Why sigma-1 receptor dysfunction might confer vulnerability to cannabis-induced psychosis.

The N-methyl-D-aspartate (NMDA) receptor has long been implicated in the pathophysiology of schizophrenia. NMDA receptor antagonists induce psychotic states in humans and when administered to rodents promote lasting behavioural phenotypes relevant to schizophrenia (Javitt and Zukin, 1991; Abi-Saab et al., 1998; Javitt, 2007). Further, schizophrenia brain tissue contains reduced expression and function of NMDA receptors (Errico et al., 2013). It is well established that the use of cannabis increases the risk of psychosis in vulnerable individuals; however, our understanding of the molecular basis of this susceptibility is limited. In this issue of the International Journal of Neuropsychopharmacology Javier Garzon and colleagues delineate a mechanism of relevance to cannabis-induced psychosis by uncovering that the sigma-1 receptor prevents cannabinoids from provoking NMDA receptor hypofunction. Garzon and colleagues have recently shown that CB1 receptors regulate NMDA receptors at the postsynaptic membrane (Sanchez-Blazquez et al., 2013, 2014; VicenteSanchez et al., 2013). This provides an additional CB1 receptor-mediated homoeostatic mechanism against neurotoxicity provoked by excessive glutamate activation of NMDA receptors. Most cannabinoid CB1 receptors are expressed presynaptically and excessive NMDA stimulation by glutamate triggers the synthesis of endocannabinoids like anandamide. Anandamide then behaves as a retrograde transmitter; travelling from the postsynaptic membrane to presynaptic CB1 receptors, which when activated reduce glutamate release (Brown et al., 2003; Melis et al., 2004). Garzon and colleagues’ research has shown that CB1 receptors may also offset excessive NMDA receptor activation via a postsynaptic mechanism. CB1 receptor activation inhibits NMDA receptor function at the postsynapse by CB1 and NMDA receptors forming a complex that is moved from the cell membrane to the cytosol (Sanchez-Blazquez et al., 2013; Vicente-Sanchez et al., 2013). Thus, CB1 receptor activation induces NMDA receptor hypofunction by reducing the synaptic membrane expression of NMDA receptors. Garzon’s group has been working on detailing the molecules involved in this CB1-NMDA co-internalization process and has shown that the histidine triad nucleotidebinding protein 1 (HINT1) plays a critical role in binding CB1 and NMDA receptors together (Sanchez-Blazquez et al., 2013; Vicente-Sanchez et al., 2013). While the CB1-HINT1-NMDA receptor complex may protect against excitotoxicity, the question remained whether a molecular sensor might switch-off NMDA hypofunction – prolongation of reduced NMDA function is also detrimental to brain function and evidence suggests this is sufficient to trigger psychosis. In the present manuscript the sigma-1 receptor is identified as the molecule that helps dissociate the CB1-NMDA receptor complex, allowing the NMDA receptor to be reincorporated into the postsynaptic density thus normalizing NMDA receptor signalling. First using cultured cortical neurons Garzon and colleagues demonstrated that the ability of the synthetic cannabinoid receptor agonist WIN 55,212-2 to protect against NMDA-induced neurotoxicity was absent in mice lacking sigma-1 receptors. Then, using biomolecular fluorescence complementation in CHO cells it was shown that the sigma-1 receptor forms physical complexes with CB1, NR1 subunits of the NMDA receptor and HINT1 proteins. The presence of the sigma-1 receptor almost abolished the association of HINT1 with NR1 subunits, which is critical for CB1-NMDA receptor binding. Further, mice lacking sigma-1 receptors displayed reduced associations betweenCB1,HINT1andNR1subunits,with the results inferring sigma-1 bindsNR1 subunits andprevents the translocation of the HINT1 protein from CB1 to the NMDA receptor. Sigma-1 receptors also regulated the ability of NMDA receptor antagonism to reduce the analgesic effects of cannabinoids via the physical postsynaptic association of CB1 and NMDA receptors. CB1 receptor internalization and recycling is critical to effective cannabinoid analgesia as it allows resensitized CB1 receptors to be replaced at the cell surface for agonist binding. NMDA Address for correspondence: Jonathon Arnold, The Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia. Tel.: +61 2 9351 0762 Fax: +61 2 9351 4717 Email: [email protected] See: Sanchez-Blazquez P, Rodriguez-Munoz M, Herrero-Labrador R, Burgueno J, Zamanillo D, Garzon J (2014) The calcium-sensitive Sigma-1 receptor prevents cannabinoids from provoking glutamate NMDA receptor hypofunction: implications in antinociception and psychotic diseases. Int J Neuropsychopharmacol:1–13. International Journal of Neuropsychopharmacology (2014), 17, 1911–1913. © CINP 2014 doi:10.1017/S1461145714000960 FOCUS