Orexin A Expression and Promoter Methylation in Patients with Cannabis Dependence in Comparison to Nicotine-Dependent Cigarette Smokers and Nonsmokers

Abstract

Background: The orexins (hypocretins) are neuropeptides with an origin in the lateral hypothalamus. They have been found to be crucial within the context of drug craving, withdrawal und relapse. Methods: Therefore, orexin A gene expression and promoter methylation in peripheral blood cells of 77 subjects [36 with tetrahydrocannabinol (THC) dependence, 20 nicotine-dependent cigarette smokers and 21 nonsmokers] were assessed by quantitative real-time PCR and methylation-specific digestion PCR. Results: There was a statistically significant difference in orexin A expression between the three groups [p = 0.000, F = 131.4, d.f. = 2, analysis of variance (ANOVA)]. Orexin A gene expression was statistically significantly correlated with the Satisfaction with Life Scale (r = –0.28, p = 0.018), a visual analogue scale of craving (r = 0.734, p = 0.000) and three subscales of the World Health Organization Alcohol, Smoking and Substance Involvement Screening Test, i.e. nicotine consumption (r = 0.388, p = 0.001), alcohol consumption (r = 0.354, p = 0.002) and cannabis consumption (r = 0.783, p = 0.000). The mean promoter methylation (as a percentage) was not statistically related to orexin gene expression. However, there was a statistically significant difference in promoter methylation with regard to body mass index in general (F = 2.37, d.f. = 54, p = 0.016, ANOVA). Conclusions: Orexin might be a possible target in THC as well as nicotine dependence, taking into account the effect of THC on energy homeostasis in the circuit of reward and motivation and its impact on appetite and body weight.

Orexin 1 receptor antagonists in compulsive behavior and anxiety: possible therapeutic use

“…Changes of hypocretin/orexin levels in blood were observed in alcoholics during alcohol withdrawal, showing positive association with distress scores (von der Goltz et al, 2011), while negative association was observed with craving scores in abstinent smokers (von der Goltze et al, 2010). Increased expression of hypocretin/orexin levels was also found in the in peripheral blood of cigarette smokers and cannabis abusers (Rotter et al, 2012). While the interpretation of these finding is still unclear, subjects affected by narcolepsy were studied for their liability to addiction with the hope to get more informative results.…”

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

“…Systemic SB-334867, but not TCS OX2 29, reduces signs of mecamylamine-induced nicotine withdrawal [140] and the operant acquisition, self-administration and break-point for a synthetic cannabinoid agonist, WIN55,212-2 [141]. Additionally, there is emerging evidence for interactions between the orexin system and endogenous cannabinoid signalling [19,36,142] and orexin-A expression is downregulated in tetrahydrocannabinol-dependent patients [143]. Collectively, these studies indicate that the OX 1 receptor may have clinical relevance for drug addiction more broadly but the OX 2 receptor is more specifically implicated in mediating the primary reinforcing properties of depressant drugs such as alcohol and opiates.…”

Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far

“…Other recent evidence supports the relationship between hypocretins and cannabis dependence. It has been reported that hypocretin-1 expression in peripheral blood cells is modified in cannabis-dependent smokers when compared to nicotine-dependent smokers and non-smokers (Rotter et al, 2012). However, these data provide poor functional information, as peripheral hypocretin mRNA levels do not necessarily reflect the situation in the CNS.…”