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.

Do specific NMDA receptor subunits act as gateways for addictive behaviors?

“…Decreased NMDAR function could contribute to the cortical hypofunction that can promote cocaine seeking, likely by decreasing cortical control over behavioral inhibition and regulation (Chen et al ; McGinty et al ; Murphy et al ). However, systemic GluN2B inhibition does not reduce lever‐pressing for cocaine (deBacker et al ), which might not be predicted if reducing cortical NMDAR function promotes self‐administration. One possibility is that more moderate GluN2B changes (after drug intake) could have different effects relative to more complete GluN2B inhibition (by pharmacological blockers).…”

“…Recent studies have identified cocaine‐related NMDAR changes in the bed nucleus of the stria terminalis (BNST), a subcortical region which plays a critical role in anxiety and other emotion‐related behaviors. Cocaine self‐administration increases the decay time of NMDAR currents in BNST, suggesting an increase in GluN2B subunits (deBacker et al ), and also impairs NMDAR‐dependent LTD induction in the BNST. Interestingly, impaired LTD induction could be reversed by blocking GluN2B function, indicating that greater GluN2B function can actually impair some forms of synaptic plasticity.…”

“…Interestingly, impaired LTD induction could be reversed by blocking GluN2B function, indicating that greater GluN2B function can actually impair some forms of synaptic plasticity. However, systemic inhibition of GluN2B subunits did not reduce responding for cocaine (deBacker et al ), suggesting that BNST GluN2B adaptations do not regulate ongoing self‐administration. An interesting alternate possibility for this study, and other studies where adaptations are observed but do not seem to have behavioral consequences, is that GluN2B regulate the re‐forming of drug‐related memories during intake.…”

“…In addition, while a number of studies have examined the impact of NMDAR inhibitors that do not have clear subunit selectivity, many studies of addiction implicate GluN2B subunits. GluN2B subunits are interesting in that there can be a sizable population of extrasynaptic receptors, which can be rapidly trafficked into the synapse, and can produce differential regulation of plasticity induction relative to synaptic NMDARs (deBacker et al ; Newpher & Ehlers ; Traynelis et al ). There are also relatively selective antagonists for GluN2B subunits (ifenprodil, Ro 04‐5595, deBacker et al , but see Trovero et al ).…”

“…GluN2B subunits are interesting in that there can be a sizable population of extrasynaptic receptors, which can be rapidly trafficked into the synapse, and can produce differential regulation of plasticity induction relative to synaptic NMDARs (deBacker et al ; Newpher & Ehlers ; Traynelis et al ). There are also relatively selective antagonists for GluN2B subunits (ifenprodil, Ro 04‐5595, deBacker et al , but see Trovero et al ). The increasing evidence for a central role for GluN2B might, in part, reflect the presence of selective tools to interrogate GluN2B subunits, and subunits other than GluN2B may be assessed as more selective antagonists for other subunits are developed.…”