Importance of inter-hemispheric prefrontal connection in the effects of non-competitive NMDA receptor antagonists

Abstract

Previous studies have shown that systemic, but not unilateral intra-prefrontal cortex administration of non-competitive NMDA antagonists, increased prefrontal activity, the cortical efflux of serotonin, and induced stereotypies. In this work we used in-vivo microdialysis and immunohistochemistry to test the hypothesis as to whether MK-801 and ketamine need to act on both prefrontal cortices to reproduce these neurochemical and behavioural changes. Dialysis probes were implanted in the medial prefrontal cortex, and extracellular serotonin as well as behavioural stereotypies was measured after systemic administration of MK-801 and ketamine (1 mg/kg and 25 mg/kg, respectively), and unilateral and bilateral perfusion of both drugs (300 μm and 3 mm, respectively). Additionally, the prefrontal (glutamatergic) level of activity was measured using c-Fos immunohistochemistry. Systemic and bilateral (but not unilateral) prefrontal administration of MK-801 and ketamine increased serotonin efflux whereas only systemic administration of both drugs produced hyperlocomotion and stereotypies. The unilateral perfusion of 1 μm tetrodotoxin in the medial prefrontal cortex reduced increases of serotonin in both hemispheres, the expression of c-Fos in the contralateral side, and stereotypy scores after systemic NMDA antagonists. Our results support the hypothesis that a bilateral impairment of cortical inhibition in the medial prefrontal cortex is needed for non-competitive NMDA antagonists to induce the state of pyramidal cell hyperactivity and concurrent efflux of serotonin. Furthermore, hyperlocomotion and stereotypies produced by MK-801 and ketamine do not appear to result from changes in the activity of prefrontal cortex although this structure exerts some control over these behaviours.

Impact of subanesthetic doses of ketamine on AMPA-mediated responses in rats: An in vivo electrophysiological study on monoaminergic and glutamatergic neurons

“…These results revealed that the increase in the number of c-Fos-positive cells following administration of the NMDA antagonist MK-801 was altered by application of tetrodotoxin in the medial prefrontal cortex (mPFC), but not the in DRN. While this result indicates an involvement of the mPFC, it did not show a greater activation in DRN following NMDA receptor blockade (Lopez-Gil et al, 2011), which is concordant with results obtained herein on the firing activity of 5-HT neurons. Altogether, these data show that although there was no change in firing activity of 5-HT neurons, an increase of 5-HT neurotransmission can be observed in projection areas following acute ketamine administration.…”

Does ketamine ameliorate the social stress‐related bladder dysfunction in mice?

“…The FVB mice were randomly assigned to either SS exposure for 60 minutes on seven consecutive days for 4 weeks or control without SS. SS model was referred to the previous studies 3,8 …”

The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN

“…For the intracerebral microinjection experiments, LY341495 (0.003 and 0.03 pmol/0.1 μl/side) or ketamine (0.3 and 3 nmol/0.1 μl/side) was injected 30 min or 24 h before the test, and NBQX (0.01 and 0.03 nmol/0.1 μl/side) was injected 35 min before the test. The doses for the intracerebral microinjection of LY341495, ketamine, and NBQX were selected based on the observations in previous studies (Iijima et al, 2013;López-Gil et al, 2007;López-Gil et al, 2012;Nishitani et al, 2014).…”