Repeated exposure to physiologically effective doses of contraceptive hormones ethinyl estradiol or levonorgestrel do not alter the reinforcing effects of a brief visual stimulus in ovary-intact rats.

Estradiol and progesterone potentiate and attenuate reward processes, respectively. Despite these well-characterized effects, there is minimal research on the effects of synthetic estrogens (e.g., ethinyl estradiol, or EE) and progestins (e.g., levonorgestrel, or LEVO) contained in clinically-utilized hormonal contraceptives. The present study characterized the separate effects of repeated exposure to EE or LEVO on responding maintained by a reinforcing visual stimulus. Forty ovary-intact female Sprague-Dawley rats received either sesame oil vehicle (n = 16), 0.18 µg/day EE (n = 16), or 0.6 µg/day LEVO (n = 8) subcutaneous injections 30-min before daily one-hour sessions. Rats' responding was maintained by a 30-sec visual stimulus on a Variable Ratio-3 schedule of reinforcement. The day after rats' last session, we determined rats estrous cycle phase via vaginal cytology before sacrifice and subsequently weighing each rat's uterus to further verify the contraceptive hormone manipulation. The visual stimulus functioned as a reinforcer, but neither EE nor LEVO enhanced visual stimulus maintained responding. Estrous cytology was consistent with normal cycling in vehicle rats and halting of normal cycling in EE and LEVO rats. EE increased uterine weights consistent with typical uterotrophic effects observed with estrogens, further confirming the physiological impacts of our EE and LEVO doses. In conclusion, a physiologically effective dose of neither EE nor LEVO did not alter the reinforcing efficacy of a visual stimulus reinforcer. Future research should characterize the effects of hormonal contraceptives on responding maintained by other reinforcer types to determine the generality of the present findings.

CATALYST: challenging antibiotic allergy status.

OBJECTIVES: To develop a transferable process, CATALYST (challenging antibiotic allergystatus), to assess and challenge penicillin allergy status of inpatients within an NHS Foundation Hospital. METHODS: A multidisciplinary team (MDT) steering group reviewed existing literature and protocols enabling penicillin allergy assessment, challenge and de-labelling. Using this, they identified five key steps forming the basis of CATALYST: clinical assessment of the nature of allergy; inclusion/exclusion criteria; consent; direct oral penicillin challenge; and removal of allergy label. A pharmacist-led pilot was conducted to assess the process, during which a continuous PDSA (plan-do-study-act) cycle was observed. This included formally auditing endpoint data such as accuracy of allergy status in medical records post-intervention. RESULTS: CATALYST was successfully developed with key resources produced to support clinicians. It was piloted in 304 patients, with 172 patients excluded and 132 successful allergy challenges. There was one incident of an adverse event (acute kidney injury) in the 132 successful patients, which occurred as a delayed reaction following 22 days of penicillin therapy. Only 64% of permanent records (held by GP) were appropriately updated when audited at the end of the pilot. CONCLUSIONS: CATALYST is a transferable process to facilitate safe assessment, challenge and removal of spurious penicillin allergy labels. Handover between care sectors forms a key element of allergy removal to ensure all records are updated and work is needed to ensure this process is done effectively.

Varenicline serves as the training stimulus in the drug-discriminated goal-tracking task with rats: initial evaluation of potential neuropharmacological processes.

Varenicline (Chantix) is an FDA-approved smoking cessation aid that is pharmacologically similar to nicotine, the primary addictive component found within tobacco. In support of this similarity, previous drug discrimination research in rats has reported that the internal or interoceptive stimulus effects of nicotine and varenicline share stimulus elements. Those shared elements appear to be mediated, in part, by overlapping action at alpha4beta2-containing nicotinic acetylcholine receptors (nAChRs). The research supporting this conclusion, however, has only used nicotine, and not varenicline, as the training drug. Accordingly, we used the discriminated goal tracking (DGT) task in which 1 mg/kg varenicline signaled intermittent access to sucrose. On separate intermixed saline days, sucrose was not available. Rats acquired the discrimination as measured by a differential increase in dipper entries (goal tracking) evoked by varenicline. These rats then received a series of tests with several doses of varenicline, nicotine, nornicotine (a metabolite of nicotine and tobacco alkaloid), sazetidine-A (a partial alpha4beta2 agonist), PHA-543613 (an alpha7 agonist), and bupropion (a norepinephrine and dopamine reuptake inhibitor). Control of goal tracking by varenicline was dose-dependent. Nicotine and nornicotine evoked responding comparable to the varenicline training dose indicating full substitution. Sazetidine-A partially substituted for the varenicline stimulus, whereas bupropion and PHA-543613 evoked little to no varenicline-like responding. These findings indicate that varenicline can serve as the training stimulus in the DGT task. Further, stimulus control of varenicline in the DGT task is driven by its partial agonist activity at alpha4beta2-containing nAChRs. The use of this approach could lead to a better understanding of the pharmacological action of varenicline and help guide treatment geared towards tobacco cessation through a more targeted development of novel synthetically designed, subunit-specific pharmacological interventions.

Social dimensions of fertility behavior and consumption patterns in the Anthropocene.

We consider two aspects of the human enterprise that profoundly affect the global environment: population and consumption. We show that fertility and consumption behavior harbor a class of externalities that have not been much noted in the literature. Both are driven in part by attitudes and preferences that are not egoistic but socially embedded; that is, each household's decisions are influenced by the decisions made by others. In a famous paper, Garrett Hardin [G. Hardin, Science 162, 1243-1248 (1968)] drew attention to overpopulation and concluded that the solution lay in people "abandoning the freedom to breed." That human attitudes and practices are socially embedded suggests that it is possible for people to reduce their fertility rates and consumption demands without experiencing a loss in wellbeing. We focus on fertility in sub-Saharan Africa and consumption in the rich world and argue that bottom-up social mechanisms rather than top-down government interventions are better placed to bring about those ecologically desirable changes.

Population, Ecological Footprint and the Sustainable Development Goals.

The Anthropocene can be read as being the era when the demand humanity makes on the biosphere's goods and services-humanity's 'ecological footprint'-vastly exceeds its ability to supply it on a sustainable basis. Because the 'ecological' gap is met by a diminution of the biosphere, the inequality is increasing. We deploy estimates of the ecological gap, global GDP and its growth rates in recent years, and the rate at which natural capital has declined, to study three questions: (1) at what rate must efficiency at which Nature's services are converted into GDP rise if the UN's Sustainable Development Goals for year 2030 are to be sustainable; (2) what would a sustainable figure for world population be if global living standard is to be maintained at an acceptably high level? (3) What living standard could we aspire to if world population was to attain the UN's near lower-end projection for 2100 of 9 billion? While we take a global perspective, the reasoning we deploy may also be applied on a smaller scale. The base year we adopt for our computations is the pre-pandemic 2019.

Linkages between Forestry Best Management Practices and erosion in the southeastern U.S.

Numerous studies have concluded that forestry Best Management Practices (BMPs) are effective at mitigating erosion and sedimentation caused by forest operations; however, the complex relationship between forestry BMPs and erosion is largely unexamined. In this study, BMP implementation rates, which are percentages ranging from 0 to 100% that indicates how well an operator instituted recommended practices in the field, and predicted erosion rates, obtained by using USLE-Forest, were calculated for 108 recent harvests in twelve states and three physiographic regions in the southeastern U.S. BMP implementation rates were subdivided into three levels of application: BMP+ (>90% implementation), BMP-standard (80-90% implementation), and BMP- (<80% implementation). Skid trails (86.5 Mg ha-1 yr-1) and haul roads (90.3 Mg ha-1 yr-1) eroded at relatively high rates at the BMP- level across the southeast. This emphasizes the importance of adequate BMP measures such as utilizing water diversion structures and cover management at these features to better protect water quality. The overall weighted average erosion estimates for all regions at the BMP-standard (10.4 Mg ha-1 yr-1) and BMP+ (6.6 Mg ha-1 yr-1) levels were <11 Mg ha-1 yr-1, indicating that water quality and site productivity are largely protected when adequate BMPs are implemented, and Streamside Management Zones (SMZs) are utilized along streams. Approximately 94% of the sites sampled were classified as either BMP-standard or BMP+, demonstrating that BMPs are being implemented consistently throughout the southeast. Spearman ρ correlation analyses were performed for all variables. Forestry BMP implementation and erosion estimates had significant negative correlations, especially for skid trails (Spearman ρ = -0.59, p-value < 0.0001) and haul roads (Spearman ρ = -0.39, p-value = < 0.0001), as well as for all regions across the southeast. These variables, however, were poorly correlated for stream crossings, indicating that current audit questions in the southeast may not fully address erosion. Additionally, BMP implementation and erosion estimates exhibited a significant negative correlation (R2 = 0.28, p-value < 0.0001) based on a quadratic regression line for all features, reinforcing that as BMP implementation increases, predicted erosion generally decreases.

Reward-enhancing effects of d-amphetamine and its interactions with nicotine were greater in female rats and persisted across schedules of reinforcement.

Nicotine enhances the value of environmental stimuli and rewards, and reward enhancement can maintain nicotine consumption. Stimulants such as d-amphetamine are misused more by women and are commonly co-used with nicotine. d-Amphetamine potentiates nicotine's effects in human and animal research. To date, there are no published studies examining this interaction in a reward-enhancement task. The current study sought to investigate the reward-enhancing effects of nicotine alongside and coadministered with d-amphetamine. Further, we evaluated the persistence of reward enhancement across ratio and temporal schedules of reinforcement. We used 10 male and 10 female Sprague-Dawley rats. Enhancement was assessed within subjects by examining active lever pressing for a visual stimulus reinforcer on variable ratio 3, variable interval 30 s and variable time 30 s - variable ratio 3 schedules. Before 1-h sessions, rats received one injection of saline, 0.1 or 0.3 mg/kg d-amphetamine and one of saline or 0.4 mg/kg nicotine, making six possible drug combinations (saline + saline, saline + nicotine, 0.1 d-amphetamine + aline, 0.1 d-amphetamine + nicotine, 0.3 d-amphetamine + saline and 0.3 d-amphetamine + nicotine) experienced in a randomized order by each rat. When d-amphetamine was coadministered with nicotine, we found an interaction effect on reward enhancement that persisted across schedules of reinforcement. Males and females exhibited reward enhancement by 0.3 d-amphetamine, while only females showed reward enhancement by 0.1 d-amphetamine. Further, females responded more for the visual stimulus than males in all d-amphetamine conditions. Future studies should assess how reward enhancement is involved in high nicotine-amphetamine comorbidity rates and enhanced amphetamine misuse in women.

Advanced bioinformatics rapidly identifies existing therapeutics for patients with coronavirus disease-2019 (COVID-19).

BACKGROUND: The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19). METHODS: We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform. RESULTS: Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2. CONCLUSIONS: While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.

Corridors of Clarity: Four Principles to Overcome Uncertainty Paralysis in the Anthropocene.

Global environmental change challenges humanity because of its broad scale, long-lasting, and potentially irreversible consequences. Key to an effective response is to use an appropriate scientific lens to peer through the mist of uncertainty that threatens timely and appropriate decisions surrounding these complex issues. Identifying such corridors of clarity could help understanding critical phenomena or causal pathways sufficiently well to justify taking policy action. To this end, we suggest four principles: Follow the strongest and most direct path between policy decisions on outcomes, focus on finding sufficient evidence for policy purpose, prioritize no-regrets policies by avoiding options with controversial, uncertain, or immeasurable benefits, aim for getting the big picture roughly right rather than focusing on details.

Sex Differences in the Reward-Enhancing Effects of Nicotine on Ethanol Reinforcement: A Reinforcer Demand Analysis.

BACKGROUND: Alcohol is often consumed with tobacco, and dependence to alcohol and tobacco are highly comorbid. In addition, there are differences in the prevalence of nicotine- and alcohol-abuse between the sexes. Nicotine produces enhancing effects on the value of other reinforcers, which may extend to alcohol. METHODS: Male and female Wistar rats were trained to self-administer 15% ethanol solution in 30-minute sessions. Once ethanol self-administration was established, demand for ethanol was evaluated using an exponential reinforcer demand method, in which the response cost per reinforcer delivery was systematically increased over blocks of several sessions. Within each cost condition, rats were preinjected with nicotine (0.05, 0.1, 0.2, or 0.4 mg/kg base, SC) or saline 5 minutes before self-administration sessions. The effects of nicotine dose and biological sex were evaluated using the estimates generated by the reinforcer demand model. RESULTS: Under saline conditions, males showed greater sensitivity to ethanol reinforcement than females. Nicotine enhanced the reinforcement value of alcohol and this varied with sex. In both sexes, 0.4 mg/kg nicotine decreased intensity of ethanol demand. However, 0.05, 0.1, and 0.2 mg/kg nicotine decreased elasticity of ethanol demand in females, but not in males. CONCLUSIONS: Nicotine enhances ethanol reinforcement, which may partially drive comorbidity between nicotine-abuse and alcohol-abuse. Males showed signs of greater ethanol reinforcement value than females under saline conditions, and nicotine attenuated this effect by increasing ethanol reinforcement value in the females. These findings highlight that a complete understanding of alcohol-abuse must include a thorough study of alcohol use in the context of other drug use, including nicotine. IMPLICATIONS: Nicotine dose dependently enhances the alcohol reinforcement value in a manner that is clearly influenced by biological sex. Under saline baseline conditions, males show lower elasticity of demand for alcohol reinforcement than females, indicative of greater reinforcement value. However, nicotine attenuated this difference by enhancing alcohol reward in the females. Specifically, low-to-moderate doses (0.05-0.2 mg/kg) of nicotine decreased elasticity of alcohol demand in female rats, increasing the perseverance of their alcohol taking behavior. These data indicate that the well-documented reward-enhancing effects of nicotine on sensory reinforcement extend to alcohol reinforcement and that these vary with biological sex.

Coordination vs. voluntarism and enforcement in sustaining international environmental cooperation.

The fates of "transboundary" environmental systems depend on how nation states interact with one another. In the absence of a hegemon willing and able to coerce other states into avoiding a "tragedy of the commons," shared environments will be safeguarded if international cooperation succeeds and degraded or even destroyed if it fails. Treaties and related institutions of international law give form to these efforts to cooperate. Often, they implore states to act in their collective (as opposed to their national) interests. Sometimes, they impel cooperating states to punish free riders. A few agreements coordinate states' behavior. Here, I present simple game-theoretic models showing whether and how treaties and related institutions can change incentives, aligning states' self-interests with their collective interests. I show that, as a general matter, states struggle to cooperate voluntarily and enforce agreements to cooperate but that they find it relatively easy to coordinate actions. In some cases, the need for coordination is manifest. In other cases, it requires strategic thinking. Coordination may fall short of supporting an ideal outcome, but it nearly always works better than the alternatives.

Substituent Effects and Mechanism in a Mechanochemical Reaction.

We report the effect of substituents on the force-induced reactivity of a spiropyran mechanophore. Using single molecule force spectroscopy, force-rate behavior was determined for a series of spiropyran derivatives substituted with H, Br, or NO2 para to the breaking spirocyclic C-O bond. The force required to achieve the rate constants of ∼10 s-1 necessary to observe transitions in the force spectroscopy experiments depends on the substituent, with the more electron withdrawing substituent requiring less force. Rate constants at 375 pN were determined for all three derivatives, and the force-coupled rate dependence on substituent identity is well explained by a Hammett linear free energy relationship with a value of ρ = 2.9, consistent with a highly polar transition state with heterolytic, dissociative character. The methodology paves the way for further application of linear free energy relationships and physical organic methodologies to mechanochemical reactions, and the characterization of new force probes should enable additional, quantitative studies of force-coupled molecular behavior in polymeric materials.

A behavioral economic analysis of the value-enhancing effects of nicotine and varenicline and the role of nicotinic acetylcholine receptors in male and female rats.

Reinforcement value enhancement by nicotine of non-nicotine rewards is believed to partially motivate smoking behavior. Recently, we showed that the value-enhancing effects of nicotine are well characterized by reinforcer demand models and that the value-enhancing effects of the smoking-cessation aid bupropion (Zyban) are distinct from those of nicotine and differ between the sexes. The present study evaluated potential sex differences in the enhancement effects of nicotine and varenicline (Chantix) using a reinforcer demand methodology. The role of α4ß2* and α7 nicotinic acetylcholine receptors (nAChRs) in the enhancing effects of nicotine and varenicline is also evaluated. Male and female rats (n=12/sex) were trained to lever press maintained by sensory reinforcement by visual stimulus (VS) presentations. Changes in the VS value following nicotine and varenicline administration were assessed using an established reinforcer demand approach. Subsequently, the effects of antagonism of α4ß2* and α7 nAChRs on varenicline and nicotine-induced enhancement active lever-pressing were assessed using a progressive ratio schedule. Nicotine and varenicline enhanced VS demand equivalently between the sexes as evaluated by reinforcer demand. However, α4ß2* receptor antagonism attenuated value enhancement by nicotine and varenicline in females, but only of nicotine in males.

Does aquaculture add resilience to the global food system?

Aquaculture is the fastest growing food sector and continues to expand alongside terrestrial crop and livestock production. Using portfolio theory as a conceptual framework, we explore how current interconnections between the aquaculture, crop, livestock, and fisheries sectors act as an impediment to, or an opportunity for, enhanced resilience in the global food system given increased resource scarcity and climate change. Aquaculture can potentially enhance resilience through improved resource use efficiencies and increased diversification of farmed species, locales of production, and feeding strategies. However, aquaculture's reliance on terrestrial crops and wild fish for feeds, its dependence on freshwater and land for culture sites, and its broad array of environmental impacts diminishes its ability to add resilience. Feeds for livestock and farmed fish that are fed rely largely on the same crops, although the fraction destined for aquaculture is presently small (∼4%). As demand for high-value fed aquaculture products grows, competition for these crops will also rise, as will the demand for wild fish as feed inputs. Many of these crops and forage fish are also consumed directly by humans and provide essential nutrition for low-income households. Their rising use in aquafeeds has the potential to increase price levels and volatility, worsening food insecurity among the most vulnerable populations. Although the diversification of global food production systems that includes aquaculture offers promise for enhanced resilience, such promise will not be realized if government policies fail to provide adequate incentives for resource efficiency, equity, and environmental protection.

Climate negotiations under scientific uncertainty.

How does uncertainty about "dangerous" climate change affect the prospects for international cooperation? Climate negotiations usually are depicted as a prisoners' dilemma game; collectively, countries are better off reducing their emissions, but self-interest impels them to keep on emitting. We provide experimental evidence, grounded in an analytical framework, showing that the fear of crossing a dangerous threshold can turn climate negotiations into a coordination game, making collective action to avoid a dangerous threshold virtually assured. These results are robust to uncertainty about the impact of crossing a threshold, but uncertainty about the location of the threshold turns the game back into a prisoners' dilemma, causing cooperation to collapse. Our research explains the paradox of why countries would agree to a collective goal, aimed at reducing the risk of catastrophe, but act as if they were blind to this risk.

Use of the overexpectation effect to reduce conditioned seeking behavior controlled by nicotine.

Nicotine produces robust stimulus effects that can be conditioned to form associations with reinforcing nondrug stimuli. We examine how established associations to the nicotine stimulus may be weakened via the overexpectation effect. In two experiments, we separately conditioned sucrose associations to the interoceptive nicotine stimulus (0.4 mg/kg, SC) and to a "noisy" exteroceptive contextual stimulus (oscillating houselight and white noise) via the discriminated goal-tracking task. Thereafter, we presented additional sucrose pairings with the nicotine and noisy stimuli, now in compound. Testing of the conditioned goal-tracking evoked by the nicotine and noisy stimuli in isolation-before versus after compound conditioning (Experiment 1) or between treatment and control groups (Experiment 2)-demonstrated an attenuation of conditioned responding via the overexpectation effect. We suggest that applications of the overexpectation effect may provide some promise for treatments seeking to attenuate drug-evoked conditioned responses in situations where extinction-based interventions are not suitable.

Varenicline but not cotinine increased the value of a visual stimulus reinforcer in rats: No evidence for synergy of the two compounds.

Smoking is the leading cause of preventable death worldwide, with <7 % of smoking cessation attempts being met with success. Nicotine, the main addictive agent in cigarettes, enhances the reinforcing value of other environmental rewards. Under some circumstances, this reward enhancement maintains nicotine consumption. Varenicline (i.e., cessation aid Chantix™) also has reward-enhancement effects via nicotinic acetylcholine receptor agonism (nAChRs) - albeit less robust than nicotine. Cotinine is the major metabolite of nicotine. Recent studies suggest that cotinine is a positive allosteric modulator (PAM) and/or a weak agonist at nAChRs. Thus, cotinine may enhance the behavioral effects of nAChR compounds such as varenicline and/or exert some behavioral effects alone. We used 20 (10M, 10F) Sprague-Dawley rats to assess reward-enhancement within-subjects by examining responding maintained by a reinforcing visual stimulus on a Variable Ratio 2 schedule of reinforcement. To assess the reward-enhancing effects of cotinine, rats received one injection of cotinine (saline, 0.1, 0.3, 1.0, 3.0, 6.0 mg/kg) before each 1 h session. To assess cotinine and varenicline interactions, rats received an injection of cotinine (saline, 0.1, 1.0, or 6.0 mg/kg) and of varenicline (saline, 0.1, 0.3, 1.0, or 3.0 mg/kg) before the session. While we replicated prior work identifying reward-enhancement by 0.1, 0.3, and 1.0 mg/kg varenicline, cotinine alone did not produce reward-enhancement nor augment the reward-enhancing effects of varenicline. Future studies may consider examining the reward-enhancing effects of cotinine with other reinforcers or co-administered with other smoking cessation aids such as bupropion.

"A robust and simple catheter connector assembly for long-term self-administration experiments".

Intravenous self-administration in rats is used widely to study the reinforcing effects of drugs and serves as the gold standard for assessing their use and misuse potential. One challenge that researchers often encounter when scaling up experiments is balancing the cost, time investment to construct, and robustness of each implanted catheter. These catheters include multiple components such as surgical meshing and a variety of entry ports designed to facilitate the connection of the rat to a catheter port tethering system. Other considerations include maintaining the catheters free of blockage during the extent of the drug self-administration experiment. These large-scale studies provide ample opportunity for the catheter system to fail. The failure and replacement of commercially purchased catheters leads to ballooning expenses, and the failure of in-lab manufactured catheters requires the manufacture of reserves, also increasing costs, as these handmade products are inherently more variable. We have developed a catheter system that combines a commercially available implantable back-mounted entry connector system with inexpensive medical items such as surgical mesh, sutures, and an air-tight back flow prevention system to bolster the overall success of self-administration experiments.•Method to bolster commercially available jugular catheter components for long-lasting self-administration experiments.•Reduces the overall cost per unit of self-administration experiments.•Easily assembled by laboratory students and staff.

Social Norms and Global Environmental Challenges: The Complex Interaction of Behaviors, Values, and Policy.

Government policies are needed when people's behaviors fail to deliver the public good. Those policies will be most effective if they can stimulate long-term changes in beliefs and norms, creating and reinforcing the behaviors needed to solidify and extend the public good.It is often the short-term acceptability of potential policies, rather than their longer-term efficacy, that determines their scope and deployment. The policy process should consider both time scales. The academy, however, has provided insufficient insight on the coevolution of social norms and different policy instruments, thus compromising the capacity of decision makers to craft effective solutions to the society's most intractable environmental problems. Life scientists could make fundamental contributions to this agenda through targeted research on the emergence of social norms.

Assessment of ethanol and nicotine interactions using a reinforcer demand modeling with grouped and individual levels of analyses in a long-access self-administration model using male rats.

Previous reports have indicated the reciprocal effects of nicotine and ethanol on their rewarding and reinforcing properties, but studies using methodological approaches resembling substance use in vulnerable populations are lacking. In our study, rats first self-administered ethanol, and their sensitivity to ethanol's reinforcing effects was assessed using a reinforcer demand modeling approach. Subsequently, rats were equipped with intravenous catheters to self-administer nicotine, and their sensitivity to nicotine's reinforcing effects was evaluated using the same approach. In the final phase, rats were allowed to self-administer ethanol and nicotine concurrently, investigating the influence of one substance on the rate of responding for the other substance. Group analyses revealed notable differences in demand among sucrose, sweetened ethanol, and ethanol-alone, with sucrose demonstrating the highest demand and ethanol-alone exhibiting greater sensitivity to changes in cost. At the individual level, our study finds significant correlations between rats' demand for sucrose and sweetened ethanol, suggesting parallel efforts for both substances. Our individual data also suggest interconnections in the elasticity of demand for sweetened ethanol and ethanol-alone, as well as a potential relationship in price response patterns between ethanol and nicotine. Furthermore, concurrent self-administration of ethanol and nicotine at the group level displayed reciprocal effects, with reduced responding for nicotine in the presence of ethanol and increased responding for ethanol in the presence of nicotine. This study provides valuable insights into modeling the co-use of ethanol and nicotine and assessing their interaction effects using reinforcer demand modeling and concurrent self-administration or noncontingent administration tests. These findings contribute to our understanding of the complex interplay between ethanol and nicotine and have implications for elucidating the underlying mechanisms involved in polydrug use.