Abstract
The endocannabinoid system is widespread throughout the central nervous system and its type 1 receptor (CB1) plays a crucial role in preventing the neurotoxicity caused by activation of glutamate N-methyl-D-aspartate receptors (NMDARs). Indeed, it is the activity of NMDARs themselves that provides the demands on the endogenous cannabinoids in order to control their calcium currents. Therefore, a physiological role of this system is to maintain NMDAR activity within safe limits, thereby protecting neural cells from excitotoxicity. Thus, cannabinoids may be able to control NMDAR overactivation-related neural dysfunctions; however, the major obstacles to the therapeutic utilization of these compounds are their psychotropic effects and negative influence on cognitive performance. Studies in humans have indicated that abuse of smoked cannabis can promote psychosis and even circumstantially precipitate symptoms of schizophrenia, although the latter appears to require a prior vulnerability in the individual. It is possible that cannabinoids provoke psychosis/schizophrenia reflecting a mechanism common to neuroprotection: the reduction of NMDAR activity. Cannabinoids are proposed to produce such effect by reducing the pre-synaptic release of glutamate or interfering with post-synaptic NMDAR-regulated signaling pathways. The efficacy of such control requires the endocannabinoid system to apply its negative influence in a manner that is proportional to the strength of NMDAR signaling. Thus, cannabinoids acting at the wrong time or exerting an inappropriate influence on their receptors may cause NMDAR hypofunction. The purpose of the present review is to draw the attention of the reader to the newly described functional and physical CB1–NMDAR association, which may elucidate the scenario required for the rapid and efficacious control of NMDAR activity. Whether alterations in these mechanisms may increase NMDAR hypofunction leading to vulnerability to schizophrenia will be outlined.
Highlights
Schizophrenia is a debilitating psychiatric illness that affects approximately 1% of the world’s population
The negative regulation of N-methyl-D-aspartate receptors (NMDARs) by cannabinoids is relevant because their persistent activation produces a series of perturbations that may lead to neurodegenerative diseases (Lipton, 2006), mood disorders, such as depression (Maeng and Zarate, 2007), and neuropathic pain (Sigtermans et al, 2009)
The CB1–NMDAR association plays a significant role in the efficacy of cannabinoids in combating NMDAR hyperactivityinduced insults
Summary
Schizophrenia is a debilitating psychiatric illness that affects approximately 1% of the world’s population. The excitotoxicity mediated by experimental activation of NMDARs is enhanced in cortical cultured neurons following targeted deletion of the cannabinoid receptor type 1 gene (CNR1; Kim et al, 2006; Vicente-Sánchez et al, 2013) Since in this paradigm alternative systems do not appear to exert significant control, CB1 emerges as a decisive negative physiological regulator of NMDAR function in the earliest development of cerebral cortical structures. The constraints that CB1 activity imposes on NMDAR function may underlie both neuroprotection and the negative effects of cannabinoids, and smoked cannabis abuse may lead to psychosis and circumstantially precipitate or intensify symptoms of schizophrenia (Degenhardt et al, 2003; Fernandez-Espejo et al, 2009), albeit mostly in subjects bearing a previous vulnerability (Cannon and Clarke, 2005;Harrison and Weinberger, 2005). If NMDARs and D1/D2 receptors establish such regulatory associations, NMDAR hypofunction would increase dopamine activity contributing to the symptoms of schizophrenia
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