Metropolitan Reclassification and the Urbanization of Rural America.

We highlight the paradoxical implications of decadal reclassification of U.S. counties (and America's population) from nonmetropolitan to metropolitan status between 1960 and 2017. Using data from the U.S. Census Bureau, we show that the reclassification of U.S. counties has been a significant engine of metropolitan growth and nonmetropolitan decline. Over the study period, 753-or nearly 25% of all nonmetropolitan counties-were redefined by the Office of Management and Budget (OMB) as metropolitan, shifting nearly 70 million residents from nonmetropolitan to metropolitan America by 2017. All the growth since 1970 in the metropolitan share of the U.S. population came from reclassification rather than endogenous growth in existing metropolitan areas. Reclassification of nonmetropolitan counties also had implications for drawing appropriate inferences about rural poverty, population aging, education, and economic growth. The paradox is that these many nonmetropolitan "winners"-those experiencing population and economic growth-have, over successive decades, left behind many nonmetropolitan counties with limited prospects for growth. Our study provides cautionary lessons regarding the commonplace narrative of widespread rural decline and economic malaise but also highlights the interdependent demographic fates of metropolitan and nonmetropolitan counties.

Sprawling and diverse: The changing U.S. population and implications for public lands in the 21st Century.

Public lands are typically established in recognition of their unique ecological value, yet both ecological and social values of public lands change over time, along with human distribution and land use. These transformations are evident even in developed countries with long histories of public land management, such as the United States. The 20th Century saw dramatic changes in the American population, in distribution and in racial and ethnic diversity, leading to new challenges and new roles for public lands. Our goal with this paper is to review changing demographics and implications for terrestrial protected areas in the U.S. We overview the fundamentals of population change and data, review past trends in population change and housing growth and their impacts on public lands, and then analyze the most recent decade of demographic change (2000-2010) relative to public lands. Discussions of demographic change and public lands commonly focus on the rural West, but we show that the South is also experiencing substantial change in rural areas with public lands, including Hispanic population growth. We identify those places, rural and urban, where demographic change (2000-2010), including diversification and housing growth, coincide with public lands. Understanding the current trends and long-term demographic context for recent changes in populations can help land managers and conservation scientists mitigate the effects of residential development near public lands, serve a more diverse population, and anticipate future population changes.

The Influence of Human Demography on Land Cover Change in the Great Lakes States, USA.

The Great Lakes region contains productive agricultural and forest lands, but it is also highly urbanized, with 32 of its 52 million residents living in nine large metropolitan areas. Urbanization of undeveloped areas may adversely affect the productivity of agricultural and forest lands, and the provision of ecosystem services. We combine demographic and remote sensing data to evaluate land cover change in the region using a two-phase statistical modeling approach that predicts the incidence and extent of land cover change for each of the region's 10,579 county subdivisions. Observed patterns are spatially uneven, and the probability of land cover change is influenced by current land use, human habitation, industry, and demographic change. Pseudo R2 values varied from 0.053 to 0.338 for the first-phase logistic models predicting the presence of land cover change; second-stage beta models predicting the rate of change were more reliable, with pseudo R2 ranging from 0.225 to 0.675. Overall, changes from agriculture or greenspace to development were much more predictable than changes from agriculture to greenspace or vice versa, and demographic variables were much more important in models predicting change to development. Although models successfully predicted the general location of land cover change, and models from before the Great Recession were useful for predicting the location but not the amount of change during the recession, fine-grained prediction remained challenging. Understanding where future changes are most probable can inform planning and policy-making, which may reduce the impact of development on resource production, environmental health, and ecosystem services.

Moving Toward Integration? Effects of Migration on Ethnoracial Segregation Across the Rural-Urban Continuum.

This study analyzes the impact of migration on ethnoracial segregation among U.S. counties. Using county-level net migration estimates by age, race, and Hispanic origin from 1990-2000 and 2000-2010, we estimate migration's impact on segregation by age and across space. Overall, migration served to integrate ethnoracial groups in both decades, whereas differences in natural population change (increase/decrease) would have increased segregation. Age differences, however, are stark. Net migration of the population under age 40 reduced segregation, while net migration of people over age 60 further segregated people. Migration up and down the rural-urban continuum (including suburbanization among people of color) did most to decrease segregation, while interregional migration had only a small impact. People of color tended to move toward more predominantly white counties and regions at all ages. Migration among white young adults (aged 20-39) also decreased segregation. Whites aged 40 and older, however, showed tendencies toward white flight. Moderate spatial variation suggests that segregation is diminishing the most in suburban and fringe areas of several metropolitan areas in the Northeast and Midwest, while parts of the South, Southwest, and Appalachia show little evidence of integration.

Migration signatures across the decades: Net migration by age in U.S. counties, 1950-2010.

BACKGROUND: Migration is the primary population redistribution process in the United States. Selective migration by age, race/ethnic group, and spatial location governs population integration, affects community and economic development, contributes to land use change, and structures service needs. OBJECTIVE: Delineate historical net migration patterns by age, race/ethnic, and rural-urban dimensions for United States counties. METHODS: Net migration rates by age for all US counties are aggregated from 1950-2010, summarized by rural-urban location and compared to explore differential race/ethnic patterns of age-specific net migration over time. RESULTS: We identify distinct age-specific net migration 'signatures' that are consistent over time within county types, but different by rural-urban location and race/ethnic group. There is evidence of moderate population deconcentration and diminished racial segregation between 1990 and 2010. This includes a net outflow of Blacks from large urban core counties to suburban and smaller metropolitan counties, continued Hispanic deconcentration, and a slowdown in White counterurbanization. CONCLUSIONS: This paper contributes to a fuller understanding of the complex patterns of migration that have redistributed the U.S. population over the past six decades. It documents the variability in county age-specific net migration patterns both temporally and spatially, as well as the longitudinal consistency in migration signatures among county types and race/ethnic groups.

α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor activation protects against phencyclidine-induced caspase-3 activity by activating voltage-gated calcium channels.

Phencyclidine (PCP) is a noncompetitive, open channel blocker of the N-methyl-D-aspartate (NMDA) receptor-ion channel complex. When administered to immature animals, it is known to cause apoptotic neurodegeneration in several regions, and this is followed by olanzapine-sensitive, schizophrenia-like behaviors in late adolescence and adulthood. Clarification of its mechanism of action could yield data that would help to inform the treatment of schizophrenia. In our initial experiments, we found that α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) inhibited PCP-induced apoptosis in organotypic neonatal rat brain slices in a concentration-dependent and 6-cyano-7-nitroquinoxaline-2,3-dione-sensitive manner. Calcium signaling pathways are widely implicated in apoptosis, and PCP prevents calcium influx through NMDA receptor channels. We therefore hypothesized that AMPA could protect against this effect by activation of voltage-dependent calcium channels (VDCCs). In support of this hypothesis, pretreatment with the calcium channel blocker cadmium chloride eliminated AMPA-mediated protection against PCP. Furthermore, the L-type VDCC inhibitor nifedipine (10 µM) fully abrogated the effects of AMPA, suggesting that L-type VDCCs are required for AMPA-mediated protection against PCP-induced neurotoxicity. Whereas the P/Q-type inhibitor ω-agatoxin TK (200 nM) reduced AMPA protection by 51.7%, the N-type VDCC inhibitor ω-conotoxin (2 µM) had no effect. Decreased AMPA-mediated protection following cotreatment with K252a, a TrkB inhibitor, suggests that brain-derived neurotrophic factor signaling plays an important role. By analogy, these results suggest that activation of L-type, and to a lesser extent P/Q-type, VDCCs might be advantageous in treating conditions associated with diminished NMDAergic activity during early development.

The role of inflammation in brain cancer.

Malignant brain tumors are among the most lethal of human tumors, with limited treatment options currently available. A complex array of recurrent genetic and epigenetic changes has been observed in gliomas that collectively result in derangements of common cell signaling pathways controlling cell survival, proliferation, and invasion. One important determinant of gene expression is DNA methylation status, and emerging studies have revealed the importance of a recently identified demethylation pathway involving 5-hydroxymethylcytosine (5hmC). Diminished levels of the modified base 5hmC is a uniform finding in glioma cell lines and patient samples, suggesting a common defect in epigenetic reprogramming. Within the tumor microenvironment, infiltrating immune cells increase oxidative DNA damage, likely promoting both genetic and epigenetic changes that occur during glioma evolution. In this environment, glioma cells are selected that utilize multiple metabolic changes, including changes in the metabolism of the amino acids glutamate, tryptophan, and arginine. Whereas altered metabolism can promote the destruction of normal tissues, glioma cells exploit these changes to promote tumor cell survival and to suppress adaptive immune responses. Further understanding of these metabolic changes could reveal new strategies that would selectively disadvantage tumor cells and redirect host antitumor responses toward eradication of these lethal tumors.

Hispanic Assimilation and Fertility in New Destinations.

This paper evaluates comparative patterns of fertility in new Hispanic destinations and established gateways using pooled cross-sectional data from the 2005-2009 microdata files of the American Community Survey. Changing Hispanic fertility provides a useful indicator of cultural incorporation. Analyses show that high fertility among Hispanics has been driven in part by the Mexican-origin and other new immigrant populations (e.g., noncitizens, those with poor English language skills, etc.). However, high fertility rates among Hispanics - and Mexican-origin Hispanics in particular - cannot be explained entirely by socio-demographic characteristics that place them at higher risk of fertility. For 2005-2009, Hispanic fertility rates were 48 percent higher than fertility among whites; they were roughly 25 percent higher after accounting for differences in key social characteristics, such as age, nativity, county of origin, and education. Contrary to most previous findings of spatial assimilation among in-migrants, fertility rates among Hispanics in new destinations exceeded fertility in established gateways by 18 percent. In the multivariate analyses, Hispanics in new destinations were roughly 10 percent more likely to have had a child in the past year than those living in established gateways. Results are consistent with sub-cultural explanations of Hispanic fertility and raise new questions about the spatial patterning of assimilation and the formation of ethnic enclaves outside traditional settlement areas.

Practice What We Preach: Beginning a Journey to Embrace Patient-Centered Outcomes Research.

BACKGROUND: Patient-centered outcomes research seeks to answer patient-centered questions. The process includes varied locations and individuals throughout the care continuum to address individual differences and constraints in implementation and dissemination. PROBLEM: This paper intends to answer this question: do academic nurses practice what they preach by assisting patient-centered outcomes research and researchers through their engagement with patients, caregivers, and other community stakeholder partners in nursing research? APPROACH: This paper provides an overview of how academic nurses in a single institution (the University of Texas Medical Branch at Galveston School of Nursing) began to embrace patient-centered outcomes research. CONCLUSION: Whether academic nurses are practicing what they preach in terms of patient-centered outcomes research remains uncertain. More examples from academia are required to make that determination. Academic nurses worldwide have embarked on a steep learning curve to embrace patient-centered outcomes research. This journey will require patience and a systematic strategy.

As Births Diminish and Deaths Increase, Natural Decrease becomes More Widespread in Rural America.

Even before the onset of the Covid-19 pandemic, the U.S. population growth rate last year was the lowest in 100 years. And, from 2010 to 2019 nonmetropolitan America lost population for the first time in history. Diminished natural increase was a major contributor to this and also accelerated the incidence of natural decrease (more deaths than births), particularly in rural America. Deaths exceeded births in 46 percent of all U.S. counties-a near record high. Nearly 79 percent of these natural decrease counties were nonmetropolitan. This research uses recent data and a multivariate spatial regression model to update our understanding of the growing incidence of natural decrease in both rural and urban America. In light of the mortality increase and likely fertility declines stemming from the Covid-19 pandemic, these findings have significant implications for future nonmetropolitan demographic trends.

Activation of dopamine D1 receptors blocks phencyclidine-induced neurotoxicity by enhancing N-methyl-D-aspartate receptor-mediated synaptic strength.

Early postnatal blockade of NMDA receptors by phencyclidine (PCP) causes cortical apoptosis in animals. This is associated with the development of schizophrenia-like behaviors in rats later in life. Recent studies show that the mechanism involves a loss of neurotrophic support from the phosphoinositol-3 kinase/Akt pathway, which is normally maintained by synaptic NMDA receptor activation. Here we report that activation of dopamine D1 receptors (D1R) with dihydrexidine (DHX) prevents PCP-induced neurotoxicity in cortical neurons by enhancing the efficacy of NMDAergic synapses. DHX increases serine phosphorylation of the NR1 subunit through protein kinase A activation and tyrosine phosphorylation of the NR2B subunit via Src kinase. DHX enhances recruitment of NR1 and NR2B, but not NR2A, into synapses. DHX also facilitated the synaptic response in cortical slices and this was blocked by an NR2B antagonist. DHX pre-treatment of rat pups prior to PCP on postnatal days 7, 9 and 11 inhibited PCP-induced caspase-3 activation on PN11 and deficits in pre-pulse inhibition of acoustic startle measured on PN 26-28. In summary, these data demonstrate that PCP-induced deficits in NMDA receptor function, neurotoxicity and subsequent behavioral deficits may be prevented by D1R activation in the cortex and further, it is suggested that D1R activation may be beneficial in treating schizophrenia.

Differential regulation of the NMDA receptor by acute and sub-chronic phencyclidine administration in the developing rat.

Neurodegeneration induced by the NMDA receptor antagonist, phencyclidine (PCP), has been used to model the pathogenesis of schizophrenia in the developing rat. Acute and sub-chronic administration of PCP in perinatal rats results in different patterns of neurodegeneration. The potential role of an alteration in the membrane expression of NMDA receptors in PCP-induced degeneration is unknown. Acute PCP treatment on postnatal day 7 increased membrane levels of both NMDA receptor subunit 1 (NR1) and NMDA receptor subunit 2B (NR2B) proteins in the frontal cortex; conversely, NR1 and NR2B protein levels in the endoplasmic reticulum fraction were decreased. Acute PCP administration also resulted in increased membrane cortical protein levels of post-synaptic density-95, as well as the activation of calpain, which paralleled the observed increase in membrane expression of NR1 and NR2B. Further, administration of the calpain inhibitor, MDL28170, prevented PCP-induced up-regulation of NR1 and NR2B. On the other hand, sub-chronic PCP treatment on postnatal days 7, 9 and 11 caused an increase in NR1 and NR2A expression, which was accompanied by an increase in both NR1 and NR2A in the endoplasmic reticulum fraction. Sub-chronic PCP administration did not alter levels of post-synaptic density-95 and had no effect on activation of calpain. These data suggest that increased trafficking accounts for up-regulation of cortical NR1/NR2B subunits following acute PCP administration, while increased protein synthesis likely accounts for the increased expression of NR1/NR2A following sub-chronic PCP treatment of the developing rat. These results are discussed in the context of the differential neurodegeneration caused by acute and subchronic PCP administration in the developing rat brain.

The role of Akt-GSK-3beta signaling and synaptic strength in phencyclidine-induced neurodegeneration.

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) can induce positive and negative symptoms of schizophrenia in humans and related effects in rodents. PCP treatment of developing rats induces apoptotic neurodegeneration and behavioral deficits later in life that mimic some symptoms of schizophrenia. The precise mechanism of PCP-induced neural degeneration is unknown. This study used selective antagonists, siRNA, and Western analysis to investigate the role of the Akt-glycogen synthase kinase-3beta (GSK-3beta) pathway in PCP-induced neuronal apoptosis in both neuronal culture and postnatal day 7 rats. PCP administration in vivo and in vitro reduced the phosphorylation of Akt Ser427 and GSK-3beta Ser9, decreasing Akt activity and increasing GSK-3beta activity. The alteration of Akt-GSK-3beta signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3beta activity by application of selective inhibitors or depletion of GSK-3beta by siRNA attenuates caspase-3 activity and blocks PCP-induced neurotoxicity. Moreover, increasing synaptic strength by either activation of L-type calcium channels with BAY K8644 or potentiation of synaptic NMDA receptors with either a low concentration of NMDA or bicuculline plus 4-aminopyridine completely blocks PCP-induced cell death by increasing Akt phosphorylation. These neuroprotective effects are associated with activation of phosphoinositide-3-kinase-Akt signaling, and to a lesser extent, the MAPK signaling pathway. Overall, these data suggest that PCP-induced hypofunction of synaptic NMDA receptors impairs the Akt-GSK-3beta cascade, which is necessary for neuronal survival during development, and that interference with this cascade by PCP or natural factors may contribute to neural pathologies, perhaps including schizophrenia.

Lithium protection of phencyclidine-induced neurotoxicity in developing brain: the role of phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways.

Phencyclidine (PCP) and other N-methyl-D-aspartate (NMDA) receptor antagonists have been shown to be neurotoxic to developing brains and to result in schizophrenia-like behaviors later in development. Prevention of both effects by antischizophrenic drugs suggests the validity of PCP neurodevelopmental toxicity as a heuristic model of schizophrenia. Lithium is used for the treatment of bipolar and schizoaffective disorders and has recently been shown to have neuroprotective properties. The present study used organotypic corticostriatal slices taken from postnatal day 2 rat pups to investigate the protective effect of lithium and the role of the phosphatidylinositol-3 kinase (PI-3K)/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways in PCP-induced cell death. Lithium pretreatment dose-dependently reduced PCP-induced caspase-3 activation and DNA fragmentation in layers II to IV of the cortex. PCP elicited time-dependent inhibition of the MEK/ERK and PI-3K/Akt pathways, as indicated by dephosphorylation of ERK1/2 and Akt. The proapoptotic factor glycogen synthase kinase (GSK)-3beta was also dephosphorylated at serine 9 and thus activated. Lithium prevented PCP-induced inhibition of the two pathways and activation of GSK-3beta. Furthermore, blocking either PI-3K/Akt or MEK/ERK pathway abolished the protective effect of lithium, whereas inhibiting GSK-3beta activity mimicked the protective effect of lithium. However, no cross-talk between the two pathways was found. Finally, specific GSK-3beta inhibition did not prevent PCP-induced dephosphorylation of Akt and ERK. These data strongly suggest that the protective effect of lithium against PCP-induced neuroapoptosis is mediated through independent stimulation of the PI-3K/Akt and ERK pathways and suppression of GSK-3beta activity.

Atypical anti-schizophrenic drugs prevent changes in cortical N-methyl-D-aspartate receptors and behavior following sub-chronic phencyclidine administration in developing rat pups.

We sought to determine the relationship between phencyclidine (PCP)-induced alterations in behavior and NMDAR expression in the cortex by examining the effect of anti-schizophrenic drug treatment on both. Sprague-Dawley rat pups were pretreated with risperidone or olanzapine prior to treatment with PCP on postnatal day 7 (PN7) or sub-chronically on PN7, 9, and 11. Pre-pulse inhibition (PPI) of acoustic startle was measured on PN24-26 and following a challenge dose of 4 mg/kg PCP, locomotor activity was measured on PN28-35. PCP treatment on PN7 did not cause a deficit in PPI, but did cause locomotor sensitization. This was prevented by both antipsychotics. PCP treatment on PN7 caused an up-regulation of NR1 and NR2B, which was not affected by either anti-schizophrenic drug. PCP treatment on PN7, 9, and 11 caused a deficit in PPI and a sensitized locomotor response to PCP challenge as well as an up-regulation of NR1 and NR2A, all of which were prevented by both atypical anti-schizophrenic drugs. These data support the hypothesis that sub-chronic, but not single injection PCP treatment in developing rats results in behavioral alterations that are sensitive to antipsychotic drugs and these behavioral changes observed could be related to up-regulation of cortical NR1/NR2A receptors.

The role of caspase-3 activation in phencyclidine-induced neuronal death in postnatal rats.

This study determined the role of caspase-3 in phencyclidine (PCP)-induced neurodegeneration in postnatal rats. PCP administration to postnatal day 7 rats induced a dose-dependent increase in caspase-3 enzymatic activity in frontal cortex, striatum, and hippocampus. Enzymatic activation was present at 4 h, peaked between 6 and 12 h, and disappeared by 24 h. Further, cleaved caspase-3-immunoreactive neurons were detected as early as 2 h in the cortex, and were found throughout the brain, including, in addition, the thalamus and striatum. Within the cingulate, frontal, parietal, and retrosplenial cortices, immunoreactivity was specific for layers II-IV (especially layer II). Neurons positive for both silver staining and terminal deoxynucleotidyl transferase biotin-d-UTP nick-end labeling (TUNEL) were found in the same brain regions and subregions. Double labeling experiments confirmed that cleaved caspase-3 and TUNEL were coexpressed in many neurons in all brain regions and subregions studied. Temporal studies revealed that procaspase-3 cleavage preceded TUNEL staining by about 3 h, with many neurons being positive for both caspase-3 and TUNEL 9 h after PCP treatment. In organotypic corticostriatal slices, PCP caused a concentration- and time-dependent cleavage of procaspase-3 that was also colocalized with TUNEL staining in layers II-IV of the parietal cortex. Caspase-3 activation again preceded PCP-induced DNA damage assessed by TUNEL. PCP-induced neuronal death in vitro as measured by TUNEL staining was blocked 85% by Ac-AAVALLPAVLLALLAPDEVD-CHO, a cell-permeable selective caspase-3 inhibitor. These data demonstrate that caspase-3 activation plays a necessary role in the regionally selective neuronal death induced by PCP in the developing rat brain.

Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications.

Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5 field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the reinstatement of cocaine self-administration caused by the presentation of environmental cues previously associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of gaining a better understanding of the structural features relevant to its antagonist potency and with the ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine. These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists that are 490 and 230 times, respectively, better than that of MTEP.

The relocation bump: Memories of middle adulthood are organized around residential moves.

The lifetime temporal distribution of older adults' autobiographical memories peaks during the transitional period of late adolescence and early adulthood, a phenomenon known as the reminiscence bump. This age-specific memory enhancement suggests that transitions may provide a more general organizing structure for autobiographical memory. To test this hypothesis, we examined how older adults' memories of events that occurred between the ages of 40 and 60 were distributed around residential relocations occurring within this same time frame. The temporal distribution of memories showed a marked relocation bump around the age of the most important residential move. Although previous research has focused on the negative effects of relocation, the current findings suggest that transitions could have a positive effect on autobiographical memory. (PsycINFO Database Record

Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors.

4-(4-Chlorophenyl)piperidine analogues each bearing a thioacetamide side chain appendage similar to that found in the wake-promoting drug modafinil have been synthesized. The transporter inhibitory activity of both the cis and trans isomers of these 3,4-disubstituted piperidines in both their (+)- and (-)-enantiomeric forms was determined. These studies reveal that the (-)-cis analogues exhibit dopamine transporter/norepinephrine transporter (DAT/NET) selectivity as was previously reported for the (+)-trans analogues. On the other hand, the (-)-trans and the (+)-cis isomers show serotonin transporter (SERT) or SERT/NET selectivity. Among them, (+)-cis-5b shows a low nanomolar Ki for the NET with 39-fold and 321-fold lower potency at the DAT and SERT, respectively, thus making it a useful pharmacological research tool for exploring NET-associated behavioral signatures. On the other hand, several of the compounds described herein, such as (+)-trans-5c, show comparable activity at all three transporters. Because broad-spectrum transporter inhibitors have been hypothesized to exhibit a more rapid onset of action and/or a greater efficacy as antidepressant agents than those selective for SERT or SERT + NET, some of the present compounds will be valuable to study in animal models of depression.

The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture.

Phencyclidine (PCP) is an N-methyl-D-aspartate receptor (NMDAR) antagonist known to cause selective neurotoxicity in the cortex following subchronic administration. The purpose of this study was to test the hypothesis that upregulation of the NMDAR plays a role in PCP-induced apoptotic cell death. Corticostriatal slice cultures were used to determine the effects of NMDAR subunit antisense oligodeoxynucleotides (ODNs) on PCP-induced apoptosis and NMDAR upregulation. NR1, NR2A or NR2B antisense ODNs were incubated alone or with PCP for 48h. One day following washout, it was observed that PCP treatment caused an increase in NR1, NR2A and Bax polypeptides in the cortex, but had no effect on Bcl-xL. These increases were associated with an increase in cortical histone-associated DNA fragments. Co-incubation of PCP with either NR1 or NR2A antisense significantly reduced PCP-induced apoptosis, while neither NR2B antisense ODN nor NR1 sense ODN used as a control had an effect. This effect was exactly correlated with the ability of the antisense ODNs to prevent PCP-induced upregulation of NR subunit proteins and the pro-apoptotic protein, Bax. That is, western analysis showed that antisense ODNs directed against either NR1 or NR2A prevented PCP-induced increases in Bax in addition to preventing the upregulation of the respective receptor proteins. On the other hand, the NR2B antisense ODN had no effect on either NR2B protein or on Bax. These data suggest that NR1 and NR2A antisense ODNs offer neuroprotection from apoptosis, and that upregulation of the NR1 and NR2A subunits following PCP administration is at least partly responsible for the observed apoptotic DNA fragmentation.