Chemical Probes of Endocannabinoid Metabolism.

Chemical probes of endocannabinoid metabolism.

Pharmacol Rev. 2013; 65(2): 849-71
Blankman JL, Cravatt BF, Barker EL

The endocannabinoid signaling system regulates diverse physiologic processes and has attracted considerable attention as a potential pharmaceutical target for treating diseases, such as pain, anxiety/depression, and metabolic disorders. The principal ligands of the endocannabinoid system are the lipid transmitters N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which activate the two major cannabinoid receptors, CB1 and CB2. Anandamide and 2-AG signaling pathways in the nervous system are terminated by enzymatic hydrolysis mediated primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. In this review, we will discuss the development of FAAH and MAGL inhibitors and their pharmacological application to investigate the function of anandamide and 2-AG signaling pathways in preclinical models of neurobehavioral processes, such as pain, anxiety, and addiction. We will place emphasis on how these studies are beginning to discern the different roles played by anandamide and 2-AG in the nervous system and the resulting implications for advancing endocannabinoid hydrolase inhibitors as next-generation therapeutics. HubMed – addiction


Global burden of alcoholic liver diseases.

J Hepatol. 2013 Mar 16;
Rehm J, Samokhvalov AV, Shield KD

BACKGROUND & AIMS: Liver diseases contribute markedly to the global burden of mortality and disease.This paper provides an overview from a global perspective of the contribution of alcohol to liver diseases. METHODS: The Global Burden of Disease study methodology was used to estimate the burden of alcohol-attributable liver cirrhosis and alcohol-attributable liver cancer in 2010 as measured by deaths and Disability Adjusted Life Years (DALYs). This methodology estimates attributable fractions based on alcohol exposure distribution and relative risks associated with different levels of drinking. RESULTS: Globally, in 2010, alcohol-attributable liver cirrhosis was responsible for 493,300 deaths (156,900 female deaths and 336,400 males deaths) and 14,544,000 DALYs (4,112,000 DALYs for women and 10,432,000 DALYs for men), representing 0.9% (0.7% for women and 1.2% for men) of all global deaths and 0.6% (0.4% for women and 0.8% for men) of all global DALYs, and 47.9% of all liver cirrhosis deaths (46.5% for women and 48.5% for men) and 46.9% of all liver cirrhosis DALYs (44.5% for women and 47.9% for men). Alcohol-attributable liver cancer was responsible for 80,600 deaths (14,800 female deaths and 65,900 male deaths) and 2,142,000 DALYs (335,000 DALYs for women and 1,807,000 DALYs for men). CONCLUSIONS: The burden of alcohol-attributable liver cirrhosis and liver cancer is high and entirely preventable. Interventions to reduce alcohol consumption are recommended as a population health priority and may range from taxation increases for alcoholic beverages to increases in screening and treatment rates for alcohol use disorders. HubMed – addiction


Positive association between -1021TT genotype of dopamine beta hydroxylase gene and progressive behavior of injection heroin users.

Neurosci Lett. 2013 Mar 16;
Xie X, Xu L, Liu H, Chen W, Zhuang D, Zhang J, Duan S, Zhou W

By balancing the ratios of dopamine and norepinephrine, dopamine beta hydroxylase (DBH) plays an important role in brain reward circuit that is involved with behavioral effects of heroin addiction. DBH -1021C/T (rs1611115) is a functional variant with strong correlation with plasma DBH activity and several nerval and psychic disorders. In the present study, we have collected 333 male cases with heroin addiction and 200 male healthy controls to explore the role of -1021C/T in heroin addiction. There is no evidence of association between -1021C/T and heroin addiction on both genotype and allele levels (P>0.05). In the injection subgroup of cases, -1021TT carriers have longer heroin addiction time (P<0.001) and higher dosage of self-administered heroin (P=0.045) than carriers with -1021CC or -1021CT, suggesting that patients with TT genotype are likely to have more progressive style of heroin users with injection route. In conclusion, our results support -1021TT genotype may be implicated with a more progressive nature of heroin addiction, although DBH -1021C/T is unlikely to be involved in the risk of heroin addiction. HubMed – addiction


Effects of environmental enrichment on nicotine-induced sensitization and cross-sensitization to d-amphetamine in rats.

Drug Alcohol Depend. 2013 Mar 16;
Adams E, Klug J, Quast M, Stairs DJ

INTRODUCTION: Research indicates that adolescent nicotine exposure may predispose individuals to use other psychostimulants later in adulthood, offering support for the incentive-sensitization theory of addiction. Preclinical studies testing the incentive-sensitization theory show that repeated nicotine exposure in adolescent rats can lead to an increased sensitivity to the motor stimulant effects of nicotine and other psychostimulants in adulthood. Although previous nicotine exposure can increase sensitivity to stimulant drugs, rats raised in enriched conditions (EC) show, decreased sensitivity to psychostimulant drugs compared to rats raised in isolation conditions (IC). METHODS: We examined whether nicotine sensitization or cross-sensitization to d-amphetamine induced by adolescent nicotine exposure is altered by exposure to environmental enrichment. Adolescent EC and IC male rats received subcutaneous (s.c.) injections of saline or 0.4mg/kg of nicotine once daily for seven days. Thirty-five days following the last nicotine injection EC and IC animals were challenged with saline, nicotine (0.2 or 0.4mg/kg) or d-amphetamine (0.5 or 1.0mg/kg). RESULTS: EC rats failed to show nicotine sensitization at either nicotine dose tested while IC rats showed nicotine sensitization following the 0.4mg/kg nicotine dose. EC rats also failed to show nicotine-induced cross-sensitization to the 0.5mg/kg dose of d-amphetamine while IC rats displayed cross-sensitization. However, EC rats did exhibit nicotine-induced cross-sensitization to the 1.0mg/kg dose of d-amphetamine. CONCLUSION: These findings indicate that environmental enrichment can alter the ability of adolescent nicotine exposure to induce sensitization and cross-sensitization in adulthood and may be used as a protectant factor against adolescent nicotine exposure. HubMed – addiction