NR2B subunit-specific NMDA antagonist Ro25-6981 inhibits the expression of conditioned fear

Abstract

N-methyl-D-asparate (NMDA)-mediated glutamatergic neurotransmission is strongly involved in the development of trauma-induced behavioral dysfunctions, and indirect evidence suggests that NR2B subunit-expressing NMDA receptors are primarily involved in this process. Earlier studies showed that NR2B blockers inhibit the acquisition of conditioned fear, a frequently used model of post-traumatic stress disorder, but their effects on the expression of conditioned fear was poorly studied. We investigated here the effects of the selective serotonin reuptake blocker, fluoxetine, the NMDA blocker, MK-801, and the NR2B subunit blocker, Ro25-6981 on the expression of conditioned fear. Rats received 10 foot shocks administered over 5 min and were tested 24 h later in the shocking context. Treatments were administered 1 h before testing. Shocks dramatically increased freezing and reduced exploration. MK-801 and Ro25-6981 significantly ameliorated both changes. The effects of fluoxetine were less pronounced. In the open field, MK-801 increased locomotion, ataxia, and stereotypy (effects typical of NMDA blockade). Neither fluoxetine nor Ro25-6981 affected locomotion in the open field. Thus, the NR2B-specific NMDA blockade preserved the beneficial effects of general NMDA antagonists on the expression of conditioned fear but did not produce the locomotor side-effects typical of the latter. These findings warrant further studies on the effects of NR2B antagonists in models of post-traumatic stress disorder.

Genetic, pharmacological and lesion analyses reveal a selective role for corticohippocampal GLUN2B in a novel repeated swim stress paradigm

“…Importantly, GluN2B KO mice tested on a standard, single exposure mouse version of the forced swim test were no different from GluN2B FLOX controls, whereas, on the same test, C57BL/6J mice systemically treated with Ro 25-6981 showed reduced immobility. This latter observation concurs with prior studies in rat and mice (Maeng et al, 2008; Li et al, 2010), although interpretation of the effect as being genuinely “depression-related” was complicated by an open field locomotor hyperactivity effect at the same dose, that was not seen in prior work (Mathur et al, 2009; Haller et al, 2011). Notwithstanding, taking these findings together further supports a dissociation between an effect of brain-wide GluN2B inactivation on acute stress responsivity, and a more selective effect of loss of cortical/CA1 GluN2B impacting behavioral adaptations to repeated swim stress.…”

“…spatial memory) forms of learning and memory. Systemic treatment of rats and mice with Ro 25-6981 also impairs Pavlovian fear memory and extinction (Duffy et al, 2008; Haller et al, 2011; Mathur et al, 2009). Moreover, either GluN2B gene inactivation or Ro 25-6981 application disrupts long-term depression (LTD), and to some extent, long-term potentiating (LTP), at hippocampal synapses (Duffy et al, 2008; von Engelhardt et al, 2008; Brigman et al, 2010; Ge et al, 2011).…”

Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein–protein interaction inhibitors

“…at systemic doses similar to those used here [6, 28]. We propose that this difference is due to evaluation of doses that (1) show therapeutic efficacy and (2) do not impair motor performance (i.e.…”

“…MK-801 reliably attenuates hyperalgesia and alleviates pain behavior at a dose of 0.1 mg/kg [2, 11, 29, 30]. However, the therapeutic range of 0.1-0.3 mg/kg is also associated with cognitive impairments, followed closely by motor impairments at doses of 0.3 mg/kg and greater [6-8, 28]. We, thus, propose that the absence of MK-801-induced impairment in spatial working memory observed here is due to our use of a therapeutically-effective low dose of MK-801 that did not impair motor behavior in our task.…”

Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects

“…Ro 25-6981 (supplied by BMS) dissolved in vehicle was tested at doses of 1, 3, and 10mg/kg IP, based on previous reports of behavioral efficacy 6, 23, 24 , alongside the ketamine studies at 1, 30, and 80mg/kg. Effects of all treatments were compared to unique control groups receiving IP infusions of saline as previously described 12 (for the ketamine 3 and 10mg) and vehicle (for ketamine 1, 30 and 80mg/kg and Ro 25-6981 1, 3 and 10mg/kg) since Ro 25-6981 was not soluble in saline.…”