Altered CB₁ receptor coupling to G-proteins in the post-mortem caudate nucleus and cerebellum of alcoholic subjects

Abstract

Biochemical, pharmacological and genetic evidence suggests the involvement of the endocannabinoid system in alcohol dependence. The aim of the present study was to evaluate the state of CB1 receptors in post-mortem caudate nucleus, hippocampus and cerebellum of alcoholic subjects.CB1 protein levels were measured by Western blot, CB1 receptor density and affinity by [(3)H]WIN55,212-2 saturation assays and CB1 functionality by [(35)S]GTPγS binding assays. Experiments were performed in samples from 24 subjects classified as non-suicidal alcoholics (n = 6), suicidal alcoholics (n = 6), non-alcoholic suicide victims (n = 6) and control subjects (n = 6).Alcoholic subjects presented hyperfunctional CB1 receptors in the caudate nucleus resulting in a higher maximal effect in both alcoholic groups compared to the non-alcoholic groups (p < 0.001). Conversely, in the cerebellum the non-suicidal alcoholic subjects showed hypofunctional receptors with lower maximal effect and potency (p < 0.001). No changes were found in the CB1 protein expression in either region. In the hippocampus of alcoholic subjects, no changes were observed either in the functionality, density or protein levels.Our data support an association between endocannabinoid system activity and alcoholism. The modifications reported here could be either a consequence of high lifetime ethanol consumption or a vulnerability factor to develop alcohol addiction.

Alcohol-dose-dependent DNA methylation and expression in the nucleus accumbens identifies coordinated regulation of synaptic genes

“…Clinical studies have revealed that Zn 2+ deficiency is common among alcoholics, 48 and numerous studies have reported significant alterations in the endocannabinoid system following chronic ethanol consumption. 49 , 50 In addition, Zn 2+ modulates alcohol-sensitive targets, including GABA A and GABA B , N-methyl-d-aspartate, AMPA and glycine receptors. 51 Our finding that heavy alcohol use is associated with decreased GPR39 expression predicts a role in downregulating the inhibitory endocannabinoid pathway, facilitating glutamate release 52 and, to a lesser extent, GABA release at GABAergic synapses.…”

Exo- and Endo-cannabinoids in Depressive and Suicidal Behaviors

“…The positive correlation of upregulation of CB1 and FAAH activity indicates that CB1 receptor sensitization in the ventral striatum of suicide victims could be contributed to a decrease in AEA levels. However, an increase in CB1 receptor expression and lower levels of MAGL activity were reported in postmortem PFC of subjects with AUD (123). In addition to the findings related to CB1, density of CB2 receptors and GPR55 gene expression were found to be significantly lower in the dlPFC of suicide victims (124).…”

Molecular Alterations of the Endocannabinoid System in Psychiatric Disorders

“…For example, protein expression of the CB2r and the non-cannabinoid receptor G proteincoupled receptor 55 (GPR55r) has been measured in post-mortem brain tissue of suicide completers [64]. Protein levels of CB1r were examined in post-mortem caudate nucleus, Hipp and cerebellum of alcoholic subjects using WB [154]. Similarly, protein levels of CB2r, CB1r and the metabolizing enzymes FAAH and MAGL were measured by WBs in the motor cortex of motor neuron disease patients [155].…”

“…Cloninger type 1 alcohol-dependent subjects showed significantly increased docosahexaenoyl ethanolamide (DHEA) levels in the AMY, and a significant negative correlation between AEA concentrations and mGlu1/5 receptor density in the HIPP compared to Cloninger type 2 alcohol-dependent subjects and controls [437]. Moreover, Erdozain et al (2015) [438] carried out several postmortem studies on the alcohol-dependent population. In the first study, the state of the CB1r, the enzymes FAAH and MAGL, and the extracellular signal-regulated kinase (ERK) and cyclic-AMP response element-binding protein (CREB) were assessed in the post-mortem PFC of alcohol-dependent subjects and controls, who were classified into four different groups: (1) non-suicidal alcohol-dependent subjects; (2) suicidal alcohol-dependent subjects;…”