Differential Roles of GABAA Receptor Subtypes in Benzodiazepine-Induced Enhancement of Brain-Stimulation Reward

Benzodiazepines such as diazepam are widely prescribed as anxiolytics and sleep aids. Continued use of benzodiazepines, however, can lead to addiction in vulnerable individuals. Here, we investigate the neural mechanisms of the behavioral effects of benzodiazepines using the intracranial self-stimulation (ICSS) test, a procedure with which the reward-enhancing effects of these drugs can be measured. Benzodiazepines bind nonselectively to several different GABA_A receptor subtypes. To elucidate the α subunit(s) responsible for the reward-enhancing effects of benzodiazepines, we examined mice carrying a histidine-to-arginine point mutation in the α1, α2, or α3 subunit, which renders the targeted subunit nonresponsive to diazepam, other benzodiazepines and zolpidem. In wild-type and α1-point-mutated mice, diazepam caused a dose-dependent reduction in ICSS thresholds (reflecting a reward-enhancing effect) that is comparable to the reduction observed following cocaine administration. This effect was abolished in α2- and α3-point-mutant mice, suggesting that these subunits are necessary for the reward-enhancing action of diazepam. α2 Subunits appear to be particularly important, since diazepam increased ICSS thresholds (reflecting an aversive-like effect) in α2-point-mutant animals. Zolpidem, an α1-preferring benzodiazepine-site agonist, had no reward-enhancing effects in any genotype. Our findings implicate α2 and α3 subunit containing GABA_A receptors as key mediators of the reward-related effects of benzodiazepines. This finding has important implications for the development of new medications that retain the therapeutic effects of benzodiazepines but lack abuse liability.     

Exploring the link between serum peroxides and angiogenesis in a bi-ethnic population from South Africa: The SAfrEIC study

BackgroundReactive oxygen species (ROS) play a fundamental role in angiogenesis, and in turn, angiogenic growth factors also affect ROS. Angiogenesis and ROS are intricately involved in vascular deterioration. Since black populations are known to have elevated oxidative stress and hypertension, we determined whether relationships exist between angiogenic growth factors and serum peroxides in Africans and Caucasians and evaluated the relationships with cardiovascular measurements.MethodsWe measured vascular endothelial growth factor-A (VEGF), angiopoietin 2 (Ang-2), and serum peroxides in Africans (N = 262) and Caucasians (N = 364) aged 20 to 70 years.ResultsAfricans displayed higher blood pressure, serum peroxide levels, VEGF, and Ang-2 (all P ≤ .002) than similarly aged Caucasians (P = .44). In multivariable adjusted analyses, Ang-2 was independently associated with serum peroxides in African men (R² = 0.31; β = 0.21; P = .014) and women (R² = 0.09; β = 0.22; P = .025); and VEGF with serum peroxides in African men (R² = 0.12; β = 0.24; P = .014), with no statistically significant associations in Caucasians. Cardiovascular measurements did not associate with serum peroxides or angiogenic factors in any subgroup.ConclusionsSignificant independent relationships exist between angiogenic growth factors and serum peroxides only in Africans who also displayed an unfavorable cardiovascular profile when compared with Caucasians. These results suggest that interplay between ROS and angiogenesis occur in African individuals that may form part of the mechanisms involved in vascular deterioration.     

Impact of a conjugate vaccine on community-wide carriage of nonsusceptible Streptococcus pneumoniae in Alaska

BACKGROUND: Streptococcus pneumoniae is a leading cause of invasive bacterial disease and pneumonia among children. Antimicrobial resistance among pneumococci has increased in recent years and complicates treatment. The introduction of heptavalent pneumococcal conjugate vaccine (PCV7) could reduce acquisition of antimicrobial-resistant pneumococci. METHODS: We obtained 1350 nasopharyngeal swabs for culture from 1275 children aged 3-59 months presenting at 3 clinics in Anchorage, Alaska, during the winters of 2000, 2001, and 2002, as PCV7 was being introduced into the routine immunization schedule. We recorded the frequency of use of antibiotics as well as the dates of doses of PCV7 for enrolled children. We used multivariate logistic regression modeling to identify independent risk factors for overall carriage of pneumococci and carriage of PCV7-type pneumococci, cotrimoxazole-nonsusceptible (COT-NS) pneumococci, or penicillin-nonsusceptible (PCN-NS) pneumococci. RESULTS: The proportion of children who were up-to-date for age, with respect to PCV7 vaccination, increased from 0% in 2000 to 55% in 2002. Carriage of PCV7-type pneumococci decreased by 43% (P<.0001). Risk of carriage of PCV7-type pneumococci was lower in 2002 than in 2000, independent of vaccination status, suggesting an indirect effect of vaccination. Carriage of COT-NS, but not PCN-NS, pneumococci also decreased (38%; P=.02), not only among vaccinated children but also among unvaccinated children without recent use of antibiotics. CONCLUSIONS: Introduction of PCV7 into the routine infant immunization schedule in a community with a high prevalence of antimicrobial-resistant pneumococci appears to reduce transmission of PCV7 vaccine serotypes and COT-NS pneumococci but has no impact on overall carriage of pneumococci or carriage of PCN-NS pneumococci.