Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity

Abstract

NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (eg antimuscarinics, non-NMDA glutamate antagonists, and ␣ 2 adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an ␣ 2 adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m 3 ) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated.

Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial

“…This is arguably similar to previous research showing that antidepressant effects of brief ketamine infusions are not correlated with psychotomimetic effects (Luckenbaugh et al, 2014). Since blockade of NMDA receptors also produces hyperactivity in glutamatergic pathways that putatively project onto non-NMDA receptors in corticolimbic brain regions (Duman and Aghajanian, 2012; Farber, 2003) and alpha-2 agonists are not expected to normalize this excessive activity (Farber et al, 2002; Jevtovic-Todorovic et al, 1998), our findings would be consistent with the proposal that activation of non-NMDA receptors may be the necessary mechanism for NMDA antagonists' antidepressant effects (Akinfiresoye and Tizabi, 2013; Dwyer and Duman, 2013) (See Figure in Appendix). We also note that clonidine's cholinergic-dampening effect in the ketamine-disinhibited circuit (depicted in the figure in the appendix) bears some resemblance to the anticholinergic scopolamine.…”

“…These two excitatory pathways converge on the same downstream corticolimbic neurons, thus hyperactivating them and leading to cognitive deficits and complex behavioral effects (Farber, 2003; Newcomer et al, 1999). Alpha-2 agonist co-administration dampens the cholinergic pathway (Farber et al, 2002), relieving some of the excessive stimulation of the downstream corticolimbic neurons, thereby reducing pathologic effects of NMDA antagonists (Jevtovic-Todorovic et al, 1998; Newcomer et al, 1998). Thus, clonidine co-administration may allow for prolonged ketamine infusions for treatment-resistant depression.…”

Successful management of dexmedetomidine for postoperative intensive care sedation in a patient with anti-NMDA receptor encephalitis: a case report and animal experiment

“…4a, b). Consistent with our observations, it has been reported that clonidine, another clinically available α 2 adrenergic agonist, could protect against MK-801-induced neurotoxicity (vacuole reaction) in rat retrosplenial cortex (Farber et al 2002). Furthermore, the most significant side-effects of dexmedetomidine are hypotension and bradycardia (Carollo et al 2008).…”

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

“…Excitotoxicity has been observed in multiple neurodegenerative disease states, including ALS, AD, PD, stroke and METH toxicity [20, 26, 35, 50, 51]. Through the modulation of glutamate and its receptors, sigma ligands have been reported to be neuroprotective against excitotoxicity in retinal ganglion cells (RGCs), primary neuronal cultures, and ischemic stroke models [23, 52–57]. …”