Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction

Abstract

Glutamate is probably the most important excitatory neurotransmitter in the brain. The glutamate N-methyl-D-aspartate receptor (NMDAR) is a calcium-gated channel that coordinates with G protein-coupled receptors (GPCRs) to establish the efficiency of the synaptic transmission. Cross-regulation between these receptors requires the concerted activity of the histidine triad nucleotide-binding protein 1 (HINT1) and of the sigma receptor type 1 (σ1R). Essential brain functions like learning, memory formation and consolidation, mood and behavioral responses to exogenous stimuli depend on the activity of NMDARs. In this biological context, endocannabinoids are released to retain NMDAR activity within physiological limits. The efficacy of such control depends on HINT1/σ1R assisting in the physical coupling between cannabinoid type 1 receptors (CB1Rs) and NMDARs to dampen their activity. Subsequently, the calcium-regulated HINT1/σ1R protein tandem uncouples CB1Rs to prevent NMDAR hypofunction. Thus, early recruitment or a disproportionate cannabinoid induced response can bring about excess dampening of NMDAR activity, impeding its adequate integration with GPCR signaling. Alternatively, this control circuit can apparently be overridden in situations where bursts of NMDAR overactivity provoke convulsive syndromes. In this review we will discuss the possible relevance of the HINT1/σ1R tandem and its use by endocannabinoids to diminish NMDAR activity and their implications in psychosis/schizophrenia, as well as in NMDAR-mediated convulsive episodes.

Ketamine administered pregnant rats impair learning and memory in offspring via the CREB pathway

“…It is generally accepted that ketamine blocks NMDAR, thus mediating the neurotransmission of postsynaptic receptors [36]. NMDAR in turn mediates the release of neurotransmitters (such as acetylcholine, dopamine, GABA, and NE), and regulates the levels of sodium and calcium.…”

Focus on cannabinoids and synthetic cannabinoids

“…The main synapses affected by the retrograde signaling endocannabinoid system are the glutamatergic and GABAergic, with strong CB1R expression in glutamatergic and GABAergic cells. Through CB1R activation, the endocannabinoid system plays a relevant role in reducing N‐methyl‐D‐aspartate (NMDA) receptor activity and therefore limits the excitotoxicity resulting from their excess activity . Thus, this endogenous system could be pharmacologically manipulated to reestablish the function of deregulated NMDA receptors, such as psychosis/schizophrenia or convulsive episodes.…”

“…Through CB1R activation, the endocannabinoid system plays a relevant role in reducing N-methyl-D-aspartate (NMDA) receptor activity and therefore limits the excitotoxicity resulting from their excess activity. 20 Thus, this endogenous system could be pharmacologically manipulated to reestablish the function of deregulated NMDA receptors, such as psychosis/schizophrenia or convulsive episodes. On the other hand, endocannabinoids stimulate or inhibit GABA release, depending on the dose and brain regions, probably via dopaminergic modulation.…”

Medical Cannabis for Adult Attention Deficit Hyperactivity Disorder: Sociological Patient Case Report of Cannabinoid Therapeutics in Finland

“…In addition to dopamine, the role of for instance glutamate, GABA, and other neurotransmitter systems need consideration, as well as N -methyl-D-aspartate and cannabinoid 2 (CB2) receptors, which have been suggested to modulate, for instance, impulsivity in interaction with endocannabinoids [10, 22, 23, 34, 35]. Therefore, further preclinical and clinical studies are warranted to map the complex interactions involved with the ECS in various pathophysiologies [35].…”

“…Therefore, further preclinical and clinical studies are warranted to map the complex interactions involved with the ECS in various pathophysiologies [35]. The case report presented below offers potential directions for future research and clinical practice.…”