In the past years, the relationship between the endocannabinoid system (ECS) and other hormonal and neuromodulatory systems has been intensively studied. G protein-coupled receptors (GPCRs) can stimulate endocannabinoid (eCB) production via activation of Gq/11 proteins and, in some cases, Gs proteins. In this review, we summarize the pathways through which GPCR activation can trigger eCB release, as well as the best known examples of this process throughout the body tissues. Angiotensin II-induced activation of AT1 receptors, similar to other Gq/11-coupled receptors, can lead to the formation of 2-arachido-noylglycerol (2-AG), an important eCB. The importance of eCB formation in angiotensin II action is supported by the finding that the hypertensive effect of angiotensin II, injected directly into the hypothalamic paraventricular nucleus of anaesthetized rats, can be abolished by AM251, an inverse agonist of CB1 cannabinoid receptors (CB1Rs). We conclude that activation of the ECS should be considered as a general consequence of the stimulation of Gq/11-coupled receptors, and may mediate some of the physiological effects of GPCRs.

Interleukin-1β is one of the main mediators in the cross-talk between the immune system and the central nervous system. Higher interleukin-1β levels are found in mood spectrum disorders, and the stress-induced expression rate of the interleukin-1β gene (IL1B) is altered by polymorphisms in the region. Therefore we examined the effects of rs16944 and rs1143643 single nucleotide polymorphisms (SNPs) within the IL1B gene on depressive and anxiety symptoms, as measured by the Brief Symptom Inventory, in a Hungarian population sample of 1053 persons. Distal and proximal environmental stress factors were also included in our analysis, namely childhood adversity and recent negative life-events. We found that rs16944 minor (A) allele specifically interacted with childhood adversity increasing depressive and anxiety symptoms, while rs1143643's minor (A) allele showed protective effect against depressive symptoms after recent life stress. The genetic main effects of the two SNPs were not significant in the main analysis, but the interaction effects remained significant after correction for multiple testing. In addition, the effect of rs16944 A allele was reversed in a subsample with low-exposure to life stress, suggesting a protective effect against depressive symptoms, in the post hoc analysis. In summary, both of the two IL1B SNPs showed specific environmental stressor-dependent effects on mood disorder symptoms. We also demonstrated that the presence of exposure to childhood adversity changed the direction of the rs16944 effect on depression phenotype. Therefore our results suggest that it is advisable to include environmental factors in genetic association studies when examining the effect of the IL1B gene.

Serotonin-1A (5-HT(1A)) receptors are known to play a role in impulsivity-related behavior. The C(-1019)G functional polymorphism (rs6295) has been suggested to regulate the 5-HT(1A) receptor gene (HTR(1A)) expression in presynaptic raphe neurons, namely, increased receptor concentration and reduced neuronal firing could be associated with the G allele. Previous studies indicate that this polymorphism is associated with aggression, suicide, and several psychiatric disorders, yet its association with impulsivity has rarely been investigated. We studied the relationship between impulsivity and the C(-1019)G polymorphism of the HTR(1A) in a population sample of 725 volunteers using the Impulsiveness subscale (IVE-I) of the Eysenck Impulsiveness, Venturesomeness, and Empathy scale and also the Barratt Impulsiveness Scale (BIS-11). Data were analyzed using analysis of variance with age and gender as covariates and Tukey's HSD post-hoc test. Post-hoc analysis revealed that the study had 0.958 power to detect 0.15 effect size. Significant differences between the C(-1019)G genotype groups (GG vs. GC vs. CC) were found. Subjects carrying GG genotype showed significantly higher impulsiveness scores compared to GC or CC carriers for the IVE-I scale (P = 0.014), for the Motor (P = 0.021), Cognitive Impulsiveness (P = 0.002), and for the BIS total score (P = 0.008) but not for the Nonplanning Impulsiveness (P = 0.520) subscale of the BIS-11. Our results suggest the involvement of the HTR(1A) in the continuum phenotype of impulsivity.

Previous studies have demonstrated that migraine is associated with enhanced perception and altered cerebral processing of sensory stimuli. More recently, it has been suggested that this sensory hypersensitivity might reflect a more general enhanced response to aversive emotional stimuli. Using functional magnetic resonance imaging and emotional face stimuli (fearful, happy and sad faces), we compared whole-brain activation between 41 migraine patients without aura in interictal period and 49 healthy controls. Migraine patients showed increased neural activation to fearful faces compared to neutral faces in the right middle frontal gyrus and frontal pole relative to healthy controls. We also found that higher attack frequency in migraine patients was related to increased activation mainly in the right primary somatosensory cortex (corresponding to the face area) to fearful expressions and in the right dorsal striatal regions to happy faces. In both analyses, activation differences remained significant after controlling for anxiety and depressive symptoms. These findings indicate that enhanced response to emotional stimuli might explain the migraine trigger effect of psychosocial stressors that gradually leads to increased somatosensory response to emotional clues and thus contributes to the progression or chronification of migraine.

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