Effects on child and adolescent health of climate change mitigation policies: A systematic review of modelling studies.

There is a growing body of modelling evidence that demonstrates the potential for immediate and substantial benefits to adult health from greenhouse gas mitigation actions, but the effects on the health of younger age groups is largely unknown. We conducted a systematic review to identify the available published evidence of the modelled effects on child and adolescent health (≤18 years of age) of greenhouse gas mitigation. We searched six databases of peer-reviewed studies published between January 1, 1990 and July 27, 2022, screened 27,282 original papers and included 23 eligible papers. All included studies were set in high- and middle-income countries; and all studies modelled the effects of interventions that could mitigate greenhouse gas emissions and improve air quality. Most of the available evidence suggests positive benefits for child and adolescent respiratory health from greenhouse gas mitigation actions that simultaneously reduce air pollution (specifically PM2.5 and nitrogen dioxide). We found scant evidence on child and adolescent health from regions more vulnerable to climate change, or on mitigation interventions that could affect exposures other than air pollution.

Nitrate and nitrite contamination in drinking water and cancer risk: A systematic review with meta-analysis.

BACKGROUND: Pollution of water sources, largely from wide-scale agricultural fertilizer use has resulted in nitrate and nitrite contamination of drinking water. The effects on human health of raised nitrate and nitrite levels in drinking water are currently unclear. OBJECTIVES: We conducted a systematic review of peer-reviewed literature on the association of nitrate and nitrite in drinking water with human health with a specific focus on cancer. METHODS: We searched eight databases from 1 January 1990 until 28 February 2021. Meta-analyses were conducted when studies had the same exposure metric and outcome. RESULTS: Of 9835 studies identified in the literature search, we found 111 studies reporting health outcomes, 60 of which reported cancer outcomes (38 case-control studies; 12 cohort studies; 10 other study designs). Most studies were set in the USA (24), Europe (20) and Taiwan (14), with only 3 studies from low and middle-income countries. Nitrate exposure in water (59 studies) was more commonly investigated than nitrite exposure (4 studies). Colorectal (15 studies) and gastric (13 studies) cancers were the most reported. In meta-analyses (4 studies) we identified a positive association of nitrate exposure with gastric cancer, OR = 1.91 (95%CI = 1.09-3.33) per 10 mg/L increment in nitrate ion. We found no association of nitrate exposure with colorectal cancer (10 studies; OR = 1.02 [95%CI = 0.96-1.08]) or cancers at any other site. CONCLUSIONS: We identified an association of nitrate in drinking water with gastric cancer but with no other cancer site. There is currently a paucity of robust studies from settings with high levels nitrate pollution in drinking water. Research into this area will be valuable to ascertain the true health burden of nitrate contamination of water and the need for public policies to protect human health.

Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial.

BACKGROUND: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0·5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixed-effect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. RESULTS: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L-1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. CONCLUSIONS: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov).

The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries.

BACKGROUND: Post-partum haemorrhage (PPH) is a leading cause of maternal death worldwide. The WOMAN trial assessed the effects of tranexamic acid (TXA) on death and surgical morbidity in women with PPH. The trial recorded 483 maternal deaths. We report the circumstances of the women who died. METHODS: The WOMAN trial recruited 20,060 women with a clinical diagnosis of PPH after a vaginal birth or caesarean section. We randomly allocated women to receive TXA or placebo. When a woman died, we asked participating clinicians to report the cause of death and to provide a short narrative of the events surrounding the death. We collated and edited for clarity the narrative data. RESULTS: Case fatality rates were 3.0% in Africa and 1.7% in Asia. Nearly three quarters of deaths were within 3 h of delivery and 91% of these deaths were from bleeding. Women who delivered outside a participating hospital (12%) were three times more likely to die (OR = 3.12, 95%CI 2.55-3.81) than those who delivered in hospital. Blood was often unavailable due to shortages or because relatives could not afford to buy it. Clinicians highlighted late presentation, maternal anaemia and poor infrastructure as key contributory factors. CONCLUSIONS: Although TXA use reduces bleeding deaths by almost one third, mortality rates similar to those in high income countries will not be achieved without tackling late presentation, maternal anaemia, availability of blood for transfusion and poor infrastructure.

Mapping the evidence of novel plant-based foods: a systematic review of nutritional, health, and environmental impacts in high-income countries.

CONTEXT: Shifting from current dietary patterns to diets rich in plant-based (PB) foods and lower in animal-based foods (ABFs) is generally regarded as a suitable strategy to improve nutritional health and reduce environmental impacts. Despite the recent growth in supply of and demand for novel plant-based foods (NPBFs), a comprehensive overview is lacking. OBJECTIVES: This review provides a synthesis of available evidence, highlights challenges, and informs public health and environmental strategies for purposeful political decision-making by systematically searching, analyzing, and summarizing the available literature. DATA SOURCES: Five peer-reviewed databases and grey literature sources were rigorously searched for publications. DATA EXTRACTION: Study characteristics meeting the inclusion criteria regarding NPBF nutrient composition and health and environmental outcomes in high-income countries were extracted. DATA ANALYSIS: Fifty-seven peer-reviewed and 36 grey literature sources were identified; these were published in 2016-2022. NPBFs typically have substantially lower environmental impacts than ABFs, but the nutritional contents are complex and vary considerably across brands, product type, and main primary ingredient. In the limited evidence on the health impacts, shifts from ABFs to PB meats were associated with positive health outcomes. However, results were mixed for PB drinks, with links to micronutrient deficiencies. CONCLUSION: If carefully selected, certain NPBFs have the potential to be healthier and nutrient-rich alternatives to ABFs and typically have smaller environmental footprints. More disaggregated categorization of various types of NPBFs would be a helpful step in guiding consumers and key stakeholders to make informed decisions. To enable informed policymaking on the inclusion of NPBFs in dietary transitions as part of a wider net-zero and health strategy, future priorities should include nutritional food standards, labelling, and subdivisions or categorizations of NPBFs, as well as short- and long-term health studies evaluating dietary shifts from ABFs to NPBFs and standardized environmental impact assessments, ideally from independent funders.

Air pollution and child health impacts of decarbonization in 16 global cities: Modelling study.

Most research on the air pollution-related health effects of decarbonization has focused on adults. We assess the potential health benefits that could be achieved in children and young people in a global sample of 16 cities through global decarbonization actions. We modelled annual average concentrations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at 1x1 km resolution in the cities using a general circulation/atmospheric chemistry model assuming removal of all global combustion-related emissions from land transport, industries, domestic energy use and power generation. We modelled the impact on childhood asthma incidence and adverse birth outcomes (low birthweight, pre-term births) using published exposure-response relationships. Removal of combustion emissions was estimated to decrease annual average PM2.5 by between 2.9 µg/m3 (8.4%) in Freetown and 45.4 µg/m3 (63.7%) in Dhaka. For NO2, the range was from 0.3 ppb (7.9%) in Freetown to 18.8 ppb (92.3%) in Mexico City. Estimated reductions in asthma incidence ranged from close to zero in Freetown, Tamale and Harare to 149 cases per 100,000 population in Los Angeles. For pre-term birth, modelled impacts ranged from a reduction of 135 per 100,000 births in Dar es Salaam to 2,818 per 100,000 births in Bhubaneswar and, for low birthweight, from 75 per 100,000 births in Dar es Salaam to 2,951 per 100,000 births in Dhaka. The large variations chiefly reflect differences in the magnitudes of air pollution reductions and estimated underlying disease rates. Across the 16 cities, the reduction in childhood asthma incidence represents more than one-fifth of the current burden, and an almost 10% reduction in pre-term and low birthweight births. Decarbonization actions that remove combustion-related emissions contributing to ambient PM2.5 and NO2 would likely lead to substantial but geographically-varied reductions in childhood asthma and adverse birth outcomes, though there are uncertainties in causality and the precision of estimates.

Let's just ask them. Perspectives on urban dwelling and air quality: A cross-sectional survey of 3,222 children, young people and parents.

This research aimed to capture and synthesise the views of children, young people, parents and expectant parents (CYPP) about the cities where they live, with a specific focus on air pollution (AP), in order to support the generation of evidence-informed policy that reflects CYPP's perspectives, ultimately contributing to the development of child-centered, healthier, sustainable cities. The Children, Cities and Climate (CCC) project used targeted social media adverts to recruit CYPP to complete an online survey with a combination of open and closed questions in order to collect perceptions about air quality in their home cities, the main sources of AP, and how they would improve their cities. The survey was completed by 3,222 CYPP in 59 of the most polluted cities in 14 countries. Nearly two in five (39%) CYPP cited AP as one of the worst things about their city, with motor transport perceived as the main contributor. CYPP reported differing views on whether their cities were becoming better (43%) or worse (34%) places to live (33% reported it was 'staying the same'). Numerous specific ideas to improve cities and urban air quality emerged, alongside an emphasis on also addressing structural barriers to change. A clear set of principles that should guide how city leaders act was also described, including the need to engage with young people meaningfully. CYPPs articulated good and bad experiences of urban living and perceived AP and traffic as pressing concerns. They provided a clear set of suggestions for improving their cities. Further efforts to engage young people on these issues are warranted.

Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. Treatment success is dependant on early intervention and rapid systemic exposure to TXA. The requirement for intravenous (IV) administration can in some situations limit accessibility to TXA therapy. Here we employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration. METHODS: A commercially available PBPK software (GastroPlus®) was used to model published TXA pharmacokinetics. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n = 48 participants). The model was verified using separate IV and oral validation datasets (n = 26 participants). Oral, IM and sub-cutaneous (SQ) dose finding simulations were performed. RESULTS: Across the different TXA regimens evaluated TXA plasma concentrations varied from 0.1 to 94.0 µg/mL. Estimates of the total plasma clearance of TXA ranged from 0.091 to 0.104 L/h/kg, oral bioavailability from 36 to 67% and Tmax from 2.6 to 3.2 and 0.4 to 1.0 h following oral and intramuscular administration respectively. Variability in the observed TXA PK could be captured through predictable demographic effects on clearance, combined with intestinal permeability and stomach transit time following oral administration and muscle blood flow and muscle/plasma partition coefficients following intra-muscular dosing. CONCLUSIONS: This study indicates that intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures. Plasma levels following an IM dose of 1000 mg TXA are predicted to exceed 15 mg/mL in < 15 min and be maintained above this level for approximately 3 h, achieving systemic exposure (AUC0-6) of 99 to 105 µg*hr/mL after a single dose. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended.

Neuropeptide S reinstates cocaine-seeking behavior and increases locomotor activity through corticotropin-releasing factor receptor 1 in mice.

Neuropeptide S (NPS) is a recently discovered neuropeptide that increases arousal and wakefulness while decreasing anxiety-like behavior. Here, we used a self-administration paradigm to demonstrate that intracerebroventricular infusion of NPS reinstates extinguished cocaine-seeking behavior in a dose-dependent manner in mice. The highest dose of NPS (0.45 nM) increased active lever pressing in the absence of cocaine to levels that were equivalent to those observed during self-administration. In addition, we examined the role of the corticotropin-releasing factor receptor 1 (CRF(1)) in this behavior as well as locomotor stimulation and anxiolysis. CRF(1) knock-out mice did not respond to either the locomotor stimulant or cocaine reinstatement effects of NPS, but still responded to its anxiolytic effect. The CRF(1) antagonist antalarmin also blocked the increase in active lever responding in the reinstatement model and the locomotor activating properties of NPS without affecting its anxiolytic actions. Our results suggest that NPS receptors may be an important target for drug abuse research and treatment and that CRF(1) mediates the cocaine-seeking and locomotor stimulant effects of NPS, but not its effects on anxiety-like behavior.

What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies.

: Intravenous tranexamic acid (TXA) reduces death because of bleeding in patients with trauma and postpartum haemorrhage. However, in some settings intravenous injection is not feasible. To find different routes of administration, we first need to determine the minimal concentration of TXA in the blood that is required to inhibit fibrinolysis.We conducted a systematic review of in-vitro and in-vivo pharmacodynamics studies. We searched MEDLINE, EMBASE, OviSP, and ISI Web of Science from database inception to November 2017 for all in-vitro (including simulated clotting models) or in-vivo studies reporting the relationship between the TXA concentration in blood or plasma and any reliable measure of fibrinolysis.We found 21 studies of which 20 were in vitro and one was in vivo. Most in-vitro studies stimulated fibrinolysis with tissue plasminogen activator and measured fibrinolysis using viscoelastic, optical density, or immunological assays. TXA concentrations between 10 and 15 mg/l resulted in substantial inhibition of fibrinolysis, although concentrations between 5 and 10 mg/l were partly inhibitory.TXA concentrations of 10-15 mg/l may be suitable targets for pharmacokinetic studies, although TXA concentrations above 5 mg/l may also be effective.

Comparison of built environment adaptations to heat exposure and mortality during hot weather, West Midlands region, UK.

There is growing recognition of the need to improve protection against the adverse health effects of hot weather in the context of climate change. We quantify the impact of the Urban Heat Island (UHI) and selected adaptation measures made to dwellings on temperature exposure and mortality in the West Midlands region of the UK. We used 1) building physics models to assess indoor temperatures, initially in the existing housing stock and then following adaptation measures (energy efficiency building fabric upgrades and/or window shutters), of representative dwelling archetypes using data from the English Housing Survey (EHS), and 2) modelled UHI effect on outdoor temperatures. The ages of residents were combined with evidence on the heat-mortality relationship to estimate mortality risk and to quantify population-level changes in risk following adaptations to reduce summertime heat exposure. Results indicate that the UHI effect accounts for an estimated 21% of mortality. External shutters may reduce heat-related mortality by 30-60% depending on weather conditions, while shutters in conjunction with energy-efficient retrofitting may reduce risk by up to 52%. The use of shutters appears to be one of the most effective measures providing protection against heat-related mortality during periods of high summer temperatures, although their effectiveness may be limited under extreme temperatures. Energy efficiency adaptations to the dwellings and measures to increase green space in the urban environment to combat the UHI effect appear to be less beneficial for reducing heat-related mortality.

Strain and cocaine-induced differential opioid gene expression may predispose Lewis but not Fischer rats to escalate cocaine self-administration.

The aim of the present study was to investigate alterations in gene expression of opioid system components induced by extended access (18 h) cocaine self-administration and to determine the impact of genetic background in the vulnerability to escalate cocaine intake. Comparing two inbred rat strains, we previously reported that Lewis rats progressively escalated cocaine consumption compared to Fischer rats, in a new translational model of intravenous cocaine self-administration, which included 14 sessions of 18-h operant sessions in which rats were allowed to select the cocaine unit dose to self-administer. We compare here Fischer and Lewis rats in the gene expression of endogenous opioid peptides (Pomc, Penk, Pdyn) and cognate receptors (Oprm, Oprk and Oprd) in reward-related brain regions, after exposure to either cocaine self-administration or yoked-saline, in the aforementioned translational paradigm. We performed a correlation analysis between the mRNA level, found in the Dorsal Striatum (DS), Nucleus accumbens (NAcc) shell and core respectively, and individual cocaine intake. Our findings show that the gene expression of all the aforementioned opioid genes exhibit strain-dependent differences in the DS, in absence of cocaine exposure. Also, different strain-specific cocaine-induced mRNA expression of Oprm and Oprk was found in DS. Only few differences were found in the ventral parts of the striatum. Moreover, gene expression level of Pdyn, Penk, Oprk, and Oprm in the DS was significantly correlated with cocaine intake only in Fischer rats. Overall, these data shed light on potential genetic differences which may predispose of subjects to initiate and escalate cocaine consumption.

Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior.

Corticotropin-releasing factor (CRF) and its family of peptides are critical coordinators of homeostasis whose actions are mediated through their receptors, CRF receptor 1 (CRFR1) and CRFR2, found throughout the CNS and periphery. The phenotypes of mice deficient in either CRFR1 or CRFR2 demonstrate the critical role these receptors play. CRFR1-mutant mice have an impaired stress response and display decreased anxiety-like behavior, whereas CRFR2-mutant mice are hypersensitive to stress and display increased anxiety-like behavior. To further elucidate the roles of both CRF receptors and determine their interaction in behaviors, we have generated mice deficient in both CRFR1 and CRFR2. The behavioral phenotype of these mice demonstrates a novel role of the mother's genotype on development of pup anxiety. We have found that although the female double-mutant mice display anxiolytic-like behavior, the male double-mutant mice show significantly more anxiety-like behavior compared with the females. We have also determined that the dam's CRFR2 genotype affects the anxiety-like behavior of the male mice, such that a pup born to a heterozygous or mutant dam displays significantly more anxiety-like behavior regardless of that pup's genotype. Double-mutant mice also display an even greater impairment of their hypothalamic-pituitary-adrenal axis response to stress than that of the CRFR1-mutant mice. CRF mRNA levels are elevated in CRFR1- and double-mutant mice, and urocortin III and vasopressin mRNA levels are increased in CRFR2- and double-mutant mice. These results indicate that both CRFR1 and CRFR2 have critical roles in gene regulation and the maintenance of homeostasis in response to stress.

Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice.

Mu-opioid receptors (MOPRs) are the target of heroin and other prescription opioids, which are currently responsible for massive addiction morbidity in the US. The gene coding for the human MOPR (OPRM1) has an important functional single nucleotide polymorphism (SNP), A118G. The OPRM1 A118G genotype results in substantially increased risk of heroin addiction in humans; however, the neurobiological mechanism for this increased risk is not fully understood. This study examined heroin self-administration (SA) behavior in A112G (G/G) mice, harboring a functionally equivalent SNP in Oprm1 with a similar amino acid substitution, in extended (4 h) SA sessions. Adult male and female G/G mice and 'wild-type' litter mates (A/A) were allowed to self-administer heroin (0.25 mg/kg/unit dose, FR1 with a nose poke response) for 4 h/day, for 10 consecutive days. Half of the mice then continued in a heroin dose-response study, while extinction from heroin SA was studied in the other half. In vivo microdialysis was used to measure acute heroin-induced increases of striatal dopamine in the GG vs AA genotypes. Male and female G/G mice responded for heroin significantly more (and thus had greater intake) than A/A mice, in the initial 10 days of heroin SA, and in the subsequent dose-response study. There were no significant differences in extinction of SA between the A/A and G/G mice. Heroin-induced increases in striatal dopamine levels are higher in the GG mice than in the AA mice. Both male and female G/G mice self-administered more heroin than did A/A mice over a 10-day period, possibly because of the greater increases of heroin-induced striatal dopamine in the GG mice. Furthermore, G/G male mice escalated the amount of heroin self-administration across 10 extended-access sessions more than A/A male mice did. These are the first studies to examine the acquisition of heroin SA in this mouse model. These studies may lead to a better understanding of the neurobiological and behavioral mechanisms that underlie greater risk of heroin addiction in carriers of the A118G SNP.

Effects of handling and vehicle injections on adrenocorticotropic and corticosterone concentrations in Sprague-Dawley compared with Lewis rats.

The hypothalamic-pituitary-adrenal (HPA) axis is a key factor in the trajectory of the addiction-like cycle (a pattern of behavior characterized by escalating drug use, withdrawal, and relapse) in preclinical and clinical studies. Concentrations of HPA hormones change in laboratory animals in response to standard experimental procedures, including handling and vehicle injections. We compared HPA activity in adult male Lewis (inbred) and Sprague-Dawley (outbred) rats, 2 common strains in rodent models of addiction, after different schedules of handling and saline injections, to explore the extent to which HPA responses differ by strain and whether interindividual differences underlie addiction vulnerability. The 4 treatment conditions were no, short, or long handling and saline injections. In handled groups, rats were handled for 1 to 2 min for 3 times daily and were euthanized after 7 d (short handling) or 14 d (long handling). The injection schedule in the saline injection group mimicked that in a model of binge-like cocaine exposure. Across all treatment groups, concentrations of adrenocorticotropic hormone were higher in Sprague-Dawley than in Lewis rats. In Sprague-Dawley rats, corticosterone concentrations decreased after continued handling but remained constant in Lewis rats. Interindividual variability in hormone levels was greater in Sprague-Dawley than Lewis rats, although corticosterone variability decreased after continued handling. Prolactin did not differ between groups of either Sprague-Dawley and Lewis rats before or after handling. This study underscores the importance of prolonged handling before experimenter-provided drug-administration paradigms and of strain-associated differences that may affect study outcomes.

Lack of reward and locomotor stimulation induced by heroin in mu-opioid receptor-deficient mice.

The micro-opioid receptor is the main substrate mediating opiate reward. Multiple micro-opioid receptor subtypes have been postulated to underlie opiate actions. Animals treated with antisense oligonucleotides targeting specific micro-opioid receptor exons show differential sensitivity to morphine versus heroin. The present work examined the rewarding and locomotor activating effects of heroin in mutant mice with a disrupted exon 2 of the micro-opioid receptor. Heroin (1-3 mg/kg) produced significant place preferences and stimulated locomotor activity in wild-type mice, whereas it had no effect in micro-opioid receptor-deficient mice. In contrast, treatment with cocaine (10-30 mg/kg) produced comparable place preferences and locomotor activation in both wild-type and micro-opioid receptor-deficient mice, thus providing evidence that the mutant mice are able to show drug-induced effects in the two behavioral paradigms used here. These results support an essential role for the micro-opioid receptor in the rewarding and locomotor activating effects of heroin.

Dose escalation and dose preference in extended-access heroin self-administration in Lewis and Fischer rats.

RATIONALE: A genetic component may be involved in different stages of the progression of drug addiction. Heroin users escalate unit doses and frequency of self-administration events over time. Rats that self-administer drugs of abuse over extended sessions escalate the amount of drug infused over days. OBJECTIVES: Using a recently developed model of extended-access self-administration allowing for subject-controlled dose escalation of the unit dose, thus potentially escalating the unit dose and number of infusions, we compared for the first time two genetically different inbred rat strains, Fischer and Lewis. METHODS: Extended (18 h/day) self-administration lasted for 14 days. Rats had access to two active levers associated with two different unit doses of heroin. If a rat showed preference for the higher unit dose, then the available doses were escalated in the following session. Four heroin unit doses were available (20, 50, 125, 250 µg/kg per infusion). RESULTS: Fischer rats did not escalate the unit dose of heroin self-administered; daily amount of heroin administered remained low, with a mean daily intake of 1.27 ± 0.22 mg/kg per session. In marked contrast, Lewis rats escalated the total daily amount of heroin self-administered from 3.94 ± 0.82 mg/kg on day 1 to 8.95 ± 2.2 mg/kg on day 14; almost half of the subjects preferred a higher heroin dose than Fischer rats. CONCLUSION: These data are consistent with the hypothesis that Lewis rats are prone to opiate taking and escalation, and are in agreement with our previous data obtained with cocaine.

Dose preference and dose escalation in extended-access cocaine self-administration in Fischer and Lewis rats.

RATIONALE: Drug addiction is a disease with a genetic component that may be involved in different stages of its progression. Cocaine users escalate unit doses and frequency of self-administration events in naturalistic settings. Rats that self-administer drugs of abuse over extended sessions increase the number of infusions over days. OBJECTIVES: Comparison of two genetically different inbred rat strains, Fischer and Lewis, in a new self-administration paradigm whereby rats select between different unit doses of cocaine, thus potentially escalating the unit dose and the number of infusions. METHODS: Extended (18 h/day) self-administration sessions lasted for 14 days. Rats had access to two active levers associated with two different unit doses of cocaine. If a rat showed preference for the higher unit dose, then the available doses were escalated in the following session. Four cocaine unit doses were available (0.2, 0.5, 1.25, and 2.5 mg/kg/infusion). RESULTS: Lewis rats showed a clear preference for the two higher doses of cocaine (70% of rats), with a high percentage (35%) of the individuals escalating to the highest unit dose, and escalated the total amount of cocaine taken over days. Fischer rats, however, preferred the two lower doses (63%) and did not escalate the amount of cocaine taken over days. Fischer, but not Lewis, rats showed an activated hypothalamic-pituitary-adrenal axis in acute withdrawal (24 h). CONCLUSION: This work shows the power of a model of extended-access self-administration that allows for the subject-controlled dose-escalation of the unit dose of cocaine, and underlines the genetic differences that modulate cocaine intake.

Behavioral and neurochemical changes induced by oxycodone differ between adolescent and adult mice.

Nonmedical use of the prescription opioid analgesic oxycodone is a major problem in the United States, particularly among adolescents and young adults. This study characterized self-administration of oxycodone by adolescent and adult mice, and how this affects striatal dopamine levels. Male C57BL/6J mice (4 or 10 weeks old) were allowed to acquire oxycodone self-administration (0.25 mg/kg per infusion) for 9 days, and then tested with varying doses of oxycodone (0, 0.125, 0.25, 0.5, and 0.75 mg/kg per infusion). On completion of the self-administration study, a guide cannula was implanted into the striatum of these mice. Six days later, microdialysis was conducted on the freely moving mouse. After collection of baseline samples, oxycodone was administered i.p. (1.25, 2.5, and 5.0 mg/kg) and samples were collected for 1 h after each dose. Adult mice self-administered significantly more oxycodone across the doses tested. After 1 week, basal striatal dopamine levels were lower in mice of both ages that had self-administered oxycodone than in yoked saline controls. Oxycodone challenge increased striatal dopamine levels in a dose-dependent manner in both age groups. Of interest, the lowest dose of oxycodone led to increased striatal dopamine levels in the mice that had self-administered oxycodone during adolescence but not those that self-administered it as adults. The lower number of infusions of oxycodone self-administered by adolescent mice, and their later increased striatal dopamine in response to the lowest dose of oxycodone (not found in adults), suggest differential sensitivity to the reinforcing and neurobiological effects of oxycodone in the younger mice.