Promoter variants of the cannabinoid receptor 1 gene (CNR1) in interaction with 5‐HTTLPR affect the anxious phenotype

Abstract

Anxiety is a polygenic condition, and the recently discovered Endocannabinoid System (ECS) is one plausible candidate. Experimental data suggest that the ECS can modulate several neurotransmitter systems, including the serotonergic system, which itself plays a significant role in anxiety. However, to date there is no evidence of gene-gene interactions; indeed genetic studies focusing separately on the two systems provide conflicting data. Thus, the aim of our study was to analyze the interaction of the promoter regions of the serotonin transporter (SLC6A4) and cannabinoid receptor 1 (CNR1) genes on anxiety. We genotyped 706 individuals for the 5-HTTLPR in the SLC6A4 promoter and 4 SNPs located in the CNR1 promoter region. Anxiety was measured by the State-Trait Anxiety Inventory (STAI-S, STAI-T), the anxiety subscale of TEMPS-A (TEMPS-Anx), and the Brief Symptom Inventory (BSI-Anx). Significant 5-HTTLPR x CNR1 promoter-promoter interaction was observed using STAI-T (P = 0.0006) and TEMPS-Anx (P = 0.0013). The risk of high anxiety scores on BSI-Anx was 4.6-fold greater in homozygous 'GG' rs2180619 in combination with homozygous 'SS' 5-HTTLPR (P = 0.0005) compared to other genotypes. The effect of previously described "TGC" haplotype in the alternative promoter of CNR1 depended both on the conventional promoter polymorphism and the 5-HTTLPR. Our haplotype and putative transcription binding profile analyses strongly suggest that certain constellations of CB1-receptor and 5-HTT promoters yield extremely high or low synaptic 5-HT concentrations, and these are associated with an anxious phenotype. In conclusion, genetically determined serotonergic and endocannabinoid dysfunctions could lead to a vulnerability causing anxiety disorders and possibly depression.

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

“…In the present research, we included participants who were European white origin, completed the questionnaires and consented to DNA. Details of the recruitment strategies and response rate were published earlier (Juhasz et al 2009a; Lazary et al 2009). …”

“…In addition, CNR1 genetic variants in interaction with recent negative life events (RLE) increased the risk of depression (Juhasz et al 2009a), and in interaction with the serotonin transporter functional polymorphism ( 5HTTLPR) exerted anxiogenic effects (Lazary et al 2009, 2011). Regarding migraine, we demonstrated that a CNR1 haplotype increased the risk of migraine headaches (Juhasz et al 2009b).…”

Blockade of Serotonin 2C Receptors with SB-242084 Moderates Reduced Locomotor Activity and Rearing by Cannabinoid 1 Receptor Antagonist AM-251

“…Regarding the development of psychiatric side effects of CB 1 receptor antagonists, animal studies have shown that activation or blockade of CB 1 receptors modulate the excitability of serotonergic neurons in dorsal raphe nucleus and influences the serotonin release [2]. Furthermore, a growing body of human studies suggests that serotonergic neurons appreciably contribute to the development of psychiatric side effects induced by CB 1 receptor antagonists [3]. At the same time, the key role of different 5-HT 2 receptor subtypes has been demonstrated in the regulation of neuronal excitability, sleepwake cycle, and also in the control of anxiety and locomotor activity [4,5].…”

Anxiogenic and depressogenic side-effects of non-psychiatric drugs

“…Emellett a rimonabant alkalmazása egyesekben jelentős szorongásfokozódással jár és insomniát is okozhat. Genetikai vizsgálatok eredményei arra utalnak, hogy az endokannabinoidok hatását köz-vetítő CB 1 -receptorok és a szerotonin neuronokba tör-ténő felvételét végző szerotonintranszporter külön-külön is, de még inkább egymással kölcsönhatásban, felelős a rimonabant szorongást és depressziót kiváltó hatásáért, és ezen két fehérje génjének polimorfi zmusai alkalmasak lehetnek a rimonabant ilyen irányú mellék-hatásaira különösen érzékeny betegcsoport kiválasztá-sára [44,50]. Az endokannabinoidok a CB 1 -receptorok közvetítésével közvetlen hatást gyakorolnak a szerotonin, noradrenalin és dopamin felszabadulására, másrészt a monoamin neurotranszmitterek elsősorban a Gq/11 fehérje aktivációján keresztül maguk is fokozzák az endokannabinoidok szintézisét [51,52,53].…”

“…A depressziót, szorongást, alvászavart okozó gyógyszer-mellékhatások a környe-zeti hatások közé tartoznak, és sok szempontból hasonlatosak a stresszhez [80]. A környezeti vagy gyógy-szerhatások által kiváltott stressz mértéke nemi és genotípus szerinti eltéréseket mutat [44,50,81]. Ebben az agyi szerotonerg, noradrenerg, endokannabinoid, GABAerg és glutamaterg rendszernek egyaránt fontos, egymással kölcsönhatásban álló szerepe van [52,53].…”