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.

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1 Serotonin-2 receptor antagonists, like ritanserin, greatly enhance deep slow wave sleep (SWS-2) and low-frequency EEG power in humans and rodents. 5-HT 2A and 5-HT 2C receptors may be involved in these effects, but the role of the 5-HT 2B receptor is still unclear. 2 To investigate the role of the 5-HT 2B receptor in regulation of the sleep-wake cycle, the subtypeselective antagonist SB-215505 (0.1, 0.3 and 1.0 mg kg À1 i.p.) was administered to Sprague-Dawley rats at light onset (beginning of passive phase). EEG, EMG and motor activity were recorded during the subsequent 8 h. 3 SB-215505 dose-dependently increased wakefulness (W) at the expense of the intermediate stage of sleep, paradoxical sleep (PS) and SWS-2 in the first hour. Parallel to increased W, significantly increased motor activity was found. Spectral analysis of the EEG in W showed a dose-dependent decrease in power density in the 3-8 Hz frequency range (maximum effect at 6 Hz). In light slow wave sleep and SWS-2, the drug reduced low-frequency (o8 Hz) EEG power, suggesting decreased sleep intensity after SB-215505 treatment. In PS, the drug dose-dependently decreased EEG power solely in the theta (6-9 Hz) band, primarily affecting the peak power value (7 Hz). 4 The well-known SWS-2 enhancing effect of 5-HT 2 receptor antagonists is mediated by 5-HT 2A and/or 5-HT 2C receptors. In contrast, blockade of 5-HT 2B receptors increases motor activity and W along with decreased theta activity during W and PS. Activation of 5-HT 2B receptors may contribute to initiation of sleep and to theta generation during W and PS under physiological conditions.

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.

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MDMA causes selective depletion of serotonergic terminals in experimental animals and the consequent decrease in synaptic 5-HT may, inter alia, increase impulsivity. To study the effects of MDMA upon brain function, the behaviour of male Dark Agouti rats exposed to MDMA (15 mg/kg i.p.), two 5-HT1B agonists (CGS-12066A and CP-94,253, both 5 mg/kg i.p.) or saline were investigated in the resident-intruder test. Studies were performed in drug-naive rats and also in rats exposed to MDMA (15 mg/kg i.p.) 21 d earlier. In parallel experiments the functional neuroanatomy of MDMA effects were assessed using 2-deoxyglucose imaging of local cerebral metabolic rate of glucose utilization (LCMRGlu) and neurotoxicity was assessed by measuring [3H]paroxetine binding. There was no significant difference in aggressive behaviour (biting, boxing, wrestling and their latencies) between drug-naive rats and rats previously exposed to MDMA 21 d earlier, despite reduced social behaviour, decreased LCMRGlu in several brain areas involved in aggression, and reductions in paroxetine binding by 30-60% in the forebrain. CGS-12066A, CP-94,253 and acute MDMA produced marked decreases in aggressive behaviours, especially in biting, boxing and kicking found in drug-naive rats. In animals previously exposed to the drug, acute anti-aggressive effects of MDMA were, in general, preserved as were MDMA-induced increases in LCMRGlu. Our studies provide evidence that in the resident-intruder test, where social isolation is a requirement, aggressive behaviour and acute anti-aggressive effects of MDMA and 5-HT1B receptor agonists remain intact 3 wk after a single dose of the drug despite significant damage to the serotonergic system.

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