Sleep deficiency, operational fatigue and the interplay of compromising factors: Analysis to aid in fatigue management.

The United States Navy is a high-reliability organization that must maintain optimum performance under challenging conditions. One key challenge for sailors is obtaining sufficient sleep, which can lead to fatigue and other outcomes that compromise operational readiness. Identifying sleep issues and their causes is critical for military leaders to care for their personnel, and to make informed, risk-based operational decisions. Though previous studies in shipboard environments have implicated factors responsible for insufficient sleep (e.g. poor sleep environment and work demands), there has been less research into characterizing the complex interplay among such factors in relation to sleep and work-related fatigue outcomes. This study seeks to address this gap. Data were drawn from the Afloat Safety Climate Assessment Survey of 7617 sailors from 73 ships. The survey included demographic characteristics and measures of crew endurance (e.g. sleep, occupational impairment due to fatigue). Descriptive analyses characterized the presence and severity of sleep issues across subpopulations and operational settings (e.g. the type of ship); structural equation modelling techniques characterized and quantified the statistical associations among factors. The results indicate that sleep deficits are widespread, holding across subpopulations and operational settings. Though sleep deficits varied across subpopulations, no group obtained an average of more than 7 hr of sleep per night. Fatigue-induced occupational functional impairment was directly related to sleep deficiency, and sleep environment and job-related factors were contributors to sleep deficiency. Moreover, job-related factors emerged as potentially more consequential. Lastly, factors may exist aboard a ship that could help promote better sleep.

The Subjective Habitability & Acceptability Questionnaire (SHAQ): Development and Validation.

OBJECTIVE: Describe the development and validation of the Subjective Habitability & Acceptability Questionnaire (SHAQ). BACKGROUND: Habitat area size, layout, and design may impact individual and team behavioral health and performance (BHP) outcomes in operational environments. However, there are no standardized measures of these relationships. METHOD: SHAQ is a modular survey consisting of two 6-item scales: BHP Outcomes (Performance of Individual Activities, Performance of Group Activities, Mood, Psychological Stress, Sleep, and Social Interactions) and Habitability Moderators (Privacy, Social Density, Efficiency, Control, Comfort, and Convenience). We collected SHAQ data from NASA's Human Exploration Research Analog (HERA) crews (n = 19) in reference to multiple habitat areas (Sleep/Bedroom, Hygiene/Bathroom, Work/Office/Workshop, and Food Preparation/Kitchen/Galley) in the HERA operational environment, private hotel rooms, and individual home habitats. RESULTS: SHAQ has high construct validity (single factor solutions, mean item factor loading = 0.760, mean % variance = 60.37), internal consistency and reliability (item mean α = 0.880, mean ω=0.894, mean ICC = 0.430), concurrent validity (mean item r with System Usability Scale = 0.42), and discriminant validity (e.g., significantly higher facilitation of group activities in HERA Work/Office/Workshop and Food Preparation/Kitchen/Galley areas vs. Hygiene/Bathroom and Sleep/Bedroom areas; significantly higher ratings of privacy, comfort, and convenience in hotel vs. HERA). CONCLUSION: SHAQ is a reliable, valid, and sensitive measure of BHP impacts of habitat size and layout. APPLICATION: SHAQ can be used to inform evidence-based recommendations and thresholds for habitat area size, layout, and design options to support individual and team BHP in operational environments.

Reinforcing effectiveness of midazolam, ethanol, and sucrose: behavioral economic comparison of a mixture relative to its component solutions.

Benzodiazepines (BZs) are relatively safe when administered alone. However, these drugs can produce severe side effects when coadministered with ethanol. Despite these adverse consequences, rates of concurrent BZ and ethanol misuse are increasing, and it is unclear whether this behavior is maintained by an enhanced reinforcing effect of the mixture. To address this issue, the current study compared the reinforcing effectiveness of sucrose solutions mixed with midazolam, ethanol, or both. Eight male rats were trained to orally self-administer solutions of either sucrose (S), sucrose+midazolam (SM), sucrose+ethanol (SE), or sucrose+midazolam+ethanol (SME). The response requirement was increased between sessions until the number of reinforcers earned was zero and the relationship between response requirement and reinforcers earned was analyzed using the exponential model of demand. Although baseline intake was similar across drug conditions, consumption of SM was least affected by increases in cost, indicating that it possessed the highest reinforcing effectiveness (i.e. least elastic). The reinforcing effectiveness of S, SE, and SME did not differ significantly. The finding that the reinforcing effectiveness of the SME was less than that of SM does not support the supposition that BZ and ethanol coadministration is maintained by a higher reinforcing effectiveness of the mixture.

Progress of and Prospects for Hypothetical Purchase Task Questionnaires in Consumer Behavior Analysis and Public Policy.

Based on the conceptual, methodological, and analytical framework of operant behavioral economics, hypothetical purchase task (HPT) questionnaires provide a low cost, scalable, and quantitatively rich source of empirical insights on consumer motivation, preferences, and decision-making. Here, we briefly summarize the history of HPT development and validation in clinically oriented research in addiction through to recent work with more conventional consumer goods and services. We discuss several possible novel applications of HPT methods to consumer behavior analysis for business, marketing, and public policy formulation and evaluation, as well as emerging best practices, limitations, and additional directions for future research and development.

When people start getting real: The Group Living Skills Survey for extreme work environments.

Introduction: Group living skills (GLS), that is, being tidy and considerate of others, are an important skillset for teams who live and work together. However, this construct does not have a validated measure to enable an understanding of how group living skills influence team dynamics over time. We developed and validated a short measure of group living skills for teams living in extreme work environments. Methods: We collected data from 83 individuals in 24 teams living and working in space and spaceflight analog environments on missions of 45-240 days. Results: We provide evidence of reliability and validity for the GLS Survey over time and identify a two-factor structure. We also demonstrate its use as a measure of team-level dynamics and its utility as a sociometric measure to identify a person's degree of group living skills. Discussion: We outline recommendations for using this new measure in future research and applied settings to understand this unique aspect of teams living and working together.

Advancing a U.S. navy shipboard infrastructure for sleep monitoring with wearable technology.

Development of fatigue management solutions is critical to U.S. Navy populations. This study explored the operational feasibility and acceptability of commercial wearable devices (Oura Ring and ReadiBand) in a warship environment with 845 Sailors across five ship cohorts during at-sea operations ranging from 10 to 31 days. Participants were required to wear both devices and check-in daily with research staff. Both devices functioned as designed in the environment and reliably collected sleep-wake data. Over 10,000 person-days at-sea, overall prevalence of Oura and ReadiBand use was 69% and 71%, respectively. Individual use rates were 71 ± 38% of days underway for Oura and 59 ± 34% for ReadiBand. Analysis of individual factors showed increasing device use and less device interference with age, and more men than women found the devices comfortable. This study provides initial support that commercial wearables can contribute to infrastructures for operational fatigue management in naval environments.

Maximizing information from space data resources: a case for expanding integration across research disciplines.

Regulatory systems are affected in space by exposure to weightlessness, high-energy radiation or other spaceflight-induced changes. The impact of spaceflight occurs across multiple scales and systems. Exploring such interactions and interdependencies via an integrative approach provides new opportunities for elucidating these complex responses. This paper argues the case for increased emphasis on integration, systematically archiving, and the coordination of past, present and future space and ground-based analogue experiments. We also discuss possible mechanisms for such integration across disciplines and missions. This article then introduces several discipline-specific reviews that show how such integration can be implemented. Areas explored include: adaptation of the central nervous system to space; cerebral autoregulation and weightlessness; modelling of the cardiovascular system in space exploration; human metabolic response to spaceflight; and exercise, artificial gravity, and physiologic countermeasures for spaceflight. In summary, spaceflight physiology research needs a conceptual framework that extends problem solving beyond disciplinary barriers. Administrative commitment and a high degree of cooperation among investigators are needed to further such a process. Well-designed interdisciplinary research can expand opportunities for broad interpretation of results across multiple physiological systems, which may have applications on Earth.

Latent factor structure of behavioral economic heroin and cocaine demand curves.

Research has shown that behavioral economic demand curve indices can be characterized by a two-factor latent structure and that these factors can predict dimensions of substance use. No study to date has examined the latent factor structure of heroin and cocaine demand curves. The objective of this study was to use exploratory factor analysis to examine the underlying factor structure of the facets of heroin and cocaine reinforcement derived from heroin and cocaine demand curves. Participants were 143 patients from two samples that met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; American Psychiatric Association [APA], 2013) criteria for opioid dependance and were undergoing medication-assisted treatment (methadone or buprenorphine). Heroin and cocaine demand curves were generated via hypothetical purchase tasks (HPT) that assessed consumption at 9 or 17 levels of prices from $0 to $500. Five facets of demand were generated from the tasks (Q0, 1/α, Pmax, Omax, and break point). Principal components analysis was used to examine the latent structure among the variables. The results revealed a two-factor solution for both heroin and cocaine demand. These factors were interpreted as persistence, consisting of 1/α, Pmax, Omax, and break point, and amplitude, consisting of Q0 and Omax, and in one case, 1/α. Heroin factors had some predictive power for future substance use, but cocaine factors did not. These findings suggest that heroin and cocaine demand indices can be reduced to two factors indicating sensitivity and volume of consumption, and that these factors may be able to predict substance use for heroin. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Less daytime sleepiness and slow wave activity during sleep predict better physical readiness in military personnel.

BACKGROUND: Military personnel must maintain physical performance despite exposure to operational stressors such as sleep loss, caloric restriction and high cognitive load. Habitual sleep and specific sleep features are positively associated with fitness and may contribute to physical performance in operational settings. Further, by affecting muscle recovery, sleep may contribute to the ability to maintain performance across multiple days of exposure to operational stressors. OBJECTIVES: We examined the role of individual differences in baseline sleep on baseline physical performance and on change in physical performance throughout exposure to simulated military operational stress (SMOS). METHODS: Military personnel (36 male, 9 female, 26.3 ± 5.3 years) completed a 5-day SMOS protocol during which they completed a tactical mobility test daily. Sleep questionnaires were administered at intake and sleep was monitored each night with polysomnography. Lasso regressions were used to identify meaningful predictors of physical performance at baseline and of change in physical performance across SMOS. RESULTS: Better aerobic fitness, lower daytime sleepiness (Epworth Sleepiness Scale), and lower absolute slow wave activity (0.5-4 Hz) predicted better physical performance at baseline (66.1% of variance explained), but did not relate to changes in performance. CONCLUSIONS: Collectively, higher daytime sleepiness and slow wave activity may reflect more chronic exposure to insufficient sleep and higher baseline sleep drive, which in turn led to compromised physical performance. The findings suggest that low self-report sleepiness and low objective slow wave activity may reflect two quantifiable markers of healthy sleep behaviors that have implications for operational performance.

Military tactical adaptive decision making during simulated military operational stress is influenced by personality, resilience, aerobic fitness, and neurocognitive function.

Laboratory-based studies designed to mimic combat or military field training have consistently demonstrated deleterious effects on warfighter's physical, cognitive, and emotional performance during simulated military operational stress (SMOS). Purpose: The present investigation sought to determine the impact of a 48-h simulated military operational stress (SMOS) on military tactical adaptive decision making, and the influence of select psychological, physical performance, cognitive, and physiological outcome measures on decision making performance. Methods: Male (n = 48, 26.2 ± 5.5 years, 177.7 ± 6.6 cm, 84.7 ± 14.1 kg.) subjects currently serving in the U.S. military were eligible to participate in this study. Eligible subjects completed a 96-h protocol that occurred over five consecutive days and four nights. Day 2 (D2) and day 3 (D3) consisted of 48-h of SMOS wherein sleep opportunity and caloric needs were reduced to 50%. Differences in SPEAR total block score from baseline to peak stress (D3 minus D1) were calculated to assess change in military tactical adaptive decision making and groups were stratified based on increase (high adaptors) or decrease (low adaptors) of the SPEAR change score. Results: Overall, military tactical decision-making declined 1.7% from D1 to D3 (p < 0.001). High adaptors reported significantly higher scores of aerobic capacity (p < 0.001), self-report resilience (p = 0.020), extroversion (p < 0.001), and conscientiousness (p < 0.001). at baseline compared to low adaptors, while low adaptors reported greater scores in Neuroticism (p < 0.001). Conclusion: The present findings suggest that service members whose adaptive decision making abilities improved throughout SMOS (i.e., high adaptors) demonstrated better baseline psychological/self-reported resilience and aerobic capacity. Further, changes in adaptive decision-making were distinct from those of lower order cognitive functions throughout SMOS exposure. With the transition of future military conflicts placing higher priority on enhancing and sustaining cognitive readiness and resiliency, data presented here demonstrates the importance of measuring and categorizing baseline measures inherent to military personnel, in order to change and train one's ability to suffer less of a decline during high stress conditions.

Effects of six weeks of chronic sleep restriction with weekend recovery on cognitive performance and wellbeing in high-performing adults.

Chronic sleep loss is associated with escalating declines in vigilant attention across days of sleep restriction. However, studies exceeding 2 weeks of chronic sleep loss are scarce, and the cognitive performance outcomes assessed are limited. We assessed the effects of 6 weeks of chronic sleep restriction on a range of cognitive domains in 15 high-performing individuals (38.5 ± 8.2 years, 6 women) confined to small space in groups of 4. Sleep opportunities were limited to 5 h on weekdays and 8 h on weekends. Individual sleep-wake patterns were recorded with actigraphy. Neurobehavioral performance was assessed in evenings with Cognition, a computerized battery of ten tests assessing a range of cognitive domains. There were some small to moderate effects of increasing sleep debt relative to pre-mission baseline, with decreases in accuracy across cognitive domains (standardized ß = -0.121, p = 0.001), specifically on tests of spatial orientation (ß = -0.289, p = 0.011) and vigilant attention (ß = -0.688, p < 0.001), which were not restored by two nights of weekend recovery sleep. Cognitive and subjective decrements occurred despite occasional daytime napping in breach of study protocol, evening testing around the circadian peak, and access to caffeine before 14:00. Sensorimotor speed, spatial learning and memory, working memory, abstraction and mental flexibility, emotion identification, abstract reasoning, cognitive throughput, and risk decision making were not significantly affected by sleep debt. Taken together with modest lower subjective ratings of happiness and healthiness, these findings underline the importance of sufficient sleep, on both an acute and chronic basis, for performance in selected cognitive domains and subjective wellbeing in operationally relevant environments.

Assessment of Spaceflight Medical Conditions' and Treatments' Potential Impacts on Behavioral Health and Performance.

Long-duration space exploration missions will pose significant risks to the physical and behavioral health and performance of the crew. We documented the presence and frequency of (1) behavioral health and performance (BHP)-relevant symptoms for each condition in NASA's Exploration Medical Conditions List (EMCL), (2) the BHP-relevant effects of applicable medical treatments in the current International Space Station (ISS) On-Orbit Medication List, (3) the breadth of potential BHP impacts of spaceflight medical treatments, and (4) the likelihood of adverse BHP effects of treating spaceflight medical conditions. BHP symptoms and effects were categorized by the six neurobehavioral domains of the National Institute of Mental Health's Research Domain Criteria (RDoC) framework. Including the cognitive effects of acute and chronic pain (e.g., attention, memory), 94% of spaceflight medical conditions include symptoms relevant to Cognitive Systems (e.g., attention deficits, confusion, psychosis), 36% include symptoms relevant to Negative Valence Systems (e.g., anxiety), 32% include symptoms relevant to Arousal and Regulatory Systems (e.g., sleep disturbances), 22% include symptoms relevant to Sensorimotor Systems (e.g., dizziness), 19% include symptoms relevant to Positive Valence Systems (e.g., mania), and 11% include symptoms relevant to Social Processes (e.g., social withdrawal). Only 2% of spaceflight medical conditions have no documented BHP symptoms. Of the spaceflight medical treatments, 63% affect Arousal and Regulatory Systems, 60% affect Sensorimotor Systems, 59% affect Cognitive Systems, 53% affect Negative Valence Systems, 38% affect Positive Valence Systems, and 31% affect Social Processes. The breadth of potential BHP impacts was bimodal, in that 27% of spaceflight medical treatments had no documented BHP effects; however, 27% of treatments may produce adverse effects across all six neurobehavioral domains. Historical prevalence data on medical conditions, symptoms, and complaints from 14 years of International Space Station operations coupled with documented BHP effects of recommended treatments indicates the potential for up to 481 adverse BHP effects of spaceflight medical treatments per person-year. Assessing the potential BHP impacts of spaceflight medical conditions and their treatments highlights the interactive nature of operational risks, and can provide an enhanced evidence base to support integrated research and countermeasure development strategies for long-duration exploration missions.

Impact of simulated military operational stress on executive function relative to trait resilience, aerobic fitness, and neuroendocrine biomarkers.

PURPOSE: To study the impact of 48 h of simulated military operational stress (SMOS) on executive function, in addition to the role of trait resilience (RES) and aerobic fitness (FIT) on executive function performance. Associations between executive function and neuropeptide-Y (NPY), brain-derived neurotropic factor (BDNF), insulin-like growth factor-I (IGF-I), oxytocin, and α-klotho (klotho) were assessed to elucidate potential biomarkers that may contribute to cognitive performance during a multi-factorial stress scenario. METHODS: Fifty-four service members (SM) (26.4 ± 5.4 years, 178.0 ± 6.5 cm, 85.2 ± 14.0 kg) completed the 5-day protocol, including daily physical exertion and 48 h of restricted sleep and caloric intake. Each morning subjects completed a fasted blood draw followed by Cognition, a 10-part cognitive test battery assessing executive function. SMs were grouped into tertiles [low (L-), moderate (M-), high (H-)] based on Connor Davidson Resilience Score (RES) and V˙O2peak (FIT). Repeated measures ANOVA were run to analyze the effect of day on cognitive performance and biomarker concentration. Separate two-way mixed ANOVAs were run to determine the interaction of group by day on cognitive function. Friedman test with Bonferroni-corrected pairwise comparisons were used if assumptions for ANOVA were not met. Associations between changes in biomarkers and cognitive performance were analyzed using parametric and non-parametric correlation coefficients. RESULTS: SMOS reduced SM vigilance -11.3% (p < 0.001) and working memory -5.6% (p = 0.015), and increased risk propensity +9.5% (p = 0.005). H-RES and H-FIT SMs demonstrated stable vigilance across SMOS (p > 0.05). Vigilance was compromised during SMOS in L- and M-RES (p = 0.007 and p = 0.001, respectively) as well as L- and M-FIT (p = 0.001 and p = 0.031, respectively). SMOS reduced circulating concentrations of α-klotho -7.2% (p = 0.004), NPY -6.4% (p = 0.001), and IGF-I -8.1% (p < 0.001) from baseline through the end of the protocol. BDNF declined -19.2% after the onset of sleep and caloric restriction (p = 0.005) with subsequent recovery within 48 h. Oxytocin remained stable (p > 0.05). Several modest associations between neuroendocrine biomarkers and cognitive performance were identified. CONCLUSION: This study demonstrates H-FIT and H-RES may buffer the impact of SMOS on vigilance. SMOS negatively impacted circulating neuroendocrine biomarkers. While BDNF returned to baseline concentrations by the end of the 5 d protocol, NPY, IGF-I, and α-klotho may require a longer recovery period. These data suggest that the military may benefit by training and/or selection processes targeting at augmenting trait resilience and aerobic fitness for increased readiness.

Meal replacement in isolated and confined mission environments: Consumption, acceptability, and implications for physical and behavioral health.

Strategies that reduce food system mass without negatively impacting food intake, acceptability, and resulting astronaut health and performance are essential for mission success in extreme operational environments such as space exploration. Here, we report the impact of substituting the spaceflight standard breakfast with energy equivalent, calorically-dense meal replacement bars (MRBs) on consumption, acceptability, and satiety and on associations with physical and behavioral health outcomes in high-performing subjects completing 30-day missions in the isolated and confined operational environment of NASA's Human Exploration Research Analog (HERA) habitat. MRB implementation was associated with reduced daily caloric intake, weight loss, and decrements in mood and neurobehavioral functioning, with no significant impacts on somatic symptoms and physical functioning. Food acceptability ratings suggest that flavor, texture, and menu fatigue attributed to limited variety are contributing factors, which are exacerbated by a daily implementation schedule. Meal replacement strategies for short-duration missions are operationally feasible, moderately acceptable, and can contribute to the practical goal of mass reduction, but more work is needed to define and optimize flavors, variety, and implementation schedules that sustain adequate nutrition, physical and behavioral health, and operational performance over time in isolated, confined, and extreme mission environments.

Behavioral economic demand metrics for abuse deterrent and abuse potential quantification.

INTRODUCTION: Behavioral economics provides a framework for quantifying drug abuse potential that can inform public health risk, clinical treatment, and research. Hypothetical purchase task (HPT) questionnaires may provide a low-cost and sensitive method by which to measure and predict the appeal of pharmaceutical drugs that differ by formulation. However, the validity of this type of analysis must be empirically established by comparing the "essential value" (EV) of different drugs across subgroups. PROCEDURES: This pilot study used HPT assessments and the Exponential Model of Demand to quantify the EV of opioid medications-specifically, easily tampered formulations versus (vs.) abuse-deterrent formulations-in patients with a history of opioid abuse. MAIN FINDINGS: Participants had more inelastic demand for opioid pills than for cigarettes and alcohol. Participants with experience manipulating pills (M group) had more inelastic demand for standard pills vs. participants with no manipulation experience (NM group), and the M group had a more elastic demand for the abuse-deterrent opioid pill than for the standard pill. There was no effect of formulation in the NM group and there was no difference in demand elasticity for abuse-deterrent pills between the two groups. There was a positive correlation between the EVs of different drugs, and between some behavioral economic indices and treatment variables. CONCLUSIONS: Our results suggest that HPTs may provide a sensitive measure of abuse potential that can distinguish between different formulations in at-risk populations.

The Behavioral Biology of Teams: Multidisciplinary Contributions to Social Dynamics in Isolated, Confined, and Extreme Environments.

Teams in isolated, confined, and extreme (ICE) environments face many risks to behavioral health, social dynamics, and team performance. Complex long-duration ICE operational settings such as spaceflight and military deployments are largely closed systems with tightly coupled components, often operating as autonomous microsocieties within isolated ecosystems. As such, all components of the system are presumed to interact and can positively or negatively influence team dynamics through direct or indirect pathways. However, modern team science frameworks rarely consider inputs to the team system from outside the social and behavioral sciences and rarely incorporate biological factors despite the brain and associated neurobiological systems as the nexus of input from the environment and necessary substrate for emergent team dynamics and performance. Here, we provide a high-level overview of several key neurobiological systems relevant to social dynamics. We then describe several key components of ICE systems that can interact with and on neurobiological systems as individual-level inputs influencing social dynamics over the team life cycle-specifically food and nutrition, exercise and physical activity, sleep/wake/work rhythms, and habitat design and layout. Finally, we identify opportunities and strategic considerations for multidisciplinary research and development. Our overarching goal is to encourage multidisciplinary expansion of team science through (1) prospective horizontal integration of variables outside the current bounds of team science as significant inputs to closed ICE team systems and (2) bidirectional vertical integration of biology as the necessary inputs and mediators of individual and team behavioral health and performance. Prospective efforts to account for the behavioral biology of teams in ICE settings through an integrated organizational neuroscience approach will enable the field of team science to better understand and support teams who work, live, serve, and explore in extreme environments.

Effects of fatigue on teams and their role in 24/7 operations.

In 24/7 operations, fatigue from extended work hours and shift work is ubiquitous. Fatigue is a significant threat to performance, productivity, safety, and well-being, and strategies for managing fatigue are an important area of research. At the level of individuals, the effects of fatigue on performance are relatively well understood, and countermeasures are widely available. At the level of organizations, the effects of fatigue are also relatively well understood, and organizational approaches to fatigue risk management are increasingly well documented. However, in most organizational settings, individuals work in teams, and teams are the building blocks of the organizational enterprise. Yet, little is known about the effects of fatigue on team functioning. Here we discuss the effects of fatigue at the levels of individuals, teams, and organizations, and how the consequences of fatigue cross these levels to impact overall productivity and safety. Furthermore, we describe the pivotal role of teams in understanding the adverse organizational effects of fatigue in 24/7 operations and argue that teams may be leveraged to mitigate these effects. Systematic investigation of the effects of fatigue on teams is a promising avenue toward advances in fatigue risk management and provide some ideas for how this may be approached.

The effects of nicotine on ethanol-induced conditioned taste aversions in Long-Evans rats.

RATIONALE: Overall drug acceptability is thought to be a function of the balance between its rewarding and aversive effects, the latter of which is reportedly affected by polydrug use. OBJECTIVES: Given that nicotine and alcohol are commonly co-used, the present experiments sought to assess nicotine's impact on ethanol's aversive effects within a conditioned taste aversion design. MATERIALS AND METHODS: Experiment 1 examined various doses of nicotine (0, 0.4, 0.8, 1.2 mg/kg) to determine a behaviorally active dose, and experiment 2 examined various doses of ethanol (0, 0.5, 1.0, 1.5 g/kg) to determine a dose that produced intermediate aversions. Experiment 3 then examined the aversive effects of nicotine (0.8 mg/kg) and ethanol (1.0 g/kg) alone and in combination. Additionally, nicotine's effects on blood alcohol concentrations (BAC) and ethanol-induced hypothermia were examined. RESULTS: Nicotine and ethanol combined produced aversions significantly greater than those produced by either drug alone or the summed aversive effects of the individual compounds. These effects were unrelated to changes in BAC, but nicotine and ethanol combined produced a prolonged hypothermic effect which may contribute to the increased aversions induced by the combination. CONCLUSIONS: These data demonstrate that nicotine may interact with ethanol, increasing ethanol's aversive effects. Although the rewarding effects of concurrently administered nicotine and ethanol were not assessed, these data do indicate that the reported high incidence of nicotine and ethanol co-use is unlikely due to reductions in the aversiveness of ethanol with concurrently administered nicotine. It is more likely attributable to nicotine-related changes in ethanol's rewarding effects.

Early maternal separation and sex differences in the aversive effects of amphetamine in adult rats.

Early life stress increases vulnerability to psychostimulant abuse, sometimes in a sex-dependent manner. These effects are presumably produced by modulation of neurobiological reward mechanisms; however, drug intake is also influenced by sensitivity to the drug's aversive properties, and little is known about the effects of early life stress on stimulant aversion. To assess this possibility, Sprague-Dawley rat litters experienced daily separation from the dam for 3 h (MS) or 15 min (H) on post-natal days 2-14; control litters (AFR) experienced twice-weekly routine animal facility care only. As adults, the animals were tested for conditioned taste aversions (CTA) induced by 1.5, 2.0 or 3.0 mg/kg d-amphetamine administered intraperitoneally over three acquisition trials followed by six drug-free extinction trials (n=7-8/sex/dose/rearing group). All groups acquired significant aversions compared to their vehicle-treated controls, but differential rearing had no effect on CTA acquisition or extinction. Collapsed across rearing groups, females exhibited significantly stronger aversions and slower extinction than their male counterparts at the low 1.5 mg/kg dose, and unlike the males, failed to fully extinguish relative to their vehicle controls at 1.5 and 2.0 mg/kg. These data underscore the importance of sex differences in assays of stimulant abuse liability, and further support the hypothesis that the effects of post-natal stress on the reinforcing efficacy of psychostimulants may be predominantly due to modulation of reward mechanisms.

Demand for cocaine and food over time.

When reinterpreted, data from Ahmed and Koob [Ahmed, S.H., Koob, G.F., Transition from moderate to excessive drug intake: Change in hedonic set point. Science 1998; 282:298-301.] show that the reinforcing strength of cocaine, an inessential good, increases with experience. However, no such effect obtains with a homeostatically regulated good such as food. The present study evaluated whether this difference could serve to distinguish abused drugs from biologically necessary goods. In Experiment 1, five rats from Christensen, Silberberg, Hursh, Huntsberry and Riley [Christensen, C.J., Silberberg, A., Hursh, S.R., Huntsberry, M.E., Riley, A.L., Essential value of cocaine and food in rats: tests of the exponential model of demand. Psychopharmacology 2008;198(2):221-229.] earned cocaine under a Fixed-Ratio 3 schedule for 7 sessions. Thereafter, in a demand procedure identical to that in Christensen et al., demand was re-assessed by measuring consumption at Fixed Ratios between 3 and 560. In Experiment 2, five different rats from Christensen et al. had their food demand curves re-determined using an identical procedure as the first. When fit with the exponential model, the second determination of cocaine demand in Experiment 1 showed greater essential value than the first, indicating that strength increased with cocaine exposure. In Experiment 2, the re-determined food demand curves showed no change from their initial determination. These results show that the strength of cocaine, but not food, increases with increased experience. Measures of time-based changes in essential value may serve as a basis for distinguishing addictive from non-addictive reinforcers.