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Federal regulations for municipal separate storm sewer systems (MS4s) in the United States have been in place since 1990 as part of the Nation Pollutant Discharge Elimination System (NPDES), aiming to reduce sediment and pollutant loads originating from urban areas. However, small-municipality (Phase II) MS4s frequently grapple with several challenges, resulting in a lack of stakeholder buy-in and actionable stormwater management plans. We identify five common challenges concerning MS4 requirements based on literature review, professional experience, and feedback solicited from stakeholders, municipal managers, and fellow professionals and offer real-world examples of efficient, effective MS4 frameworks and/or solutions. The five challenges are summarized as beliefs that: (1) agricultural land use is the largest pollutant contributor and the root cause of pollution problems; (2) stormwater management only benefits downstream communities; (3) large, expensive projects are required to comply with regulations; (4) maintenance, monitoring, and inspection of best management practices (BMPs) is overwhelmingly complex and expensive; and (5) a lack of direct funding makes complying with regulations an impossible task. These challenges are universal in nature for Phase II MS4 permittees and can create real barriers for effective stormwater management. However, we found many examples of methods or techniques to effectively address these five specific challenges, making them well-suited and important for discussion. BMPs can create tangible improvements for surrounding communities (e.g., reduced streambank erosion and flooding), and improved understanding of the structure and options within the MS4 program will help small municipalities make informed choices about management plans.

The study aim was to characterise issues faced by farmers and veterinary surgeons when making end-of-life decisions for dairy cattle.Online surveys were distributed to British dairy farmers and veterinary surgeons for 20 weeks from November 2020.There were 83 responses (37 farmers, 46 veterinary surgeons). Among youngstock, the risk of unassisted/natural death (2.6% ± 0.3%) was almost double the risk of euthanasia (1.4% ± 0.3%;The survey highlighted end-of life decision-making successes and areas for improvement on dairy farms. An evidence-based, decision-support framework may help end-of-life decision-making, particularly for complex diseases.

Este artículo contiene 16 páginas, 2 tablas, 3 figuras., Urban streams can provide amenities to people living in cities, but those benefits are reduced when streams become degraded, potentially even causing harm (disease, toxic compounds, etc.). Governments and institutions invest resources to improve the values and services provided by urban streams; however, the conception, development, and implementation of such projects may not include meaningful involvement of community members and other stakeholders. Consequently, project objectives may be misaligned with community desires and needs, and projects may fail to achieve their goals. In February 2020, the 5th Symposium on Urbanization and Stream Ecology, an interdisciplinary meeting held every 3 to 5 y, met in Austin, Texas, USA, to explore new approaches to urban stream projects, including ways to maximize the full range of potential benefits by better integrating community members into project identification and decision making. The symposium included in-depth discussion about 4 nearby field case studies, participation of multidisciplinary urban stream experts from 5 continents, and input from the Austin community. Institutional barriers to community inclusion were identified and analyzed using real-world examples, both from the case studies and from the literature, which clarified disparities in power, equity, and values. Outcomes of the symposium have been aggregated into a vision that challenges the present institutional approach to urban stream management and a set of strategies to systematically address these barriers to improve restoration solutions. Integrating community members and other stakeholders throughout the urban restoration process, and a transparent decision-making process to resolve divergent objectives, can help identify appropriate goals for realizing both the ecological and social benefits of stream restoration., Publication costs were covered by an award from the Society of Freshwater Science’s Endowed Publication Fund (https:// freshwater-science.org/publications/endowed-publication-fund).

Simple Summary Stream insects are essential components of aquatic and terrestrial ecosystems, but fewer studies have examined the terrestrial stage compared to the aquatic stage. Most adult stream insects are flight capable, which allows for short- and long-distance movements away from the stream channel into riparian or upland habitats. This study examined if adult stream insects migrate vertically into riparian forest canopies above the stream. We found a meaningful number of adult Trichoptera and Plecoptera in the forest canopy above the stream that was comparable to horizontal migrations. This result demonstrated that adult stream insects utilize riparian forest canopies and that numerous avenues for additional basic and applied research on terrestrial–aquatic linkages exist. Discovering how riparian canopy habitats are important for stream insects and how stream insects are linked to canopy ecosystems can inform restoration and conservation actions. Abstract Stream insects are essential components of aquatic and terrestrial ecosystem structure and function. Terrestrial stages are important components of terrestrial food webs, and flight-capable individuals are responsible for long-distance dispersal. Horizontal migrations by flying or crawling adults away from stream channels that link insects to riparian food webs and movements across catchment boundaries are well established through empirical research, but studies examining vertical migration of adult stream insects into forest canopies are generally lacking. This study focused on differences in adult Plecoptera and Trichoptera abundance at ground level versus the riparian canopy and differences in abundances among summer and autumn sampling periods to empirically demonstrate use of canopy ecosystems by stream insects. Malaise traps at ground level and canopy traps placed 8 to 10 m above the stream at four sites in the Mosquito Creek watershed (Pennsylvania) were used to examine vertical migration. Larval assemblages were collected and compared to adult assemblage to investigate patterns of local migration in the catchment. We found significantly more stream insects at ground level than in the forest canopy for Trichoptera, Plecoptera, and all individual plecopteran families, but a meaningful number of individuals were found in the riparian canopy. Canopy abundances were similar to abundances captured in adjacent ground-level habitats in other studies. Comparisons of adult and larval abundances among sites, taxa, and stages indicated site- and taxon-specific patterns for vertical movement into riparian canopies. Demonstrating that adult stream insects utilize riparian forest canopies indicates that riparian forest conservation should be prioritized over reforestation and that several potential research questions exist to inform riparian management.

Stream restoration projects utilize a variety of approaches to improve conditions for aquatic organisms or enhance ecosystem function. Alterations to abiotic conditions to enhance certain ecosystems services may not lead to concurrent changes in the benthic macroinvertebrate community indicative of improved stream health. Big Spring Run was the location of a novel restoration project to recreate an anabranching “wet meadow” habitat typical of precolonization conditions without the primary goal of restoring a macroinvertebrate community characteristic of single‐channel lotic systems. We examined the effect of the restoration on the macroinvertebrate community using a multivariate analysis of assemblage composition, a before‐after‐control‐impact (BACI) approach, and an assessment of potential aerial migrants. We also examined subsets of the data using a BACI approach that represented restricted sampling designs often employed in stream restoration projects. Benthic macroinvertebrates were collected in the Spring twice prior to restoration (2010 and 2011) and 3 years after restoration (2012–2014). Adult stream insects were collected in 2014. Analyses of benthic macroinvertebrates and adult insects using the full dataset suggested that restoration had no effect on the macroinvertebrate community due to poor in‐stream conditions likely from sediment deposition following restoration. Dispersal barriers are likely acting as a secondary constraint on recolonization. Analyses using subsets of the data demonstrated that reference site quality and sampling extent can alter conclusions from a BACI approach. We found that a holistic approach using multiple lines of evidence required a nuanced approach to interpreting the data but was also informative for assessing project success. Robust monitoring protocols are likely the best approach for producing convincing results through a single line of evidence. The additional BACI analyses performed for this study, however, allowed the modest sampling regime employed to generate a broad narrative demonstrating that the macroinvertebrate assemblage did not respond to this type of restoration. Thus, we believe the holistic approach we employed can strengthen assessments of stream restoration projects when resources for monitoring are limited.

Wetland restoration practices can include rehabilitating degraded wetlands or creating new wetlands. Empirical evidence is needed to determine if both rehabilitated and created wetlands can support the same macroinvertebrate communities as their natural counterparts. We measured long-term macroinvertebrate community change in seasonal wetlands known as Delmarva Bays in Maryland, U.S.A. We compared a rehabilitated, a created, and a natural Delmarva Bay. We hypothesized that the created and rehabilitated wetlands would develop different macroinvertebrate communities. We also hypothesized that the community composition of the rehabilitated wetland would become more similar to that of the natural wetland than to that of the created wetland over 9 years encompassed by this study. We monitored the macroinvertebrates, including both predators and primary consumers, and environmental conditions in the three wetlands from March to August in 2005, 2006, 2007, and 2012. Cluster analysis indicated that from 2005 to 2007, the macroinvertebrate community of the rehabilitated wetland and the created wetland were more similar to each other than to the natural wetland. In 2012, the rehabilitated wetland was more similar to the natural wetland than to the created wetland. This similarity was driven principally by changes in the composition of primary consumer taxa. Our results suggest that rehabilitated Delmarva Bays are more likely to support a natural macroinvertebrate community than are created wetlands. Restoration practices that rehabilitate existing wetlands may be preferred over practices that create new wetlands when restoration project goals include developing natural macroinvertebrate communities in a short period of time.

The field of urban stream ecology has evolved rapidly in the last 3 decades, and it now includes natural scientists from numerous disciplines working with social scientists, landscape planners and designers, and land and water managers to address complex, socioecological problems that have manifested in urban landscapes. Over the last decade, stream ecologists have met 3 times at the Symposium on Urbanization and Stream Ecology (SUSE) to discuss current research, identify knowledge gaps, and promote future research collaborations. The papers in this special series on urbanization and stream ecology include both primary research studies and conceptual synthesis papers spurred from discussions at SUSE in May 2014. The themes of the meeting are reflected in the papers in this series emphasizing global differences in mechanisms and responses of stream ecosystems to urbanization and management solutions in diverse urban streams. Our hope is that this series will encourage continued interdisciplinary an...

Adolescent nicotine induces persisting changes in development of neural connectivity. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into adulthood. Areas sensitive to, and not sensitive to, structural remodeling induced by adolescent nicotine suggest that the remodeling generally corresponds to the extended amygdala. Evidence suggests that dendritic remodeling is accompanied by persisting changes in synaptic connectivity. Modeling, electrophysiological, neurochemical, and behavioral data are consistent with the implication of our anatomical studies showing that adolescent nicotine induces persisting changes in neural connectivity. Emerging data thus suggest that early adolescence is a period when nicotine consumption, presumably mediated by nicotine-elicited changes in patterns of synaptic activity, can sculpt late brain development, with consequent effects on synaptic interconnection patterns and behavior regulation. Adolescent nicotine may induce a more addiction-prone phenotype, and the structures altered by nicotine also subserve some emotional and cognitive functions, which may also be altered. We suggest that dendritic elaboration and associated changes are mediated by activity-dependent synaptogenesis, acting in part through D1DR receptors, in a network activated by nicotine. The adolescent nicotine effects reviewed here suggest that modification of late CNS development constitutes a hazard of adolescent nicotine use.

Summary Suitability of the local habitat (‘habitat filtering’) and dispersal between stream reaches determines the composition of insect communities, and urban land use may affect both processes. While urban streams are often poor habitats for insects and dispersal between them is often hindered, conservation and restoration activities generally focus solely on the local (in-stream) environment. We determined whether in-stream habitat filtering (a ‘local’ process) or dispersal between reaches (a ‘regional’ process) controlled assemblage composition in a landscape subject to ongoing urban development (‘urbanizing’). We compared models incorporating geographic distance between sites, environmental dissimilarity, and land-use/land-cover attributes of dispersal pathways in an attempt to explain the dissimilarity of stream insect assemblages. Distance and land-use/land-cover attributes were characterised along both overland (straight line) and corridor pathways. Both in-stream habitat filtering and dispersal affected assemblage composition, but habitat had a stronger influence. Overland distance was a better predictor of assemblage dissimilarity than corridor distance, implying stream insect dispersal occurs across catchment boundaries as well as along stream corridors. The best model incorporated land-use/land-cover attributes along dispersal pathways, which supported the idea that urban land-use in the terrestrial environment mediates dispersal. Conservation and restoration strategies for streams in urbanizing landscapes that focus on local habitat quality and ignore dispersal are missing a potentially important mechanism affecting insect assemblage composition. While the primary focus should be on maintaining or improving the local habitat, potential dispersal pathways should also be considered.

Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a ( R )-hydroxy-1,5-naphthyridinone moiety ( 7 ) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25 μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED 50 ) at 3.2 and 27 mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC 50 >170 μM). In general, lower log D attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding mode that show enantiomeric preference for R isomer and explains the activity and SAR. The discovery, synthesis, SAR and X-ray crystal structure of the left-hand-side tricyclic 1,5-naphthyridinone based oxabicyclooctane linked NBTIs are described.

3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.

Nicotine is one of the most addictive substances known, targeting multiple memory systems, including the ventral and dorsal striatum. One form of neuroplasticity commonly associated with nicotine is dendrite remodeling. Nicotine-induced dendritic remodeling of ventral striatal medium spiny neurons (MSNs) is well-documented. Whether MSN dendrites in the dorsal striatum undergo a similar pattern of nicotine-induced structural remodeling is unknown. A morphometric analysis of Golgi-stained MSNs in rat revealed a natural asymmetry in dendritic morphology across the mediolateral axis, with larger, more complex MSNs found in the dorsolateral striatum (DLS). Chronic nicotine produced a lasting (at least 21day) expansion in the dendritic complexity of MSNs in the DLS, but not dorsomedial striatum (DMS). Given prior evidence that MSN subtypes can be distinguished based on dendritic morphology, MSNs were segregated into morphological subpopulations based on the number of primary dendrites. Analysis of these subpopulations revealed that DLS MSNs with more primary dendrites were selectively remodeled by chronic nicotine exposure and remodeling was specific to the distal-most portions of the dendritic arbor. Co-administration of the dopamine D1 receptor (D1R) antagonist SCH23390 completely reversed the selective effects of nicotine on DLS MSN dendrite morphology, supporting a causal role for dopamine signaling at D1 receptors in nicotine-induced dendrite restructuring. Considering the functional importance of the DLS in shaping and expressing habitual behavior, these data support a model in which nicotine induces persistent and selective changes in the circuit connectivity of the DLS that may promote and sustain addiction-related behavior.

The majority of smokers start smoking in adolescence, beginning a potentially lifelong struggle with nicotine use and abuse. In rodent models of the effects of nicotine, the drug has been shown to elicit both locomotor and anxiety-like behavioral effects. Research suggests that these behavioral effects may be due in part to dopamine (DA) receptors D1 and D2 in the mesolimbic system, specifically the nucleus accumbens (NAc). We examined early adolescent (P28), late adolescent (P45), and adult (P80) male Long-Evans rats in the elevated plus maze (EPM) under normal conditions and the open field (OF) post-nicotine in order to test locomotor and anxiety-like behavior. These behavioral findings were then correlated with expression of DA D1 and D2 mRNA levels as determined via in situ hybridization. Nicotine-induced locomotor behavior was found to be significantly different between age groups. After a single injection of nicotine, early adolescents exhibited increases in locomotor behavior, whereas both late adolescents and adults responded with decreases in locomotor behavior. In addition, it was found that among, early adolescents, open arm and center time in the EPM were negatively correlated with D2 mRNA expression. In contrast, among adults, distance traveled in the center and center time in the OF were negatively correlated with D2 mRNA expression. This study suggests that DA D2 receptors play a role in anxiety-like behavior and that the relationship between observed anxiety-like behaviors and D2 receptor expression changes through the lifespan.

Growing awareness of essential wetland functions is providing support for wetland construction projects. Biomonitoring using invertebrates is a common way to evaluate project success, but relationships between wetland invertebrates and environmental factors are often weak. In recently constructed wetlands on Maryland’s Eastern Shore, we tested the hypothesis that focusing on predator and primary consumer invertebrate assemblages versus the entire community would elucidate stronger relationships with environmental factors. Despite variation in factors that are hypothesized to control wetland invertebrates (e.g., vegetation and tendency to dry), our results indicated weak relationships between environmental factors and the structure and composition of the entire community as well as predator and primary consumer assemblages separately. Examining the entire community and individual assemblages, however, showed that invertebrates were influenced by temporal factors. We propose that a complex interaction between wetland shape/size, local weather, and seasonal changes may have driven invertebrate community patterns among wetlands. Such interactions would complicate bioassessments of wetlands that differ in size, hydrology, and local weather conditions. Further study of specific factors controlling wetland invertebrates and developing new metrics that incorporate seasonal environmental change could improve biomonitoring results and thus management strategies aimed at enhancing wetland function.

A major curriculum redesign effort at the University of Maryland is infusing all levels of our undergraduate biological sciences curriculum with increased emphasis on interdisciplinary connections and quantitative approaches. The curriculum development efforts have largely been guided by recommendations in the National Research Council's Bio 2010 report and have resulted in revisions to courses in biology, mathematics, and physics over a period of 10 years. Important components of this effort included (1) developing online modules to infuse more mathematical content into six biology courses taken by biological sciences majors during their first 2 years of study; (2) strengthening the interdisciplinary connections of ancillary courses in mathematics and physics to support the development of quantitative skills in biological contexts; and (3) creating more quantitatively intensive courses for the final 2 years of the bachelors of science programme. These efforts, carried out by a large, multidisciplinary te...

Epigenetic modifications play a crucial role in human diseases. Unlike genetic mutations, however, they do not change the underlying DNA sequences. Epigenetic phenomena have gained increased attention in the field of cancer research, with many studies indicating that they are significantly involved in tumor establishment and progression. Histone methyltransferases (HMTs) are a large group of enzymes that specifically methylate protein lysine and arginine residues, especially in histones, using S-adenosyl-L-methionine (SAM) as the methyl donor. However, in general, HMTs have no widely accepted high-throughput screening (HTS) assay format, and reference inhibitors are not available for many of the enzymes. In this study, we describe the application of a miniaturized, radioisotope-based reaction system: the HotSpot(SM) platform for methyltransferases. Since this platform employs tritiated SAM as a cofactor, it can be applied to the assay of any HMT. The key advantage of this format is that any substrate can be used, including peptides, proteins, or even nucleosomes, without the need for labeling or any other modifications. Using this platform, we have determined substrate specificities, characterized enzyme kinetics, performed compound profiling for both lysine and arginine methyltransferases, and carried out HTS for a small-library LOPAC against DOT1L. After hit confirmation and profiling, we found that suramin inhibited DOT1L, NSD2, and PRMT4 with IC₅₀ values at a low μM range.

Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) have higher rates of smoking than adolescents without ADHD. Since methylphenidate is the primary drug used to treat ADHD, it is likely that many adolescents are exposed to both methylphenidate and nicotine. Recent studies have established that adolescent nicotine induces long-term changes in several neurobehavioral variables. Limited data also suggest that adolescent methylphenidate may affect neural development. Nicotine tolerance is a well-established behavioral phenomenon in rodents, yet the underlying mechanism remains elusive. Recent theories suggest that changes in ventral striatal dopamine indices may relate to nicotine tolerance. As an initial determination of whether nicotine and methylphenidate have additive effects on neurobehavioral development, the present study investigated the combined effects of adolescent nicotine [2mg/kg/d] alone or in conjunction with methylphenidate [1.5mg/kg, 2× daily] following a one-month drug free period on adult behavioral tolerance to nicotine [0.5mg/kg s.c.] and its relation to dopamine receptor mRNA expression in the ventral striatum. Animals with chronic combined (nicotine+methylphenidate) adolescent exposure displayed stronger tolerance as adults to the nicotine-induced locomotor effects in comparison to animals with adolescent exposure to nicotine alone, methylphenidate alone, or controls. Combined chronic adolescent exposure significantly elevated adult D3nf mRNA expression levels in the nucleus accumbens, however a single nicotine injection in adults increased D3nf mRNA levels in naïve animals and decreased D3nf mRNA levels in those that had been previously exposed to combined stimulants during adolescence. Conversely, a single adult nicotine injection increased D1 mRNA levels in the adult nucleus accumbens, particularly in the shell, but only in rats previously exposed to nicotine or methylphenidate as adolescents. To our knowledge this is the first study that has shown long-term behavioral and neurochemical changes stemming from low chronic exposure of these two commonly co-consumed stimulants during adolescence.

STUDY OBJECTIVE—To examine the relation of antioxidant and other nutrient intakes in pregnancy to smoking and sociodemographic variables. DESIGN—Cohort study. SETTING—St Mary's Maternity Hospital, Portsmouth. PARTICIPANTS—Pregnant nulliparous women, with no existing complications of pregnancy, were recruited from antenatal booking clinics. A total of 774 women completed seven day food diaries, and supplied detailed data on their use of nutrient supplements. MAIN RESULTS—Smokers had lower intakes of most micronutrients. After adjustment for the confounding effects of maternal age, height, and education, only vitamin C and carotenoid intakes remained significantly depressed. Age was strongly and significantly associated with the intake of most nutrients, including antioxidants, and this association was independent of other maternal factors. Antioxidant intake was therefore lowest in young women who smoked: for example smokers under 24 years had a mean vitamin C intake of 57 mg (SD 35) compared with 106 mg (SD 52) for non-smokers aged 28 and over (difference 49 mg, 95% CI 39, 59). The corresponding intakes of carotenoid equivalents were 1335 µg (SD 982) and 2093 µg (SD 1283) (difference 758 µg, 95% CI 496, 1020). CONCLUSIONS—The study has identified, for the first time, young pregnant women as a group at particular risk of low micronutrient intake. The health implications of poor nutrition now need to be evaluated, particularly for those women who smoke. Keywords: pregnancy; nutrition; age

Pervasive human impacts on urban streams make restoration to predisturbance conditions unlikely. The effective- ness of ecologically focused restoration approaches typically is limited in urban settings because of the use of a reference-condition approach, mismatches between the temporal and spatial scales of impacts and restoration activities, and lack of an integrative ap- proach that incorporates ecological and societal objectives. Developers of new frameworks are recognizing the opportunities for and benefits from incorporating societal outcomes into urban stream restoration projects. Social, economic, cultural, or other benefits to local communities are often opportunistic or arise indirectly from actions intended to achieve ecological outcomes. We propose urban stream renovation as a flexible stream improvement framework in which short-term ecological and societal outcomes are leveraged to achieve long-term ecological objectives. The framework is designed to provide additional opportunities for beneficial outcomes that are often unattainable from ecologically focused restoration approaches. Urban stream renovation uses an iterative process whereby short-term ecological and societal outcomes generate public support for future actions, which may provide opportunities to address catchment-level causes of impairment that often exist across broad temporal scales. Adaptive management, education, and outreach are needed to maintain long-term public engagement. Thus, future work should focus on understanding how ecological and societal contexts interact, how to assess societal outcomes to maintain stewardship, developing new methods for effective education and outreach, and multidisciplinary collaborations. We discuss potential abuses and the im- portance of linking societal outcomes to long-term ecological objectives.

Nicotine has both rewarding and aversive properties in rodents, as shown by intravenous self-administration, intracranial self-stimulation, and conditioned place preference experiments. However, high throughput models of nicotine reward have not been developed in mice. In previous two-bottle studies, mice often chose to drink less from the nicotine bottle than from the water bottle, which raises the question whether these paradigms provide a model of the reinforcing properties of oral nicotine. We hypothesized that previous two-bottle choice paradigms included factors (such as the brief duration of trials, the addition of flavorings to both bottles, water bottles located relatively close to each other, etc.) that may have obstructed the formation of a learned association between the taste of nicotine and its delayed pharmacological effects. Here we show that a paradigm designed to simplify the acquisition of a learned association resulted in nicotine consumption by various strains and sexes that diverged progressively over a period of seven weeks. The strain and sex with the highest nicotine consumption (C57BL/6J females) showed steady and statistically significant increases in nicotine consumption throughout this period. C57BL/6J females were clearly responding to the reinforcing properties of nicotine because they chose to drink over 70% of their fluids from the nicotine bottle. Moreover, they became nicotine dependent, as shown by highly significant nicotine withdrawal symptoms after the nicotine bottle was removed. The strain and sex with the lowest consumption (A/J males) showed a significant decrease in nicotine consumption, and by the end of the experiment were drinking only 24% of their fluids from the nicotine bottle.

Agricultural drainage ditches are artificial structures used to optimize soil hydrology for crop production and secondarily have been co-opted as a tool to manage the quality of water draining from agricultural lands. We investigated the relationship between the aquatic macroinvertebrate community and environmental variables associated with physical and biogeochemical processes that affect water quality. Aquatic macroinvertebrates were sampled along with physical and chemical measures of the soil and water from 29 agricultural drainage ditches on the Eastern Shore of Maryland. Cluster analysis and multivariate ordination showed that ditches that had higher flow velocities supported communities of lotic invertebrates (i.e., Stenelmis, Prosimulium) versus those that had properties of linear wetlands, which supported communities of lentic invertebrates (i.e., Oligochaeta, Caecidotea). Taxon richness varied from four to 31 taxa per ditch, and was higher within ditches that had higher flow velocities....

Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity.

Studies indicate that adolescence is a time of increased sensitivity to the rewarding effects of nicotine, and that stress is associated with an increased risk for smoking initiation in this age group. It is possible that stress leads to increased nicotine use in adolescence by augmenting its rewarding properties. Corticotropin-releasing factor type 1 receptors (CRF-R1) mediate physiological and behavioral stress responses. They may also mediate stress-induced potentiation of activity in multiple neural substrates implicated in nicotine reward.The aim of the present study was to determine the effect of acute stressor exposure on single trial nicotine conditioned place preference (CPP) in adolescent male rats using a biased CPP procedure and the role of CRF-R1 in this effect.A single episode of intermittent footshock administered 24 h before the start of place conditioning dose-dependently facilitated acquisition of CPP to nicotine (0.2, 0.4, and 0.6 mg/kg). Pretreatment with CP-154,526 (20 mg/kg), a selective CRF-R1 antagonist, 30 min before footshock exposure significantly attenuated the effect of prior stress to facilitate nicotine CPP acquisition. CP-154,526 pretreatment had no effect in animals conditioned with a nicotine dose that produced CPP under non-stress conditions, suggesting a specific role for CRF-R1 following stress.Taken together, the results suggest that during adolescence, nicotine reward is enhanced by recent stressor exposure in a manner that involves signaling at CRF-R1. Information from studies such as this may be used to inform efforts to prevent and treat adolescent nicotine dependence.

Adult dispersal and completion of life cycles by aquatic insects are essential for the persistence of populations, colonization of new habitats, and maintenance of genetic diversity. However, life-cycle stages and processes associated with the terrestrial environment often are overlooked when the effect of watershed urbanization on the persistence of insects associated with streams is examined. We reviewed and synthesized current literature on the known effects of watershed urbanization on the terrestrial stage of stream insects. Some research has directly examined the effects of watershed urbanization on dispersal, but much of the evidence we present is indirect and from related studies on aquatic insect life-history traits and dispersal abilities in nonurban watersheds. Our goal is to provide examples of potential impacts that warrant further study, rather than to provide a comprehensive review of all life-history studies. We discuss how watershed land use, riparian condition, and habitat qualit...

1 Department of Geography and Environmental Engineering, National Center for Earth-surface Dynamics, Johns Hopkins University, Baltimore, Maryland 21218 USA *Corresponding author; e-mail: M.A.KenneyPHD@gmail.com 2 Smithsonian Environmental Research Center, Edgewater, Maryland 21037 USA e-mail: sutton-griera@si.edu 3 Department of Entomology, 4112 Plant Sciences Building, University of Maryland, College Park, Maryland, 20742-4454 USA e-mail: rsmith9@umd.edu 4 Department of Biological Sciences, Towson University, Towson, Maryland 21252 USA e-mail: esens@tosgrwson.edu Received: 28 April 28, 2009; accepted: 17 July 2009 Summary is review addresses the intersection of water quality policy and benthic macroinvertebrates. Speci“ cally, we examine the role that stream macroinvertebrates have played or could play in informing water quality deci-sions given the current policy framework, using this framework as the organizational structure for the review. Macroinvertebrates, as biological indicators of stream water quality, can be utilized to identify impaired waters, determine aquatic life stressors, set pollutant load reductions, and indicate improvement. We present both current approaches as well as innovative approaches to identify macroinvertebrates and aquatic life stres-sors. We also discuss an example of the environmental management approach, speci“ cally, how macroinver-tebrates can be used to indicate the relative success of stream restoration. For policymakers, this review serves to illuminate opportunities and limitations of using benthic macroinvertebrates as indicators of water qual-ity. For entomologists, this review highlights policy-relevant research questions that would further aid the classi“ cation of impaired waters, the identi“ cation of stressors, or the management of stream ecosystems. © Koninklijke Brill NV, Leiden, 2009ds ywore Kiocriteria; B biological criteria; Clean ater ct; biological A W monitoring; bioassessment; essor str identi“ ca-tion; estoration; eam strr benthic tebrates eroinvmacr

SUMMARY Exposure to anesthetic drugs during gestation has been shown to cause behavioral changes in rats, and exposure during labor and delivery also affects human neonatal behavior. In this preliminary study, nine neonates who had been exposed to anesthetic agents during gestation were tested for visual-pattern preference. These nine infants looked at the stimuli for statistically significantly longer periods compared with 30 non-exposed infants. and had significantly different preferences for some pairs of patters. The results suggest that prenatal exposure to anesthetic agents may contribute to behavioral alterations in human neonates. RESUME La preference neonatale de patterns visuels est-elle modifiee par une exposition prenatale a une anesthesie? II a ete montre qu'une exposition durant la gestation a des drogues anesthesiques provoquait des modifications de comportement chez le rat et que cette exposition durant le travail ou I'accouchement affectait egalement Ie comportement humain neo-natal. Dans ectteetude preliminaire. neuf nouveau-nes exposes a des agents anesthesiques durant la grosscsse ont ete testes a la recherche de preferences de patterns visuels. Les neuf nourrissons ont regarde les stimuli duranl des periodes significativement plus longues par comparaison avcc des 30 nourrissons non exposes et presentaient des preerences significativement differentes pour quelques pairs de patterns. Ces resultats suggerent que I'exposition prenatale a des agents anesthesiques peut favoriser des alterations comportementales chez les nouveau-nes humains. ZUSAMMENFASSUNG Wird die Praferenz visueller Muster beim Neugeborenen durch die pranatale Exposition zu Anasthelika veranderr? Die Exposition zu Anasthetika wahrend der Gestationsphase hat bei Ratten zu Verhaltensveranderungen gefuhrt und eine Exposition wahrend der Wehen und unter der Geburt beeinflust auch das Verhalten der Neugeborenen. Bci dieser vorlaufigen Studie wurden neun Neugeborene. die wahrend der Gestationszeit eine Exposition zu Anashetika hatten, auf ihre Praferenz visueller Muster getestet. Die neun Kindern betrachteten die Stimuli statistisch signifikant langer verglichen mil 30 nicht exponierten Kindern und hatten signifikant unterschiedliche Praferenzen fur einige Muster. Die Ergebnisse lassen vermuten. dap die pranatale Exposition zu Anasthetika bei Neugeborenen Verhaltensveranderungen hervorrufen kann. RESUMEN ?Esta el esquema de preferencia visual neonaral modificado por la exposicion neonatal a la anestesia? Se ha visto que la exposicion a farmacos anestesicos durante la gestacion causa cambios en el comportamiento de las ratas, y la exposicion durante el parto tambien afecta al comportamiento del recien nacido humano. En este estudio preliminar, neuve recien nacidos que habian sido expuestos a agentes anestesicos durdnte la gestacion fueron examinados en su esquema de preferencia visual. Los neuve ninos miraban a los estimulos durante un ticmpo significativamente mayor en comparacion con los 30 ninos no expuestos y tenian unas preferencias significativamente diferentes para algunos pares de esquemas. Los resultados sugiere que la exposicon prenatal a agentes anntesicos puede contribuir a alteraciones de comportamiento en el recien nacido humano.

Bees of the genusOsmiaPanzer (Hymenoptera: Megachilidae) are among the contenders to replace honey bees,Apis melliferaL. (Apidae), for pollinating tree-fruit crops. One species,Osmia lignariaSay, has shown great potential in western North America and was recently introduced into Nova Scotia for evaluation as a pollinator of apple,MalusMill. (Rosaceae). A major component of that study was to develop management options forO. lignaria, including methods of sustaining nesting females following crop flowering to maximize population recovery for pollination in subsequent seasons. The objective of this study was to evaluate bigleaf lupine,Lupinus polyphyllusLindl. (Fabaceae), as a secondary food plant for nesting femaleO. lignariaby investigating nesting activity, pollen-use patterns, and fecundity. During 2002–2003, femaleO. lignariacollected high proportions of apple pollen (>70%) during mid and late flowering; after then, most pollen (>90%) was collected from bigleaf lupine. The flowering period of lupine in Nova Scotia (late May to early July) slightly overlapped that of apple, so there was no scarcity of pollen resources during the life-span ofO. lignaria. Most nests typically showed high levels (≤200%) of population growth, but recorded levels varied among nest types and locations. In 2004, nests closer to lupine plots exhibited significantly greater population recovery than nests located farther away (i.e., approximately 600 m). Bigleaf lupine is a suitable plant species for meeting the pollen requirements of nesting populations ofO. lignariafollowing apple flowering, thus promoting the recovery of populations to meet apple pollination requirements in subsequent seasons.

Watershed urbanization decreases diversity and taxonomic richness of aquatic insect communities, and headwater streams are particularly susceptible to degradation from urbanization. Patterns of taxon loss between urban headwater communities and communities in adjacent downstream, higher-order reaches might indicate which processes are controlling taxon loss and the extent to which unique headwater taxa are lost after urbanization. We compared insect communities in urban and rural watersheds and investigated if community similarity between headwater streams and adjacent higher-order main-stem reaches was greater in urban than in rural watersheds. We sampled insect communities in 3 urban and 3 rural watersheds in Maryland's Piedmont region during 3 seasons. Mean taxonomic richness was 4.33 greater and the Shannon diversity index was 1.83 greater in rural than in urban headwater streams. Simpson's index was 1.93 greater in urban than in rural headwater streams. The Jaccard similarity index calculated between headwater and main-stem communities was 1.63 greater for urban sites than rural sites during autumn, and the proportion of headwater taxa shared with the main-stem community was 1.83 greater for urban than rural sites. Redundancy analysis also indicated significantly greater similarity between urban headwater and main-stem communities than between rural headwater and main-stem communities. As expected, urbanization decreased diversity, and the communities remaining in urban headwaters were mostly subsets of the communities in the main-stem streams. This result suggested that taxa unique to headwaters were at the greatest risk of local extirpation after watershed urbanization. A significant interactive effect of landuse type and the longitudinal position of a reach along the headwater on taxonomic richness and the Jaccard index suggested that patterns of taxon loss partially depended on the proximity of a headwater reach to the main-stem stream. Overall, the results suggested that water- and habitat-quality degradation were not the only effects of watershed urbanization that determined the composition of insect communities in urban headwaters.

Male Long-Evans rats were administered nicotine bitartrate or sodium tartrate either during adolescence (p29-43) or adulthood (p80-94). Route of administration was via subcutaneously implanted osmotic pump (initial dose 2.0 mg/kg/day, free base). Five weeks following nicotine administration, brains were processed for Golgi-Cox staining. Medium spiny neurons from nucleus accumbens (NAc) shell were digitally reconstructed for morphometric analysis. Total dendritic length and branch number were greater in medium spiny neurons from animals pretreated with nicotine during adolescence. A branch order analysis indicated that increased branch number was specific to higher order branches. Mean branch lengths did not differ with respect to treatment as a function of branch order. Thus, nicotine-induced increases in total dendritic length were a function of greater numbers of branches, not increased segment length. In contrast, adult nicotine exposure did not significantly alter total dendritic length or branch number of medium spiny neurons. Total dendritic length and branch number of a second morphological type, the large aspiny neuron, did not differ following either adolescent or adult pretreatment. The age-dependent alteration of accumbal structure was associated with qualitatively different behavioral responses to drug challenge. These data provide evidence that drug-induced structural plasticity in nucleus accumbens is considerably more pronounced during adolescence.

To provide information for the development of new antiviral compounds that inhibit orthopoxviruses, further characterization of the kinetics and thermodynamics that underlie substrate utilization reactions of vaccinia virus thymidine kinase (VVTK) has been undertaken. The kinetics of 2'deoxythymidine phosphorylation by VVTK and the thermodynamics of complex formation between VVTK and the substrate 2' deoxythymidine were determined using spectroscopic and calorimetric techniques. These studies demonstrated that kinetic parameters for 2' deoxythymidine phosphorylation by VVTK were 25 microM and 0.2s(-1) for K(m) and k(cat), respectively. The enthalpy change, Delta H, for the enzyme catalyzed reaction is -18.1 kcal/mol. Thermodynamic studies for the formation of the enzyme substrate complex demonstrated a binding affinity (K(a)) of 4 x 10(4)M(-1), an enthalpy change for binding (Delta H) of -17.4 kcal/mol, and a reaction stoichiometry of two molecules of substrate binding to each enzyme tetramer. Kinetic and thermodynamic data were in agreement (K(a) approximately 1/K(m)) and showed similarities to literature values reported for herpes simplex virus thymidine kinase (HSV-TK) and human thymidine kinase 1 (hTK1) with respect to k(cat) but not with respect to K(m). The K(m) value found for VVTK in this study is nearly two orders of magnitude larger than the values reported for the hTK1 and the HSV TK enzymes.

Background Previous data in humans and animal models has suggested connections between anxiety, depression, smoking behavior, and nicotine dependence. The importance of these connections has been confirmed by clinical studies that led to the recent FDA approval of an anti-depressant (Zyban) for use in human smoking cessation programs. Other anti-depressants (such as rolipram) specifically inhibit PDE4 phosphodiesterases. Methods We used DNA microarrays to discover gene expression changes in adolescent female rats following chronic nicotine treatments, and real-time PCR assays to confirm and extend those results. Results We found a consistent decrease in the mRNA levels encoded by the Pde4b gene in nucleus accumbens, prefrontal cortex, and hippocampus of adolescent female rats treated with .24 mg/day nicotine, and in prefrontal cortex of adolescent female rats treated with .12 mg/day nicotine. We further show that each of these brain areas produced a different profile of Pde4b isoforms. Conclusions Chronic nicotine treatments produce a dose-dependent down-regulation of Pde4b, which may have an antidepressant effect. This is the first report of a link between nicotine dependence and phosphodiesterase gene expression. Our results also add to the complex interrelationships between smoking and schizophrenia, because mutations in the PDE4B gene are associated with schizophrenia.

Sixty male and female Long-Evans hooded rats were administered 1, 2, or 5mg/kg methylphenidate (MPH) suspended in apple juice on postnatal day (P)15 or P40 using a novel, non-invasive oral administration technique. Plasma was collected 15 min after ingestion and analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS) to confirm appropriate concentrations. HPLC-MS plasma analysis showed levels comparable to previous gavage studies using MPH. We have used this method successfully in subsequent behavioral studies as well. Since therapeutic MPH in humans is typically administered orally, oral dosing methods that have been verified in the rodent model are of value. We recommend employment of this alternative oral dosing technique as it is minimally invasive, can be used anytime during postnatal development, and does not depend upon voluntary consumption.

Humans often start smoking during adolescence. Recent results suggest that rodents may also be particularly vulnerable to nicotine dependence during adolescence. We examined the effect of chronic nicotine exposure on gene expression profiles during adolescence in female rats, who were dosed with nicotine (and control animals were dosed with saline) via subcutaneously implanted osmotic minipumps. Brain samples were collected at four ages: before puberty (postnatal day 25), at about the time of puberty in females (postnatal day 35), and after puberty (postnatal days 45 and 55). The expression of 7931 genes in three brain areas was measured using DNA microarrays. Quantitative RT-PCR was also employed to confirm the expression patterns of selected genes. We used a novel clustering technique (principal cluster analysis) to classify 162 nicotine-regulated genes into five clusters, of which only one (cluster A) showed similar patterns of gene expression across all three brain areas (ventral striatum, prefrontal cortex, and hippocampus). Three clusters of genes (A, B, and C) showed dramatic peaks in their nicotine responses at the same age (p35). The other two clusters (D1 and D2) showed smaller peaks and/or valleys in their nicotine responses at p35 and p45. Thus, the age of maximal gene expression response to nicotine in female rats corresponds approximately to the age of maximal behavioral response and the age of puberty.

Methylation of histone H3 lysine-4 (H3K4) is an important, regulatory, epigenetic post-translational modification associated with actively transcribed genes. In humans, the principal mediators of this modification are part of the MLL/SET1 family of methyltransferases, which comprises six members, MLLs1-4 and SET1A/SET1B. Aberrations in the structure, expression, and regulation of these enzymes are implicated in various disease states, making them important potential targets for drug discovery, particularly for oncology indications. The MLL/SET1 family members are most enzymatically active when part of a "core complex," the catalytic SET-domain-containing subunits bound to a subcomplex consisting of the proteins WDR5, RbBP5, Ash2L and a homodimer of DPY-30 (WRAD2). The necessity of MLL/SET1 members to bind WRAD2 for full activity is the basis of a particular drug development strategy, which seeks to disrupt the interaction between the MLL/SET1 subunits and WDR5. This strategy is not without its theoretical and practical drawbacks, some of which relate to the ease with which complexes of Escherichia coli-expressed MLL/SET1 and WRAD2 fall apart. As an alternative strategy, we explore ways to stabilize the complex, focusing on the use of an excess of WRAD2 to drive the binding equilibria toward complex formation while maintaining low concentrations of the catalytic subunits. The purpose of this approach is to seek inhibitors that bind the SET domain, an approach proven successful with the related, but inherently more stable, enhancer of zeste homolog 2 (EZH2) complex.

Adolescent cigarette use is associated with reduced quitting success and continued smoking in adulthood. Interestingly, polymorphisms of the dopamine D3 receptor (DRD3) gene have been associated with smoking behavior, and the receptor is expressed in an age- and brain region-dependent manner that suggests relevance to addiction. Here, we investigate the possible role of dopamine-related receptors, including DRD3 and an intriguing splice variant known as D3nf, in nicotine-induced sensitization. In adolescent and adult male rats, we examined (1) alterations occurring in dopamine receptor-related mRNAs (DRD1, DRD2, DRD3 and D3nf) at two time points during a sensitizing regimen of nicotine and (2) whether DRD3 antagonism either during the initial treatment (induction) or at a later challenge exposure (expression) is able to block nicotine sensitization. Nicotine-induced changes were seen for DRD3 and D3nf mRNAs in the nucleus accumbens shell early in repeated exposure in both age groups. DRD3 antagonism only blocked the induction of sensitization in adolescents and did not block the expression of sensitization in either age group. Adolescents and adults showed opposite DRD1 mRNA responses to nicotine treatment, while no age- and nicotine-related changes in DRD2 mRNA were observed. These data reveal important age-dependent regulation of DRD1- and DRD3-related mRNAs during the course of nicotine exposure. Furthermore, they highlight a requirement for DRD3 signaling in the development of adolescent nicotine sensitization, suggesting it may represent an appropriate target in the prevention of nicotine dependence initiated at this age.

Intraosseous lines are a reliable and rapid tool for obtaining vascular access in emergency situations, particularly in children. Their use is recommended when intravenous access cannot be easily secured and there is a need for fluid or pharmacological resuscitation. Training in this technique is included in the Advanced Trauma Life Support (ATLS) and Advanced Paediatric Life Support course (APLS) provider courses. The objective of this study is to analyse the national use of intraosseous lines in paediatric trauma in England and Wales. Data has been collected from the Trauma Audit and Research Network (TARN) group longitudinally over 14 years from 1988 to 2002. From 23,489 paediatric trauma cases, intraosseous lines were used in only 129 patients. Compared with the remainder of the paediatric data, we found that these were the younger (1-6 years), more severely injured patients (higher ISS, lower GCS, higher head, thorax, and abdominal AIS). The mortality of these patients was high at 64% compared with 4% overall. IO line use was greater in general than in Paediatric hospitals, perhaps due to good intravenous access skills in paediatric centres. We recommend that intraosseous line use should be a skill available to everybody involved in paediatric trauma resuscitation, particularly those who may not have refined paediatric intravenous cannulation skills.

The objective of the current study was to examine how periadolescent nicotine exposure affects dendritic morphology of medium spiny neurons from the nucleus accumbens shell. Male Long-Evans hooded rats were chronically administered nicotine or saline for a period extending from postnatal day 22 (p22) to p69. Nicotine and saline administration was via subcutaneously implanted osmotic pumps. At p144, 75 days after conclusion of nicotine administration, brains were processed for Golgi-Cox staining. Medium spiny neurons from the nucleus accumbens shell were digitally reconstructed. It was found that neurons from nicotine-treated animals possessed significantly longer dendrites and a greater number of dendritic segments than control animals. A branch order analysis indicated that differences in dendritic length and segment number were most pronounced in third and fourth order segments. A subsequent behavioral experiment suggests that the observed anatomical changes are associated with enduring psychomotor differences. These findings indicate that periadolescent exposure to nicotine can result in long-lasting structural changes in the nucleus accumbens shell and are consistent with behavioral data suggesting that adolescent nicotine exposure may result in vulnerability to nicotine addiction in adulthood.

The flight activity of the apple leaf midge, Dasineura mali (Kieffer), was determined in the field and laboratory. Males and females began emerging at the onset of the photophase. In the field, delta-shaped traps baited with 6 virgin females caught males exclusively, with the most abundant catches on the ground as compared to those at 1 and 2 m. Most males were captured at 1100 hours and males remained in the vegetation under the trees throughout the day. Sweep netting revealed that conspecifics mate in the vegetation under orchard trees in the morning hours, and females move from the ground to the orchard canopy to oviposit at 1000 hours. Gas chromatographic-electroantennographic detection (GC-EAD) analyses indicated the presence of an electrophysiologically active compound in solid phase microextraction (SPME) effluvial collections and pheromone gland extractions from virgin females.

Use of addictive substances by human juveniles and adolescents is common, including use to intoxication and progression from one drug to other drugs. Until quite recently, animal studies have not addressed the periadolescent period as a time of special vulnerability to substance abuse. For ethanol (EtOH), the most studied drug in periadolescent animals, it has become clear that effects of alcohol are similar in some ways, but different in others, compared to the effects seen in adult animals. Sparse data suggest that this conclusion may apply to other drugs as well. Recent work in rats indicates that periadolescent substance use may disrupt normal pubertal development, and may induce stronger effects on systems subserving plasticity and cognition than in adults. Animal data also indicate that some drugs may produce altered subsequent sensitivity to the same or a different drug, changes in adult cognitive capabilities, and even CNS damage. It is now clear that there can be no presumption that all studies of abusable substances carried out in adult animals will generalize readily to periadolescents. Some data suggest that continuing developmental changes in receptor expression may underlie age-related changes in drug effects. However, the biological characteristics of periadolescence which predispose toward consumption to intoxication, and the mechanisms underlying drug progression and persisting drug effects, still remain to be well defined.