Adolescence and the next generation.

Adolescent growth and social development shape the early development of offspring from preconception through to the post-partum period through distinct processes in males and females. At a time of great change in the forces shaping adolescence, including the timing of parenthood, investments in today's adolescents, the largest cohort in human history, will yield great dividends for future generations.

Publisher Correction: Adolescence and the next generation.

In Fig. 4a of this Analysis, owing to an error during the production process, the year in the header of the right column was '2016' rather than '2010'. In addition, in the HTML version of the Analysis, Table 1 was formatted incorrectly. These errors have been corrected online.

Investing in non-communicable diseases: an estimation of the return on investment for prevention and treatment services.

The global burden of non-communicable diseases (NCDs) is growing, and there is an urgent need to estimate the costs and benefits of an investment strategy to prevent and control NCDs. Results from an investment-case analysis can provide important new evidence to inform decision making by governments and donors. We propose a methodology for calculating the economic benefits of investing in NCDs during the Sustainable Development Goals (SDGs) era, and we applied this methodology to cardiovascular disease prevention in 20 countries with the highest NCD burden. For a limited set of prevention interventions, we estimated that US$120 billion must be invested in these countries between 2015 and 2030. This investment represents an additional $1·50 per capita per year and would avert 15 million deaths, 8 million incidents of ischaemic heart disease, and 13 million incidents of stroke in the 20 countries. Benefit-cost ratios varied between interventions and country-income levels, with an average ratio of 5·6 for economic returns but a ratio of 10·9 if social returns are included. Investing in cardiovascular disease prevention is integral to achieving SDG target 3.4 (reducing premature mortality from NCDs by a third) and to progress towards SDG target 3.8 (the realisation of universal health coverage). Many countries have implemented cost-effective interventions at low levels, so the potential to achieve these targets and strengthen national income by scaling up these interventions is enormous.

Building the foundations for sustainable development: a case for global investment in the capabilities of adolescents.

Investment in the capabilities of the world's 1·2 billion adolescents is vital to the UN's Sustainable Development Agenda. We examined investments in countries of low income, lower-middle income, and upper-middle income covering the majority of these adolescents globally to derive estimates of investment returns given existing knowledge. The costs and effects of the interventions were estimated by adapting existing models and by extending methods to create new modelling tools. Benefits were valued in terms of increased gross domestic product and averted social costs. The initial analysis showed high returns for the modelled interventions, with substantial variation between countries and with returns generally higher in low-income countries than in countries of lower-middle and upper-middle income. For interventions targeting physical, mental, and sexual health (including a human papilloma virus programme), an investment of US$4·6 per capita each year from 2015 to 2030 had an unweighted mean benefit to cost ratio (BCR) of more than 10·0, whereas, for interventions targeting road traffic injuries, a BCR of 5·9 (95% CI 5·8-6·0) was achieved on investment of $0·6 per capita each year. Interventions to reduce child marriage ($3·8 per capita each year) had a mean BCR of 5·7 (95% CI 5·3-6·1), with the effect high in low-income countries. Investment to increase the extent and quality of secondary schooling is vital but will be more expensive than other interventions-investment of $22·6 per capita each year from 2015 to 2030 generated a mean BCR of 11·8 (95% CI 11·6-12·0). Investments in health and education will not only transform the lives of adolescents in resource-poor settings, but will also generate high economic and social returns. These returns were robust to substantial variation in assumptions. Although the knowledge base on the impacts of interventions is limited in many areas, and a major research effort is needed to build a more complete investment framework, these analyses suggest that comprehensive investments in adolescent health and wellbeing should be given high priority in national and international policy.

Advancing social and economic development by investing in women's and children's health: a new Global Investment Framework.

A new Global Investment Framework for Women's and Children's Health demonstrates how investment in women's and children's health will secure high health, social, and economic returns. We costed health systems strengthening and six investment packages for: maternal and newborn health, child health, immunisation, family planning, HIV/AIDS, and malaria. Nutrition is a cross-cutting theme. We then used simulation modelling to estimate the health and socioeconomic returns of these investments. Increasing health expenditure by just $5 per person per year up to 2035 in 74 high-burden countries could yield up to nine times that value in economic and social benefits. These returns include greater gross domestic product (GDP) growth through improved productivity, and prevention of the needless deaths of 147 million children, 32 million stillbirths, and 5 million women by 2035. These gains could be achieved by an additional investment of $30 billion per year, equivalent to a 2% increase above current spending.

ß-Lactam antibiotic produces a sustained reduction in extracellular glutamate in the nucleus accumbens of rats.

We investigated the short- and long-term effects of ceftriaxone on glutamate transporter subtype 1 (GLT-1) transporter activity and extracellular glutamate in the rat nucleus accumbens. Repeated ceftriaxone administration (50, 100 or 200 mg/kg, i.p.) produced a dose-dependent reduction in glutamate levels that persisted for 20 days following discontinuation of drug exposure. The ceftriaxone effect was prevented by the GLT-1 transporter inhibitor dihydrokainate (1 µM, intra-accumbal). These results suggest that ß-lactam antibiotics produce an enduring reduction in glutamatergic transmission in the brain reward center.

Beta-lactam antibiotic decreases acquisition of and motivation to respond for cocaine, but not sweet food, in C57Bl/6 mice.

No medication is approved to treat cocaine addiction, but mounting evidence suggests that glutamate-directed approaches may reduce cocaine dependence and relapse. We tested the hypotheses that the glutamate transporter subtype 1 activator, ceftriaxone, disrupts acquisition of cocaine self-administration, motivation to self-administer cocaine, and conditioned place preference in mice. Repeated ceftriaxone (200 mg/kg) reduced the ability of mice to acquire cocaine and the motivation to self-administer cocaine after successful acquisition without affecting acquisition of or motivation for sweet food. Repeated ceftriaxone had no effect on cocaine-conditioned place preference. These results suggest that a ß-lactam antibiotic reduces the direct reinforcing strength of cocaine without producing nonspecific deficits in conditioned learning processes.

Evaluating the Employment Benefits of Education and Targeted Interventions to Reduce Child Marriage.

PURPOSE: This study sets out to identify effective interventions to reduce child marriage, estimate their economic benefits achieved through enhanced productivity, and undertake a benefit-cost analysis of the interventions. METHODS: We model the effects of a set of identified child marriage and education interventions for 31 low- and middle-income countries,1 focusing on the reduction in child marriage rates and increasing secondary school attendance and completions. These lead to higher productivity, which generates increased gross domestic product per capita. The comparison of these benefits with the costs of the interventions generates benefit-cost ratios. RESULTS: Both types of interventions have significant effects on marriage rates for girls aged 15-17 years, which fall from 13.2% in 2015 to 5.2% in 2050. Both interventions lead to sharp increases in school attendance and secondary completion, which is 19.3% points higher by 2030. The productivity improvement is 22.7% by 2030. The average benefit-cost ratio for the 31 countries is 7.4 (standard deviation of 1.0) at a 3% discount rate. CONCLUSIONS: The results indicate that there are substantial economic gains to reducing child marriage by specific child marriage and education interventions.

Effects of nicotine on sensorimotor gating impairment induced by long-term treatment with neurotoxic NMDA antagonism.

In order to develop a model of persistent sensorimotor gating that did not require acute NMDA (N-methyl-D-aspartate) receptor blockade, adult female Sprague-Dawley rats were pre-treated with N-methyl-scopolamine (1 mg/kg s.c.), then administered MK-801 (dizocilpine, 5 mg/kg i.p.) along with two separate doses (5 mg/kg) of pilocarpine. The drug regimen was repeated four and eight days later. Controls received saline in lieu of any drug. Ten days after the last neurotoxic treatment, rats had a significant impairment (reduction) in pre-pulse inhibition (PPI). Each treatment group (neurotoxic treated and control) was then divided into two groups for treatment with saline or 0.5 mg/kg nicotine, administered s.c. twice daily from days 10 to 23. The rats were tested for sensorimotor gating on days 17 and 22 shortly after the morning nicotine administration. Nicotine did not affect the PPI in control animals. On day 17, PPI impairment was sustained in neurotoxically treated rats, regardless of saline or nicotine treatment. On day 22, however, the effect of neurotoxic treatment on PPI was totally absent in saline treated rats, whereas in nicotine treated rats, PPI impairment was still evident. Combination of nicotine and neurotoxic treatment also caused an up-regulation of high affinity nicotinic receptors in the cortex and the thalamus and apparent normalization of low affinity nicotinic receptors in the hippocampus. The findings indicate that muscarinic activation, in conjunction with neurotoxic NMDA receptor antagonism, produces relatively long-term impairment in auditory gating, a result relevant to modeling clinical observations of schizophrenia-associated symptoms. Contrary to expectation, nicotine administration in this model resulted in further impairment rather than amelioration of PPI. The results suggest a sustainable model of PPI impairment and possible role of nicotinic receptors in selective brain regions in this behavior.

Long-term effects of developmental PCP administration on sensorimotor gating in male and female rats.

RATIONALE: Acutely administered N-methyl-D-asparate (NMDA) antagonists are used to model schizophrenia, as measured by impairments in sensorimotor gating reflected in decreases in prepulse inhibition of the startle response (PPI). Aspects of acute NMDA receptor antagonism limit the applications of these models. OBJECTIVE: The aim of this paper is to determine the long-term effects of developmental phencyclidine (PCP) treatment on sensorimotor gating in both male and female rats. MATERIALS AND METHODS: Male and female Sprague Dawley rats were injected with PCP (10 mg/kg s.c.) on postnatal days (PN) 7, 9, and 11 and were tested for PPI on PN 32-34. The groups were then divided and some of the animals received a single dose of PCP (10 mg/kg s.c.) on PN 45. The animals were tested again for PPI at approximately 1, 4, and 6 weeks after the treatment. RESULTS: There were no significant effects of neonatal-only treatment. One week after the PN 45 treatment, animals that were treated as neonates and as adolescents (PCP/PCP) were significantly impaired in PPI in both sexes. Male and female PCP/PCP rats also had significant increases in acoustic startle response 4 weeks posttreatment, which subsequently declined. PPI impairments in both sexes recovered over time and the adolescent-only treated females showed significant increases (improvement) in PPI approximately 6 weeks posttreatment. CONCLUSION: These data suggest that treatment with an NMDA receptor antagonist during adolescence or early adulthood can produce a relatively long-term impairment of PPI (approximately 1 week) and that this effect is more pronounced in male animals.

An autoradiographic analysis of [125I]alpha-bungarotoxin binding in rat brain after chronic nicotine exposure.

Chronic exposure to nicotine has been shown to increase binding to high affinity nicotinic cholinergic receptors in rat brain, but the effect of this treatment on the low affinity alpha7 nicotinic receptors has been less well characterized. Male Sprague-Dawley rats were treated with saline or nicotine (6 mg/kg/day, by osmotic minipump) for 14 days. Frozen brain sections were then prepared and processed for quantitative autoradiography using [(125)I]alpha-bungarotoxin to measure the effect of this treatment on low affinity nicotinic receptors. Nicotine exposure increased [(125)I]alpha-bungarotoxin binding in 26 of 52 brain regions analyzed; increases ranged from 10 to 70% over saline controls. Increases were seen in all areas of the brain, but were more prominent in forebrain areas, and especially in cerebral cortex. These data demonstrate that low affinity alpha7 nicotinic receptors are also up-regulated by chronic nicotine. This phenomenon may be relevant to the heavy use of tobacco products in diseases like schizophrenia, and needs to be considered in the design of pharmaceuticals directed at this receptor system.

Scaling-up treatment of depression and anxiety: a global return on investment analysis.

BACKGROUND: Depression and anxiety disorders are highly prevalent and disabling disorders, which result not only in an enormous amount of human misery and lost health, but also lost economic output. Here we propose a global investment case for a scaled-up response to the public health and economic burden of depression and anxiety disorders. METHODS: In this global return on investment analysis, we used the mental health module of the OneHealth tool to calculate treatment costs and health outcomes in 36 countries between 2016 and 2030. We assumed a linear increase in treatment coverage. We factored in a modest improvement of 5% in both the ability to work and productivity at work as a result of treatment, subsequently mapped to the prevailing rates of labour participation and gross domestic product (GDP) per worker in each country. FINDINGS: The net present value of investment needed over the period 2016-30 to substantially scale up effective treatment coverage for depression and anxiety disorders is estimated to be US$147 billion. The expected returns to this investment are also substantial. In terms of health impact, scaled-up treatment leads to 43 million extra years of healthy life over the scale-up period. Placing an economic value on these healthy life-years produces a net present value of $310 billion. As well as these intrinsic benefits associated with improved health, scaled-up treatment of common mental disorders also leads to large economic productivity gains (a net present value of $230 billion for scaled-up depression treatment and $169 billion for anxiety disorders). Across country income groups, resulting benefit to cost ratios amount to 2·3-3·0 to 1 when economic benefits only are considered, and 3·3-5·7 to 1 when the value of health returns is also included. INTERPRETATION: Return on investment analysis of the kind reported here can contribute strongly to a balanced investment case for enhanced action to address the large and growing burden of common mental disorders worldwide. FUNDING: Grand Challenges Canada.

Glutamate transporter subtype 1 (GLT-1) activator ceftriaxone attenuates amphetamine-induced hyperactivity and behavioral sensitization in rats.

BACKGROUND: The ß-lactam antibiotic and glutamate transporter subtype 1 (GLT-1) activator ceftriaxone prevents relapse to cocaine-seeking and inhibits morphine-induced physical dependence and tolerance in rats, but its efficacy against amphetamine-induced behaviors is unknown. METHODS: Here, we tested the hypothesis that ceftriaxone (200mg/kg, i.p.) inhibits hyperactivity produced by acute amphetamine administration (2mg/kg, i.p.) and sensitization of hyperactivity induced by repeated amphetamine exposure (2mg/kg, i.p.). For acute experiments, rats treated with ceftriaxone for 5 days were injected with amphetamine or saline on day 6. RESULTS: Amphetamine elicited less ambulatory and stereotypical activity in ceftriaxone-treated rats than in ceftriaxone-naïve rats. For chronic experiments, rats injected with ceftriaxone or saline for 8 days were also injected with amphetamine or saline on days 6-8 and then challenged with amphetamine 5 days later. Amphetamine produced greater ambulatory and stereotypical activity in amphetamine-pretreated rats than in rats previously naïve to amphetamine. Amphetamine challenge produced less ambulatory and stereotypical activity in rats pretreated with a combination of ceftriaxone (200mg/kg) and amphetamine than in rats pretreated with only amphetamine. CONCLUSION: The present demonstration that ceftriaxone attenuates amphetamine-induced hyperactivity and behavioral sensitization suggests its documented efficacy against adverse cocaine and morphine effects extends to amphetamine.

Methanandamide blocks amphetamine-induced behavioral sensitization in rats.

Methanandamide acts at targets which modulate amphetamine-induced behaviors. Therefore, we investigated methanandamide effects on the acute hyperactivity produced by a single injection of amphetamine and behavioral sensitization induced by repeated amphetamine exposure in rats. Methanandamide (5mg/kg, i.p.) did not affect basal locomotor or stereotypical activity. Methanandamide (5mg/kg, i.p.) pretreatment did not alter the acute increase in locomotor or stereotypical activities produced by acute amphetamine (2mg/kg, i.p.). For chronic studies, rats injected with amphetamine (2mg/kg, i.p.) once daily for 3 consecutive days were then challenged with amphetamine (2mg/kg, i.p.) 5 days later. Expression of locomotor sensitization was blocked when methanandamide (5mg/kg, i.p.) was given once, just prior to amphetamine (2mg/kg, i.p.) challenge. In rats co-exposed to methanandamide (5mg/kg, i.p.) and amphetamine (2mg/kg, i.p.) on days 1-3 and then challenged with amphetamine (2mg/kg, i.p.) following 5 days of drug absence, the development of both locomotor and stereotypical sensitization was blocked. The ability of methanandamide to block amphetamine-sensitized behaviors suggests that this pharmacologically diverse lipid regulates signaling events impacted by repeated psychostimulant exposure.

Methanandamide attenuates cocaine-induced hyperthermia in rats by a cannabinoid CB1-dopamine D2 receptor mechanism.

Evidence implicates anandamide in dopamine-related cocaine function. In the present study, we investigated the effect of methanandamide (5 mg/kg, i.p.), a stable anandamide analog, on the hyperthermia and hyperactivity induced by a fixed dose of cocaine (15 mg/kg,i.p.). Cocaine administered to rats produced hyperthermia and hyperactivity whereas methanandamide was ineffective. For combined administration, methanandamide attenuated the hyperthermia, but not hyperactivity, induced by cocaine. The effect of methanandamide was abolished by pretreatment with a cannabinoid CB1 receptor antagonist, SR141716A (5 mg/kg, i.p.), or dopamine D2 receptor antagonist, S(−)-raclopride(5 mg/kg, i.p.) but not by capsazepine (40 mg/kg, i.p.), a transient receptor potential vanilloid 1 cation channel antagonist. Methanandamide also attenuated the hyperthermia caused by a dopamine D1 receptor agonist, SKF 38393 (10 mg/kg, s.c.), indicating that it reduces hyperthermia produced by dopamine D1 receptor activation. URB597 (0.25 mg/kg, i.p.), an inhibitor of anandamide metabolism, did not alter cocaine-induced hyperthermia. Our results demonstrate that methanandamide activates cannabinoid CB1 receptors to attenuate cocaine-induced hyperthermia, and that dopamine D2 receptor activation plays a permissive role in the thermoregulatory effects of methanandamide.

Subtype-selective up-regulation by chronic nicotine of high-affinity nicotinic receptors in rat brain demonstrated by receptor autoradiography.

Subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) are differentially sensitive to up-regulation by chronic nicotine exposure in vitro. To determine whether this occurs in animals, rats were implanted with minipumps containing saline +/- nicotine (6.0 mg/kg/rat/day) for 14 days. Autoradiography with [125I]epibatidine using 3-(2(S)-azetidinylmethoxy)pyridine dihydrochloride (A-85380) or cytisine as selective competitors allowed quantitative measurement in 33 regions of 3 families of nAChR binding, with properties of alpha4beta2, alpha3beta4, and alpha3/alpha6beta2. Chronic nicotine exposure caused increases of 20 to 100% for alpha4beta2-like binding in most regions surveyed. However, binding to this subtype was not increased in some regions, including habenulopeduncular structures, certain thalamic nuclei, and several brainstem regions. In 9 of 33 regions, including catecholaminergic areas and visual structures, alpha3/alpha6beta2-like binding represented >10% of total binding. Binding to this subtype was up-regulated by nicotine in only two of these nine regions: the nucleus accumbens and superior colliculus. alpha3beta4-Like binding represented >10% of total in 15 of the 33 regions surveyed. Binding to this subtype was increased by nicotine in only 1 of these 15 regions, and actually decreased in subiculum and cerebellum. These studies yielded two principal findings. First, chronic nicotine exposure selectively up-regulates alpha4beta2-like binding, with relatively little effect on alpha3/alpha6beta2-like and alpha3beta4-like binding in vivo. Second, up-regulation by chronic nicotine exposure shows considerable regional variation. Differential subtype sensitivity to chronic nicotine exposure may contribute to altered pharmacological response in individuals who smoke or use nicotine replacement therapy.

Binding and functional activity of nicotinic cholinergic receptors in selected rat brain regions are increased following long-term but not short-term nicotine treatment.

Chronic nicotine exposure up-regulates neuronal nicotinic receptors, but the functional consequences for these receptors is less well understood. Following 2 weeks of nicotine or saline treatment by osmotic minipump, the functional activity of nicotinic receptors was measured by concentration-response curves for epibatidine-stimulated (86)Rb efflux. Nicotine-treated animals had a significantly higher maximal efflux in cerebral cortex and superior colliculus, but not in thalamus or interpeduncular nucleus plus medial habenula. This increase was confirmed in a separate experiment with stimulation by single concentrations of epibatidine (cortex, superior colliculus) or nicotine (cortex only). Chronic nicotine did not alter (86)Rb efflux stimulated by cytisine, an alpha3beta4-selective agonist, or by potassium chloride, in any region. Short-term (16 h) nicotine exposure caused no changes in either (86)Rb efflux or receptor binding measured with [(3)H]epibatidine. Binding was significantly increased after 2 weeks nicotine exposure in cortex, superior colliculus and thalamus, but not in interpeduncular nucleus plus medial habenula. The increases in epibatidine-stimulated (86)Rb efflux in the four regions tested was linearly correlated with the increases in [(3)H]epibatidine binding in these regions (R(2) = 0.91), suggesting that rat brain receptors up-regulated by chronic nicotine are active. These results have important consequences for understanding nicotinic receptor neurobiology in smokers and users of nicotine replacement therapy.