Inhibition of Cyclic Nucleotide Phosphodiesterases by Methylxanthines and Related Compounds

The consumption of alcohol mixed with energy drinks (AmED) is popular on college campuses in the United States. Limited research suggests that energy drink consumption lessens subjective intoxication in persons who also have consumed alcohol. This study examines the relationship between energy drink use, high-risk drinking behavior, and alcohol-related consequences. In Fall 2006, a Web-based survey was conducted in a stratified random sample of 4,271 college students from 10 universities in North Carolina. A total of 697 students (24% of past 30-day drinkers) reported consuming AmED in the past 30 days. Students who were male, white, intramural athletes, fraternity or sorority members or pledges, and younger were significantly more likely to consume AmED. In multivariable analyses, consumption of AmED was associated with increased heavy episodic drinking (6.4 days vs. 3.4 days on average; p < 0.001) and twice as many episodes of weekly drunkenness (1.4 days/week vs. 0.73 days/week; p < 0.001). Students who reported consuming AmED had significantly higher prevalence of alcohol-related consequences, including being taken advantage of sexually, taking advantage of another sexually, riding with an intoxicated driver, being physically hurt or injured, and requiring medical treatment (p < 0.05). The effect of consuming AmED on driving while intoxicated depended on a student's reported typical alcohol consumption (interaction p = 0.027). Almost one-quarter of college student current drinkers reported mixing alcohol with energy drinks. These students are at increased risk for alcohol-related consequences, even after adjusting for the amount of alcohol consumed. Further research is necessary to understand this association and to develop targeted interventions to reduce risk.

The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.

Numerous studies dissecting the basic mechanisms that control sleep regulation have led to considerable improvement in our knowledge of sleep disorders. It is now well accepted that transitions between sleep and wakefulness are regulated by complex neurobiologic mechanisms, which, ultimately, can be delineated as oscillations between two opponent processes, one promoting sleep and the other promoting wakefulness. The role of several neurotransmitter or neuromodulator systems, including noradrenergic, serotonergic, cholinergic, adenosinergic, and histaminergic systems and, more recently, the hypocretin/orexin and dopamine systems, has been clearly established. Amphetamine-like stimulants are known to increase wakefulness by blocking dopamine reuptake, by stimulating dopamine release, or by both mechanisms. Modafinil may increase wakefulness through activation of noradrenergic and dopaminergic systems, possibly through interaction with the hypocretin/orexin system. Caffeine inhibits adenosinergic receptors, which in turn can produce activation via interaction with GABAergic and dopaminergic neurotransmission. Nicotine enhances acetylcholine neurotransmission in the basal forebrain and dopamine release. Understanding the exact role of the hypocretin/orexin and dopamine systems in the physiology and pharmacology of sleep-wake regulation may reveal new insights into current and future wakefulness-promoting drugs.