The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replications are limited.
To examine whether a synonymous polymorphism, rs1049353, in exon 4 of the gene encoding the human endocannabinoid receptor (CNR1) moderates the effect of self-reported childhood physical abuse on lifetime anhedonia and depression and to replicate this interaction in an independent sample.
Genetic association study in 1041 young US women with replication in an independent Australian sample of 1428 heroin-dependent individuals as cases and 506 participants as neighborhood controls.
Self-reported anhedonia and depression (with anhedonia).
In both samples, individuals who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with 1 or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in participants reporting childhood physical abuse, although 57.1% of those homozygous for the major allele reported anhedonia, only 28.6% of those who were carriers of the minor allele reported it (P=.01). The rs1049353 polymorphism also buffered the effects of childhood physical abuse on major depressive disorder; however, this influence was largely attributable to anhedonic depression. These effects were also noted in an independent sample, in which minor allele carriers were at decreased risk for anhedonia even when exposed to physical abuse.
Consistent with preclinical findings, a synonymous CNR1 polymorphism, rs1049353, is linked to the effects of stress attributable to childhood physical abuse on anhedonia and anhedonic depression. This polymorphism reportedly resides in the neighborhood of an exon splice enhancer; hence, future studies should carefully examine its effect on expression and conformational variation in CNR1, particularly in relation to stress adaptation.
"have been associated with heavy cannabis use in humans. For example, the endocannabinoid system has been proposed to play a role in the pathogenesis of schizophrenia (although, as noted earlier, the evidence to support this hypothesis has been mixed; Ferretjans et al., 2012), while two recent studies have provided evidence that variation in the CNRI gene moderates the effect of stressful life events on depressive symptoms (Juhasz et al., 2009; Agrawal et al., 2012). While a detailed discussion of the interaction between multiple risk factors is beyond the scope of this review, these studies provide insight into how processes associated with the development of the endocannabinoid system may impact variability in risk within adolescent populations, as well as making the developing brain vulnerable to the effects of cannabis more generally. "
[Show abstract][Hide abstract] ABSTRACT: Heavy cannabis use has been frequently associated with increased rates of mental illness and cognitive impairment, particularly amongst adolescent users. However, the neurobiological processes that underlie these associations are still not well understood. In this review, we discuss the findings of studies examining the acute and chronic effects of cannabis use on the brain, with a particular focus on the impact of commencing use during adolescence. Accumulating evidence from both animal and human studies suggests that regular heavy use during this period is associated with more severe and persistent negative outcomes than use during adulthood, suggesting that the adolescent brain may be particularly vulnerable to the effects of cannabis exposure. As the endocannabinoid system plays an important role in brain development, it is plausible that prolonged use during adolescence results in a disruption in the normative neuromaturational processes that occur during this period. We identify synaptic pruning and white matter development as two processes that may be adversely impacted by cannabis exposure during adolescence. Potentially, alterations in these processes may underlie the cognitive and emotional deficits that have been associated with regular use commencing during adolescence.
"Endocannabinoid receptor 1 receptor knockout in mice modulates the effects of chronic unpredictable stress on the development of anhedonia in mice (50). In a recent study Agrawal et al. (51) evaluated the role of a polymorphism in the human endocannabinoid receptor (CNR1), rs1049353, in moderating the association between childhood physical abuse and anhedonia or MDD in young adult US women. Those women who carried two copies of the minor allele (G/G) exhibited less anhedonia when exposed to childhood physical abuse compared to carriers of the A allele (A/A or A/G). "
[Show abstract][Hide abstract] ABSTRACT: This review focuses on current research developments in the study of gene by early life stress (ELS) interactions and depression. ELS refers to aversive experiences during childhood and adolescence such as sexual, physical or emotional abuse, emotional or physical neglect as well as parental loss. Previous research has focused on investigating and characterizing the specific role of ELS within the pathogenesis of depression and linking these findings to neurobiological changes of the brain, especially the stress response system. The latest findings highlight the role of genetic factors that increase vulnerability or, likewise, promote resilience to depression after childhood trauma. Considering intermediate phenotypes has further increased our understanding of the complex relationship between early trauma and depression. Recent findings with regard to epigenetic changes resulting from adverse environmental events during childhood promote current endeavors to identify specific target areas for prevention and treatment schemes regarding the long-term impact of ELS. Taken together, the latest research findings have underscored the essential role of genotypes and epigenetic processes within the development of depression after childhood trauma, thereby building the basis for future research and clinical interventions.
Frontiers in Endocrinology 02/2014; 5:14. DOI:10.3389/fendo.2014.00014
"This allele has a major form (G allele) and a minor form (A allele), and it would appear that the A allele of this polymorphism exerts some level of protection against stress and depression. Specifically, one report has demonstrated in two separate populations that carriers of the A allele are protected against the development of anhedonia and major depression in adulthood following early life stress or abuse
. It should be noted, however, that this effect was not entirely replicated by a second group, although they did note that was a moderate risk reduction in carriers of the A allele, but they suggested that this allele may be more specific for anhedonia than depression, per se. "
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence over the past decade has highlighted an important role of the endocannabinoid (eCB) system in the regulation of stress and emotional behavior across divergent species, from rodents to humans. The general findings from this work indicate that the eCB system plays an important role in gating and buffering the stress response, dampening anxiety and regulating mood. Work in rodents has allowed researchers to determine the neural mechanisms mediating this relationship while work in human populations has demonstrated the possible importance of this system in stress-related psychiatric diseases, such as post-traumatic stress disorder, generalized anxiety and major depression. These stress-protective effects of eCB signaling appear to be primarily mediated by their actions within corticolimbic structures, particularly the amygdala and the prefrontal cortex. The aim of this review is to provide an up-to-date discussion of the current level of knowledge in this field, as well as address the current gaps in knowledge and specific areas of research that require attention.
Biology of Mood and Anxiety Disorders 10/2013; 3(1):19. DOI:10.1186/2045-5380-3-19
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