Naltrexone Reduces Ethanol- and/or Water-Reinforced Responding in Rhesus Monkeys: Effect Depends Upon Ethanol Concentration

The opioid antagonist naltrexone reduces responding for ethanol. If naltrexone produces this effect by blocking ethanol-induced opioid activity, then naltrexone should reduce responding for ethanol regardless of level of the ethanol responding relative to an alternatively available reinforcer. In addition, if naltrexone competitively blocks ethanol-induced opioid activity, then the naltrexone effect may be surmountable by increasing ethanol concentration and, thus, ethanol intake (g/kg). This study was conducted to determine whether naltrexone will selectively reduce ethanol-reinforced responding when the ethanol concentration is varied such that ethanol fluid deliveries are less than, greater than, or equal to the fluid deliveries of concurrently available water. Methods : Four adult male rhesus monkeys were allowed to respond for ethanol or water concurrently for 2 hr per day. Ethanol concentration was either 2%, 8%, or 32%. On various days, either saline or naltrexone (0.1 mg/kg) was given intramuscularly 30 min before the drinking session. Results : When ethanol fluid deliveries were greater than those of water (at 2% ethanol), naltrexone reduced responding for ethanol. When the ethanol and water fluid deliveries were approximately equal (at 8% ethanol), naltrexone reduced both ethanol and water fluid deliveries. When water fluid deliveries were greater than those of ethanol (at 32% ethanol), naltrexone reduced responding for water. Conclusions : Thus, naltrexone reduced responding for the preferred fluid, either ethanol or water, depending on ethanol concentration. The effect was not surmountable by increasing ethanol concentration and, therefore, ethanol intake (g/kg). Naltrexone may reduce ethanol-reinforced responding by a mechanism other than that of blocking ethanol-induced opioid activity. Naltrexone may be inducing an aversive interoceptive state.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66374/1/j.1530-0277.1999.tb04668.x.pd

Enantioselective synthesis and application to the allylic imidate rearrangement of amine-coordinated palladacycle catalysts of cobalt sandwich complexes

The reaction of (η5-(N,N-dimethylaminomethyl)cyclopentadien-yl)(η4-tetraphenylcyclobutadiene)cobalt with sodium tetrachloropalladate and (R)-N-acetylphenylalanine gave planar chiral palladacycle di-μ-chloridebis[(η5-(Sp)-2-(N,N-dimethylaminomethyl)cyclopentadienyl,1-C,3′-N)(η4-tetraphenylcyclobutadiene)cobalt]dipalladium [(Sp)-Me2-CAP-Cl] in 92 % ee and 64 % yield. Enantiopurity (>98 % ee) was achieved by purification of the monomeric (R)-proline adducts and conversion back to the chloride dimer. Treatment with AgOAc gave (Sp)-Me2-CAP-OAc which was applied to asymmetric transcyclopalladation (up to 78 % ee). The (R)-N-acetylphenylalanine mediated palladation methodology was applicable also to the corresponding N,N-diethyl (82 % ee, 39 % yield) and pyrrolidinyl (>98 % ee, 43 % yield) cobalt sandwich complexes. A combination of 5 mol % of the latter [(Sp)-Pyrr-CAP-Cl] and AgNO3 (3.8 equiv) is a catalyst for the allylic imidate rearrangement of an (E)-N-aryltrifluoroacetimidate (up to 83 % ee), and this catalyst system is also applicable to the rearrangement of a range of (E)-trichloroacetimidates (up to 99 % ee). This asymmetric efficiency combined with the simplicity of catalyst synthesis provides accessible solutions to the generation of non-racemic allylic amine derivatives

Differential Responses of S100A2 to Oxidative Stress and Increased Intracellular Calcium in Normal, Immortalized, and Malignant Human Keratinocytes

S100A2 is a calmodulin-like, p53-inducible, homodimeric protein that is readily oxidized in keratinocytes subjected to oxidative stress. Here we compare the redox status and subcellular distribution of S100A2 in normal human keratinocytes, immortalized keratinocytes (HaCaT), and malignant keratinocytes (A431) as a function of oxidative stress and intracellular Ca2+ levels. Normal human keratinocytes displayed strong nuclear and moderate cytoplasmic S100A2 immunoreactivity. HaCaT and A431 cells, which lack normal p53, expressed S100A2 in similar patterns but in 4- to 8-fold lower amounts. H2O2 treatment of normal human keratinocytes caused a reduction of nuclear S100A2 staining accompanied by an increase in cytoplasmic S100A2 staining, with a delayed time course (0.5–1 h) relative to S100A2 oxidative crosslinking (15 min). This phenomenon, consistent with translocation of S100A2 from the nucleus to the cytoplasm, could also be induced in normal human keratinocytes by increasing intracellular Ca2+ levels with the ionophore A23187. Sulfhydryl reducing agents blocked these changes, whether induced by H2O2 or increased intracellular Ca2+ levels. A temporal correlation was identified between S100A2 translocation at 1 h and loss of cell viability at 24 h after H2O2 treatment. A431 and HaCaT cells were strongly resistant to H2O2-induced S100A2 crosslinking, S100A2 translocation, and cell death. Increased intracellular Ca2+ levels caused prominent translocation of S100A2 in normal human keratinocytes and HaCaT, but not in A431 cells. These results identify S100A2 oxidation and translocation as markers for early cellular responses to oxidative stress, which are markedly attenuated in immortalized and malignant keratinocytes

Noncontingent and Response-Contingent Intravenous Ethanol Attenuates the Effect of Naltrexone on Hypothalamic-Pituitary-Adrenal Activity in Rhesus Monkeys

Background : The mechanism by which the opioid antagonist naltrexone suppresses overconsumption of ethanol is unclear. Oral ethanol consumption in humans increases hypothalamic-pituitary-adrenal (HPA) activity, and recent studies suggest that naltrexone may reduce ethanol consumption by modifying the HPA-stimulating effects of ethanol. The purpose of this study was to measure in rhesus monkeys the effects of ethanol and naltrexone, alone and in combination, on plasma levels of adrenocorticotropin hormone (ACTH). Methods : Nine adult male and female rhesus monkeys with chronic, indwelling intravenous catheters were maintained on tethers that allowed ethanol delivery and blood sampling. In one study, the monkeys received intramuscular injections of saline or 0.32 mg/kg naltrexone followed by noncontingent intravenous bolus infusions of saline or 0.3 to 1.8 g/kg ethanol. In a second study, other monkeys were given intramuscular injections of saline or 0.01 to 0.3 mg/kg naltrexone and subsequently responded on levers to receive intravenous saline or ethanol 0.03 g/kg per injection. Results : Ethanol, delivered either response contingently or noncontingently, did not produce systematic changes in ACTH plasma levels. Naltrexone alone produced increases in plasma ACTH that were attenuated by the subsequent administration of noncontingent or response-contingent ethanol. Naltrexone also produced dose-dependent reductions in intravenous ethanol self-administration. Linear regression analysis indicated that ethanol intake was negatively correlated with the plasma levels of ACTH over time. Conclusions : The route of administration may modulate ethanol's effects on HPA activity. Ethanol may attenuate naltrexone's effect on the HPA axis by impairing HPA axis sensitivity to other stimuli. The negative correlation between ethanol intake and ACTH levels supports the notion that naltrexone's effect of increasing HPA axis activity may be related to its ability to suppress ethanol consumption.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66078/1/01.ALC.0000121655.48922.C4.pd

Veterinary epidemiology and economics in Africa. A manual for use in the design and appraisal of livestock health policy

Discusses basic techniques involved in the planning, monitoring and evaluation of livestock disease control programmes in Africa i.e. the theory & application of epidemiology statistical analysis, economics, estimating costs and decision making

Moderators and Predictors of Response to Behavior Therapy for Tics in Tourette Syndrome

Objective: To examine moderators and predictors of response to behavior therapy for tics in children and adults with Tourette syndrome and chronic tic disorders. Methods: Data from 2 10-week, multisite studies (1 in children and 1 in adults; total n = 248) comparing comprehensive behavioral intervention for tics (CBIT) to psychoeducation and supportive therapy (PST) were combined for moderator analyses. Participants (177 male, 71 female) had a mean age of 21.5 ± 13.9 years (range 9–69). Demographic and clinical characteristics, baseline tic-suppressing medication, and co-occurring psychiatric disorders were tested as potential moderators for CBIT vs PST or predictors of outcome regardless of treatment assignment. Main outcomes measures were the Yale Global Tic Severity Scale Total Tic score and the Clinical Global Impression–Improvement score assessed by masked evaluators. Results: The presence of tic medication significantly moderated response to CBIT vs PST (p = 0.01). Participants showed tic reduction after CBIT regardless of tic medication status, but only participants receiving tic medication showed reduction of tics after PST. Co-occurring psychiatric disorders, age, sex, family functioning, tic characteristics, and treatment expectancy did not moderate response. Across both treatments, greater tic severity (p = 0.005) and positive participant expectancy (p = 0.01) predicted greater tic improvement. Anxiety disorders (p = 0.042) and premonitory urge severity (p = 0.005) predicted lower tic reduction. Conclusions: Presence of co-occurring attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, or anxiety disorders did not moderate response to CBIT. Although participants on tic medication showed improvement after CBIT, the difference between CBIT and PST was greater for participants who were not on tic-suppressing medication. ClinicalTrials.gov identifiers: The child and adult CBIT studies are listed on clinical trials.gov (NCT00218777 and NCT00231985, respectively). Classification of evidence: This study provides Class I evidence that CBIT is effective in reducing tic severity across subgroups of patients with chronic tic disorders, although the difference between treatments was smaller for participants on tic-suppressing medications, suggesting reduced efficacy in this subgroup

Neurocognitive Correlates of Treatment Response in Children with Tourette\u27s Disorder

This paper examined neurocognitive functioning and its relationship to behavior treatment response among youth with Tourette\u27s Disorder (TD) in a large randomized controlled trial. Participants diagnosed with TD completed a brief neurocognitive battery assessing inhibitory functions, working memory, and habit learning pre- and post-treatment with behavior therapy (CBIT, Comprehensive Behavioral Intervention for Tics) or psychoeducation plus supportive therapy (PST). At baseline, youth with tics and Attention Deficit Hyperactivity Disorder (ADHD) exhibited some evidence of impaired working memory and simple motor inhibition relative to youth with tics without ADHD. Additionally, a small negative association was found between antipsychotic medications and youth\u27s performance speed. Across treatment groups, greater baseline working memory and aspects of inhibitory functioning were associated with a positive treatment response; no between-group differences in neurocognitive functioning at post-treatment were identified. Within the behavior therapy group, pre-treatment neurocognitive status did not predict outcome, nor was behavior therapy associated significant change in neurocognitive functioning post-treatment. Findings suggest that co-occurring ADHD is associated with some impairments in neurocognitive functioning in youth with Tourette\u27s Disorder. While neurocognitive predictors of behavior therapy were not found, participants who received behavior therapy exhibited significantly reduced tic severity without diminished cognitive functioning