More Aroused, Less Fatigued: Fatty Acid Amide Hydrolase Gene Polymorphisms Influence Acute Response to Amphetamine

Amphetamine is a stimulant drug that enhances attention and feelings of alertness. Amphetamine''s effects are known to be modulated by endogenous cannabinoids, which are degraded by the enzyme fatty acid amide hydrolase (FAAH). In this study we investigated inter-individual differences in mood response to amphetamine in relation to four polymorphisms in the FAAH gene, including the FAAH missense variant rs324420C → A (Pro129Thr), which was previously found to be associated with street drug use and addictive traits. One hundred and fifty-nine healthy Caucasian volunteers participated in a three-session, double-blind crossover study receiving either placebo or oral d-amphetamine (10 and 20 mg). Associations between individual genotypes and levels of self-reported Arousal (Profile of Mood States) after d-amphetamine ingestion were investigated using two-way ANOVAs/ANCOVAs. Association analyses for haplotypes were performed using the adaptive permutation approach implemented in PLINK. Genotypes at rs3766246 and rs2295633 were significantly associated with increased ratings of Arousal (p<0.05) and Fatigue (p<0.01) after the 10-mg dose. Fatigue levels were also found to be associated with the haplotypes CCC and TAT formed from rs3766246, rs324420, and rs2295633 (p<0.05). These data suggest that the endocannabinoid system influences variation in subjective response to amphetamine. This has important implications for understanding the role of endogenous cannabinoids in response to amphetamine, studies of poly-substance abuse, and understanding the genetic determinants of inter-individual differences in stimulant effects and risk of abuse.     

Legal Reviews

This review focuses on the history of, and recent developments in, the law and ethics of research with practical advice for surgeons conducting clinical research. Legal references apply to England and Wales or to Scotland, but the underlying ethical principles reflect modern approaches taken internationally.     

Influence of early neonatal phenobarbital exposure on cerebral energy metabolism and behavior

The influence of an early chronic phenobarbital (PhB) exposure on local cerebral glucose utilization (LCGU) and on behavior was studied in the rat. The animals were treated from Postnatal Day 2 to Postnatal Day 35 by a daily injection of 50 mg/kg PhB or by saline and tested between 10 and 35 days for short-term effects of the drug on LCGU and between 70 and 90 days for long-term effects of PhB on LCGU and behavior. PhB induced short- and long-lasting reductions in the overall rates of LCGU in hippocampal and cerebellar areas, but no significant changes in LCGU in the different cell layers of these two cerebral areas. PhB also changed the pattern of maturation of the rates of LCGU as compared to control subjects. The barbiturate treatment induced a decrease in the exploratory behavior of PhB- as compared to saline-treated rats in the open field, as well as a significant 25% decrease in the rate of spontaneous alternation with delay. In addition, PhB-treated rats needed significantly more time than control animals to perform their trials in the nonrewarded T maze testing. However, the neonatal barbiturate exposure did not induce changes in performances of adult rats in the rewarded eight arm maze. The results of the present study show that there is no apparent correlation between the rates of energy metabolism in the hippocampus and the impairment of learning abilities of adult rats in behavioral tests related to the hippocampus.