NMDA receptor antagonists ketamine and Ro25-6981 inhibit evoked release of glutamate in vivo in the subiculum

Abstract

Preclinical and clinical data have identified ketamine, a non-selective NMDAR (N-methyl-D-aspartate receptor) antagonist, as a promising medication for patients who do not respond to treatment with monoamine-based antidepressants. Moreover, unlike the current monoamine-based antidepressants, ketamine has a long-lasting effect already after a single dose. The mechanisms of ketamine action remain to be fully understood. Using a recently developed microelectrode array (MEA), which allows sub-second measurements of fluctuating glutamate concentrations, we studied here the effects of in vivo local application of the ketamine and of the N2B subunit-specific antagonist Ro25-6981 upon evoked glutamate release. Both ligands inhibit glutamate release in subregions of the hippocampus and prefrontal cortex. Likewise, acute systemic ketamine treatment, at an antidepressant dose, caused a reduction in evoked glutamate release in the subiculum. We suggest that the effects of ketamine and Ro25-6981 in the subiculum could involve blockade of presynaptic NMDA receptors containing N2B subunits.

Hippocampal subfield volumes in short‐ and long‐term lithium‐treated patients with bipolar I disorder

“…Furthermore, these subfields constitute an important target for psychotropic drug action. In fact, antidepressants have been found to exert a trophic effect on CA3 and DG subfields and recently, a reduction in the glutamate release in the subiculum has been related with the fast‐acting antidepressant effect of ketamine . In agreement with these data, lithium was found to act on the subicular complex and on the CA3 and DG subfields as well.…”

Roles of Presynaptic NMDA Receptors in Neurotransmission and Plasticity

“…While it is generally assumed that the majority of ketamine’s therapeutic properties result from actions at postsynaptic NMDARs [97], ketamine and other NMDAR-based therapeutics may also affect preNMDARs. For example, ketamine administered at antidepressant doses reduces evoked glutamate release in vivo measured in the subiculum and prelimbic area of the prefrontal cortex, and, while not directly demonstrated, these effects have been proposed to be mediated by preNMDARs [98]. Therefore, future studies are warranted to disambiguate how NMDAR-based therapeutics affect preNMDARs.…”

Mas-Related Gene (Mrg) C Activation Attenuates Bone Cancer Pain via Modulating Gi and NR2B

“…Tyrosine phosphorylation of NR2B in the spinal cord is associated with the central sensitization, increasing dorsal the horn excitability and facilitating the sensory input, which may be responsible for BCP [ 10 , 11 ]. Previous studies have demonstrated that NMDA receptor antagonists (such as ketamine) and NR2B-selective antagonists (such as ifenprodil and Ro25-6981) could exert potent analgesic effects in animal models of BCP [ 12 , 13 ]. However, these antagonists have also been shown to be associated with intolerable side effects, including memory impairment and psychotomimetic effects.…”