* / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D019422:Dietary Sucrose; D018765:Dopamine Uptake Inhibitors; C121001:NR2B NMDA receptor; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D003042:Cocaine