Selective up-regulation of cannabinoid CB1 receptor coupling to Go-proteins in suicide victims with mood disorders

Abstract

Brain endocannabinoid system is proposed to play a role in the pathogenesis of affective disorders. In the present study, we analyzed the functionality of the cannabinoid receptor type 1 (CB1 receptor) at different transduction levels in prefrontal cortex (PFC) of depressed suicide victims. We examined stimulation of [35S]GTPγS binding, activation of Gα protein subunits and inhibition of adenylyl cyclase by the cannabinoid agonist WIN55,212-2, as well as [3H]CP55,940 binding, in PFC homogenates from suicide victims with major depression (MD) and matched control subjects. CB1 receptor-stimulated [35S]GTPγS binding was significantly greater in the PFC of MD compared with matched controls (23%, p < 0.05). This increase was most evident in the PFC from MD subgroup with negative blood test for antidepressants (AD) at the time of death (AD-free) (38%, p < 0.05), being absent when comparing the AD-treated MD cases with their controls. The density of CB1 receptors and their coupling to adenylyl cyclase were similar between MD and control cases, regardless of the existence of AD intake. Analysis of [35S]GTPγS-labelled Gα subunits allowed for the detection of upregulated CB1 receptor coupling to Gαo, but not to Gαi1, Gαi2, Gαi3, Gαz subunits, in the PFC from AD-free MD suicides. These results suggest that increased CB1 receptor functionality at the Gαi/o protein level in the PFC of MD subjects is due to enhanced coupling to Gαo proteins and might be modulated by AD intake. These data provide new insights into the role of endocannabinoid neurotransmission in the pathobiology of MD and suggest its regulation by ADs. ; This study was partially supported by the Spanish Ministry of Economy and Competitiveness, Spain (SAF2007/61862, SAF2011-25020 and SAF2015-67457-R, MINECO/FEDER) to AP, SAF 2009-08460 to JJM, and the Basque Government (IT-616-13 to JJM).