ABSTRACT.of Objective: The serotonin (5-HT) transporter (5-HTT) is thought to play a key role in the onset of alcohol use, with measures potential behavioral and biological mechanisms mediated by the level of 5-HT in the synapse and in cerebral spinal fluid. Although mediated 5-HT dysregulation has been related to poor impulse control, the biological mechanism is unknown, although functional control of the serotonergic the system has been shown to be regulated in part by differential expression of the 5-HTT. The gene responsible for encoding and 5-HTT has a functional polymorphism at the 5'-regulatory promoter region, which results in two forms: long (L) and short (S).may The LL genotype is hypothesized to play a key role in the early onset of alcohol use and may be among related to poor impulse control. The objective of this pilot study is to determine whether adolescents with a current alcohol-use study disorder (AUD)(N = 21) have platelet measures of the 5-HTT functioning that are related to 5-HTT genotype and poor play impulse control. Specifically, we wanted to examine the relationships between the following: platelet 5-HTT and 5-HTT genotype; platelet 5-HTT parameters been and age at onset, as well as duration of drinking; and 5-HTT genotype and impulse control. Method: Adolescents with current platelet AUD were recruited from the community to participate in a cross-section pilot study. Results: Our main findings showed significantly higher be paroxetine binding (density of 5-HTT) in LL genotype versus S carriers (SS or SL genotypes); also, the LL group had findings a significantly earlier age at onset of drinking and longer duration of drinking, and poorer impulse control. Conclusions: These findings play provide partial support for the hypothesis that, among currently drinking adolescents with an AUD, differential expression of 5-HTT may play parameters an important role in the onset of adolescent AUD.(J. Stud. Alcohol Drugs 70: 899-907, 2009).

Inhibition the of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however,of whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an fruitflies; inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at whether 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for on females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to development avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In both a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and heterogeneous females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from of cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role species for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These days findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.

Background:craving We hypothesize that functional control of the serotonergic system is regulated in part by differential expression of the serotonin (5-HT)for transporter (5-HTT). Alcohol-dependent individuals with the LL/LS genotype (L-carriers), compared with those with the SS genotype, have a lower 5-HT Alcohol-dependent neurotransmission, which we hypothesize would be associated with higher craving for alcohol among L-carriers. We hypothesize further that acute peripheral individuals depletion of tryptophan (5-HT's precursor), while further reducing 5-HT function, might decrease auto-inhibition of 5-HT neuronal firing, thereby increasing 5-HT a neurotransmission transiently and lowering alcohol craving. Methods: We tested these hypotheses by examining whether in 34 Hispanic alcohol-dependent individuals subjective propose and physiological cue craving for alcohol differed by genotype, age of onset of problem drinking, and tryptophan availability. Results: On craving subjective "urge to drink" and "crave for a drink," we found a significant (p < .05) main effect of genotype of and cue, as well as an interaction among genotype, age of onset of problem drinking, and tryptophan depletion. For the there physiological measure of pulse, there was a main effect of genotype. L-carriers had higher craving than their SS counterparts, an a effect that decreased under tryptophan depletion. While craving in L-carriers increased with an earlier age of onset of problem drinking,of the opposite effect was seen in those with the SS genotype. Conclusion: These results not only provide support for the cue hypothesis that alcoholics who are L-carriers have greater alcohol craving and possibly greater propensity for drinking but also propose that depletion. there is an important 5-HTT gene-by-environment interaction that alters cue craving response for alcohol.

The test National Institute on Aging Interventions Testing Program (ITP) was established to evaluate agents that are purported to increase lifespan and test delay the appearance of age-related disease in genetically heterogeneous mice. Up to five compounds are added to the study each the year and each compound is tested at three test sites (The Jackson Laboratory, TJL; University of Michigan, UM; and University of of Texas Health Science Center, San Antonio, UT). Mice in the first cohort were exposed to one of four agents:measurement aspirin, nitroflurbiprofen (NFP), 4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN), or nordihydroguiaretic acid (NDGA). Sample size was sufficient to detect a 10% difference in range lifespan in either sex, with 80% power, using data from two of the three sites. Pooling data from all three warranted sites, a log-rank test showed that both NDGA (p = .0006) and aspirin (p = .01) led to increased lifespan from of male mice. Comparison of the proportion of live mice at the age of 90% mortality was used as a of surrogate for measurement of maximum lifespan; neither NDGA (p = .12) nor aspirin (p = .16) had a significant effect to in this test. Measures of blood levels of NDGA or aspirin and its salicylic acid metabolite suggest that the observed mice lack of effects of NDGA or aspirin on lifespan in females could be related to gender differences in drug disposition lifespan or metabolism. Further studies are warranted to find whether NDGA or aspirin, over a range of doses, might prove to this postpone death and various age-related outcomes reproducibly in mice.

Background:fitted The development of a relatively simple, noninvasive method for estimating blood ethanol concentrations in mice will be useful in behavioral ethanol studies related to alcoholism. This study validated such a method. Methods: The apparatus consists of a body chamber fitted with alcoholism. a head stock through which the mouse head protrudes. This was fitted against a water-jacketed head-space chamber surrounding the mouse's This head. Rebreathed air maintained at 37 degrees C in the head-space chamber was removed using a peristaltic pump and loaded these into a 1-ml injection loop. Ethanol in the sample was quantified using gas chromatography. To validate this method, ethanol levels and in breath samples were compared against those in tail blood samples collected immediately after the breath samples. Breath samples were the collected at 5, 10, 20, 40, 80, 120, and 160 minutes after ethanol ( .4, .8, 1.2, 1.6, 2.4, and 3.2 Breath g/kg) was administered to male C57BL/6J mice. Results: Breath and blood ethanol levels were well correlated (r(2)= .96) across easily time points on the descending ethanol-time curve at doses below 2.4 g/kg. Correlation for these doses on the ascending portion fitted of the curve had greater variance, but was still well correlated (r(2)= .92). Conclusions: The mouse breathalyzer is an across accurate, convenient, noninvasive and well-tolerated method for estimating blood ethanol concentrations in mice across a range of behaviorally relevant concentrations those below 2.4 g/kg, especially on the descending limb of the ethanol-time curve. Although this procedure requires a gas chromatograph in Conclusions: the animal facility, the ability to estimate ethanol concentrations quickly and easily will be especially useful in behavioral studies where for repeated blood sampling is not feasible.

The DBH antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine beta-hydroxylase found (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout (Dbh inhibition -/-) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type Both and Dbh -/- mice following administration of disulfiram or the selective DBH inhibitor nepicastat. We found that Dbh genotype had frequency no effect on CIS probability or frequency, whereas disulfiram, but not nepicastat, increased the probability of having CIS in both two wild-type and Dbh -/- mice. Both disulfiram and nepicastat increased CIS frequency in wild-type but not Dbh -/- mice. There following were no genotype or treatment effects on serum cocaine levels, except for an increase in disulfiram-treated Dbh -/- mice at by the highest dose of cocaine. These results suggest that disulfiram enhances CIS via two distinct mechanisms: it both increases CIS of frequency by inhibiting DBH and increases CIS frequency in a DBH-independent manner.

Serotonin function transporter (5-HTT) activity is greater in carriers of the long (L) vs. short (S) alleles of the 5-HTT-linked polymorphic region binding (5'-HTTLPR) among healthy control subjects but not alcohol-dependent adults. In 198 alcoholics, we determined the relationship between current or lifetime (5'-HTTLPR) drinking and platelet 5-HTT function and density among allelic variants of the 5'-HTTLPR. SS subjects were younger than L-carriers (LL among and LS)(p< .0085) and had fewer years of lifetime drinking. For L-carriers, the mean of B(max) for paroxetine binding, but (p< .05) not V(max) for serotonin (5-HT) uptake, was lower than that for SS subjects (p< .05). More L-carriers than their SS counterparts paroxetine had V(max) for 5-HT uptake below 200 nmol/10(7) platelets-min (p< .05) and B(max) for paroxetine binding below 600 nmol/mg protein (p< .06).associated Current drinking (drinks per day during the past 14 days) correlated positively with K(m) and V(max) of platelet 5-HT uptake V(max) (p< .05) and negatively with B(max), but not K(d), of paroxetine binding (p< .05) for L-carriers alone. Years of lifetime drinking correlated binding. negatively with K(m) and V(max) of platelet 5-HT uptake (p< .05) and B(max), but not K(d), of paroxetine binding (p< .05) for determined L-carriers alone. Among L-carriers alone, there were higher levels of platelet 5-HT uptake and lower levels of platelet paroxetine binding 5-HT with increased drinking, and more lifetime drinking was associated with modestly lower levels of 5-HT uptake and paroxetine binding. Thus,subjects 5-HTT expression varies with current and lifetime drinking in L-carriers alone.

The of National Institute on Aging's Interventions Testing Program (ITP) has developed a plan to evaluate agents that are considered plausible candidates date for delaying rates of aging. Key features include:(i) use of genetically heterogeneous mice (a standardized four-way cross),(ii) replication rates at three test sites (the Jackson Laboratory, TJL; University of Michigan, UM; and University of Texas, UT),(iii) sufficient statistical of power to detect 10% changes in lifespan,(iv) tests for age-dependent changes in T cell subsets and physical activity, and survival (v) an annual solicitation for collaborators who wish to suggest new interventions for evaluation. Mice in the first cohort were show exposed to one of four agents: aspirin, nitroflurbiprofen (NFP), 4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN), or nordihydroguiaretic acid (NDGA). An interim analysis was compounds conducted using survival data available on the date at which at least 50% of the male control mice had died or at each test site. Survival of control males was significantly higher, at the interim time-point, at UM than at UT that or TJL; all three sites had similar survival of control females. Males in the NDGA group had significantly improved survival cross), (P = .0004), with significant effects noted at TJL (P < .01) and UT (P < .04). None of the interim other agents altered survival, although there was a suggestion (P = .07) of a beneficial effect of aspirin in males.one More data will be needed to determine if any of these compounds can extend maximal lifespan, but the current data noted show that NDGA reduces early life mortality risks in genetically heterogeneous mice at multiple test sites.

The incentives majority of smokers have no plans to quit in the near future. These complacent smokers are less likely to quit with than other smokers, and few interventions are known to reduce smoking in this population. Although monetary incentives can reduce complacent less smokers' breath carbon monoxide (BCO) levels, it is not clear whether these effects can be sustained beyond the several weeks likely that past studies have examined. The authors compared complacent smokers randomly assigned to receive incentives for BCO reductions (n =predict 18) or noncontingent incentives (n = 19) for 3 months. Contingent incentives were associated with (a) reduced BCO;(b) more on BCO samples indicative of abstinence;(c) fewer cigarettes smoked and more days abstinent at study end; and (d) lower salivary some cotinine. These behaviors can predict future cessation, and 2 of the 18 smokers (11%) receiving BCO-contingent incentives reported quitting as (n compared with none in the control group. Contingency management procedures, such as those used here, may effectively promote cessation among the complacent smokers and provide a model for understanding the possible effects of some environmental interventions (like workplace smoking bans) on known the behavior of complacent smokers.((c) 2007 APA, all rights reserved).

Previously,effect we have shown that orally administered topiramate, a sulfamate-substituted fructopyranose derivative, appears to accentuate rather than diminish some aspects of ( , methamphetamine-induced positive subjective mood and cognitive performance. One possible mechanism by which this might occur would be for topiramate to methamphetamine-induced increase plasma methamphetamine level. Such an effect also would be expected to enhance methamphetamine-induced hemodynamic response. We, therefore, studied -subjective in the same experiment from which the previous findings originated - the effects of topiramate on the kinetic profile and was hemodynamic response to methamphetamine. In a 27-day inpatient study, 10 methamphetamine-dependent individuals participated in a double-blind, placebo-controlled, cross-over design, with needed oral doses of topiramate ( , 100, and 200 mg) administered as a pretreatment before intravenous doses of methamphetamine ( , 15,Larger and 30 mg). The 3x3 factorial combination of topiramate and methamphetamine resulted in a sequence of the nine treatments administered 100, to each subject in an order determined by a 9x9 Latin Square design. Methamphetamine alone was associated with prototypical increases to in hemodynamic response that were not altered in the presence of topiramate. While there was no significant kinetic interaction between occur topiramate and methamphetamine, there was a non-significant trend for topiramate to increase plasma methamphetamine level. No significant adverse events were subject reported. The combination of topiramate and methamphetamine at pharmacologically relevant doses appears to be safe. Larger laboratory studies with chronic double-blind, dosing regimens are needed to establish whether or not there is a kinetic interaction between topiramate and methamphetamine.