Validating a Procedure to Assess Declines in Acute Cigarette Self-Administration due to Reductions in Nicotine Content

The FDA has considered reducing the maximum allowable nicotine content in cigarettes to facilitate quitting in dependent smokers. To potentially inform clinical research on nicotine reduction, this laboratory-based study used a within-subjects forced-choice paradigm to assess dose-related declines in relative nicotine reinforcement in dependent adult smokers (N=37). The aim was to establish the clinically predictive validity of this paradigm by relating findings to results from the Donny et al. (2015) clinical trial on smoking reduction with reduced nicotine cigarettes. In five sessions following overnight abstinence, SPECTRUM research cigarettes varying in nicotine contents (17.4, 11.2, 5.5, 2.3, and 1.3 mg/g; one “NIC” dose per session), were compared to a very low nicotine content cigarette (“VLNC”; 0.4 mg/g). Each session began with four 4-puff exposure trials (2 each NIC or VLNC, identified by letter codes). Assessment of pleasurable sensory perceptions of smoking occurred immediately following each exposure trial. Next were four choice trials in which NIC and VLNC cigarettes were presented concurrently; participants were instructed to take four puffs from any combination of the cigarettes they wanted, totaling 16 choices. Overall, the number of NIC choices and the magnitude of difference in pleasurable sensory perceptions (NIC – VLNC) increased significantly as the nicotine content condition increased. Sensory responses were found to mediate the relationship between nicotine content condition and choice. Differences in choice and sensory responses due to menthol preference and/or ethnicity were also found. However, the pattern NIC choices across nicotine content conditions were not consistent with the pattern of results observed by Donny et al. (2015), failing to establish clinically predictive validity of the forced choice procedure. Although this within-subjects acute choice procedure did not closely relate to the between-subjects ad lib smoking behavior across weeks in Donny et al., this procedure may combine with other data to suggest a nicotine reduction to ≤2.3 mg/g may attenuate reinforcement

Transgenerational plasticity and acclimation of tropical sea urchins to ocean warming and acidification

Anthropogenic CO2 emissions are causing the oceans to simultaneously warm and become increasingly acidic, with rates of change that are putting evolutionary pressure on many marine organisms. As a result, both short-term responses and the ability of organisms to acclimate to rapid environmental change through phenotypic plasticity are expected to play a considerable role in persistence of many species under future ocean change. Evidence is accumulating that non-genetic inheritance and transgenerational plasticity (TGP) may be important mechanisms which may facilitate acclimation to ocean warming and acidification. This thesis tests the overarching hypothesis that TGP and parental acclimation to predicted ocean warming and acidification conditions promote greater resilience in offspring using two tropical sea urchins, Tripneustes gratilla and Echinometra sp. A, as model organisms. Echinoderms are an ecologically important group which have been useful models for understanding responses of developmental stages to climate change stressors. However, the majority of existing studies have examined responses within a single generation, with little allowance for acclimation. To date, only a handful of studies have examined the effects of climate stressors on offspring whose parents had also experienced similar environmental conditions. Here, transgenerational responses of T. gratilla were examined in offspring derived from parents raised in ocean warming (+2C/29C) and acidification (-0.3 pH/ pHT 7.77) treatments from juveniles to mature adults, a period encompassing the entirety of gonadogenesis. This study found that although larvae generally performed best when raised in the same treatments as their parents, parental acclimation had a predominantly negative effect on larval size. When raised in control conditions, 2 day old pluteus larvae derived from parents acclimated to warming and/or acidification were consistently smaller, with reductions in postoral arm lengths of up to 21%, compared to larvae derived from parents raised in control conditions. These results indicate that acclimation to predicted warming and acidification conditions may result in fitness trade-offs during early development, which may have consequences for later developmental stages and survival in the form of negative carryover effects. A longer-term study followed development of Echinometra sp. A progeny (throughout development to near competency) derived from parents maintained for two years in either present-day (ambient) conditions (mean = 26C/pHT 8.10) or warming (+2C/mean = 28C) and acidification (-0.3 pH/ pHT 7.80) conditions predicted for the year 2100. Egg size as well as larval survival, morphology, and respiration were quantified, and molecular analyses were performed to gain a better understanding of mechanisms underlying acclimation. Egg size was not affected by parental treatment, but larvae derived from parents acclimated to conditions predicted for the year 2100 were larger and developed faster than larvae derived from parents maintained in ambient, present-day conditions. However, offspring of urchins acclimated to predicted 2100 conditions had higher mortality than offspring of urchins cultured in present-day conditions, with up to 38% higher mortality by the time they were reaching competency at 15 days post-fertilisation. When raised in 2100 conditions, respiration rates of larvae derived from 2100 acclimated parents increased 109% while respiration rates of offspring derived from present-day parents decline 36.8%, suggesting that mortality may have been due to higher energetic consumption. Molecular analysis found that gene expression patterns in gastrula stages were strongly influenced by the environment experienced by parents. Gastrula derived from parents acclimated to predicted 2100 conditions upregulated genes involved in biomineralisation, suggesting greater allocation of energy toward calcification, which may have influenced the higher growth rates seen in these larvae. Later stage pluteus larvae showed far fewer differences in gene expression among treatments, and in contrast to gastrula stages, differences were primarily driven by the environment experienced by larvae. These results may indicate that early developmental stages were primed for similar environments to those experienced by parents while later developmental stages may be more capable of responding to their own environmental conditions. The research presented in this thesis partially supports the hypothesis that TGP and parental acclimation to ocean warming and acidification results in offspring that are more optimally suited to future ocean conditions. Reallocation of energy and resources may result in fitness gains in one developmental trait or stage while compromising another. Fitness trade-offs may be an important outcome and the results of these studies highlight the complex nature of transgenerational plasticity and acclimation to future ocean conditions.

Decision by sampling

We present a theory of decision by sampling (DbS) in which, in contrast with traditional models, there are no underlying psychoeconomic scales. Instead, we assume that an attribute’s subjective value is constructed from a series of binary, ordinal comparisons to a sample of attribute values drawn from memory and is its rank within the sample. We assume that the sample reflects both the immediate distribution of attribute values from the current decision’s context and also the background, real-world distribution of attribute values. DbS accounts for concave utility functions; losses looming larger than gains; hyperbolic temporal discounting; and the overestimation of small probabilities and the underestimation of large probabilities

On the source of human irrationality

Reasoning and decision making are error prone. This is often attributed to a fast, phylogenetically old System 1. It is striking, however, that perceptuo-motor decision making in humans and animals is rational. These results are consistent with perceptuo-motor strategies emerging in Bayesian brain theory that also appear in human data selection. People seem to have access, although limited, to unconscious generative models that can generalise to explain other verbal reasoning results. Error does not emerge predominantly from System 1, but rather seems to emerge from the later evolved System 2 that involves working memory and language. However language also sows the seeds of error correction by moving reasoning into the social domain. This reversal of roles suggests key areas of theoretical integration and new empirical directions

The ortho effect in aromatic nucleophilic substitution

M.S.Charles L. Liott

THE EFFECTS OF NICOTINE ON THE HABITUATION OF REINFORCER EFFECTIVENESS

Beyond its primary and secondary reinforcing effects, nicotine also enhances reinforcement from non-drug stimuli unrelated to smoking. Possibly relevant to that effect, preclinical research has shown that nicotine can maintain the effectiveness of a non-drug operant reinforcer across repeated presentations. Operant reinforcement is a dynamic process in which a reinforcer’s ability to promote behavior decreases systematically with each presentation, leading to within-session declines in responding. Habituation to the sensory aspects of a reinforcer is the mechanism underlying declines in its effectiveness. Nicotine’s effect on habituation of reinforcer effectiveness has not been demonstrated in humans. The current study was designed as a first step in translating animal research examining nicotine’s influence on habituation of reinforcer effectiveness to a human sample. Using a within-subjects design, 30 dependent smokers (14 males, 16 females) participated in two experimental sessions, as part of a larger study. Sessions varied by nicotine condition, no nicotine after overnight abstinence (>12 hr; CO 10 ppm; “nicotine condition”). In each session, participants engaged in a 15-min operant response task to earn time viewing a preferred picture (attractive human model; 7 sec per earned reinforcer; fixed-interval 10 schedule), with unique pictures per session. Overall, reinforced responding and duration of responding were each significantly greater in the nicotine versus no nicotine condition. When examining within-session patterns of responding, rate of reinforced responding declined less sharply early in the trial and persisted longer under the nicotine versus no nicotine condition. Exploratory analyses suggested that neither self-reported withdrawal levels nor nicotine condition order influenced differences in patterns of responding between conditions. Overall, these results are an initial demonstration of nicotine’s (via cigarette smoke) ability to maintain the effectiveness of a reinforcer longer, compared to a no nicotine control. Delaying declines in reinforcer effectiveness may be yet another way in which nicotine promotes smoking behavior

The Chimes of Freedom: Bob Dylan

In the summer of 1963, Bob Dylan first appears on television before millions of people who have never heard him nor heard of him previously. The future of this performer is legendary: He becomes a speaker for millions of dissatisfied people of the l960’s. “I was completely taken by what this man had done and how he had done it,” Daniel Kramer mentions. “His performance was perfect. With simple, basic tools--his voice, a guitar, and a harmonica--he drove his message deep into my mind.” Dylan's "message" is "freedom,” a possession which he prides for all Man. Unlike the common hits of the time which Kramer terms meaningless as far as their statements were concerned,” Dylan’s songs are very meaningful, concerned works