ASU Scholarship Showcase

Illicit psychostimulant addiction remains a significant problem worldwide, despite decades of research into the neural underpinnings and various treatment approaches. The purpose of this review is to provide a succinct overview of the neurocircuitry involved in drug addiction, as well as the acute and chronic effects of cocaine and amphetamines within this circuitry in humans. Investigational pharmacological treatments for illicit psychostimulant addiction are also reviewed. Our current knowledge base clearly demonstrates that illicit psychostimulants produce lasting adaptive neural and behavioral changes that contribute to the progression and maintenance of addiction. However, attempts at generating pharmacological treatments for psychostimulant addiction have historically focused on intervening at the level of the acute effects of these drugs. The lack of approved pharmacological treatments for psychostimulant addiction highlights the need for new treatment strategies, especially those that prevent or ameliorate the adaptive neural, cognitive, and behavioral changes caused by chronic use of this class of illicit drugs.

Attention deficit/hyperactivity disorder (ADHD) is a risk factor for tobacco use and dependence. This study examines the responsiveness to nicotine of an adolescent model of ADHD, the spontaneously hypertensive rat (SHR). The conditioned place preference (CPP) procedure was used to assess nicotine-induced locomotion and conditioned reward in SHR and the Wistar Kyoto (WKY) control strain over a range of nicotine doses (0.0, 0.1, 0.3 and 0.6 mg/kg). Prior to conditioning, SHRs were more active and less biased toward one side of the CPP chamber than WKY rats. Following conditioning, SHRs developed CPP to the highest dose of nicotine (0.6 mg/kg), whereas WKYs did not develop CPP to any nicotine dose tested. During conditioning, SHRs displayed greater locomotor activity in the nicotine-paired compartment than in the saline-paired compartment across conditioning trials. SHRs that received nicotine (0.1, 0.3, 0.6 mg/kg) in the nicotine-paired compartment showed an increase in locomotor activity between conditioning trials. Nicotine did not significantly affect WKY locomotor activity. These findings suggest that the SHR strain is a suitable model for studying ADHD-related nicotine use and dependence, but highlights potential limitations of the WKY control strain and the CPP procedure for modeling ADHD-related nicotine reward.

Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications.

Background: Increasing our understanding of the factors affecting the severity of the 2009 A/H1N1 influenza pandemic in different regions of the world could lead to improved clinical practice and mitigation strategies for future influenza pandemics. Even though a number of studies have shed light into the risk factors associated with severe outcomes of 2009 A/H1N1 influenza infections in different populations (e.g., [1-5]), analyses of the determinants of mortality risk spanning multiple pandemic waves and geographic regions are scarce. Between-country differences in the mortality burden of the 2009 pandemic could be linked to differences in influenza case management, underlying population health, or intrinsic differences in disease transmission [6]. Additional studies elucidating the determinants of disease severity globally are warranted to guide prevention efforts in future influenza pandemics.

In Mexico, the 2009 A/H1N1 influenza pandemic was characterized by a three-wave pattern occurring in the spring, summer, and fall of 2009 with substantial geographical heterogeneity [7]. A recent study suggests that Mexico experienced high excess mortality burden during the 2009 A/H1N1 influenza pandemic relative to other countries [6]. However, an assessment of potential factors that contributed to the relatively high pandemic death toll in Mexico are lacking. Here, we fill this gap by analyzing a large series of laboratory-confirmed A/H1N1 influenza cases, hospitalizations, and deaths monitored by the Mexican Social Security medical system during April 1 through December 31, 2009 in Mexico. In particular, we quantify the association between disease severity, hospital admission delays, and neuraminidase inhibitor use by demographic characteristics, pandemic wave, and geographic regions of Mexico.

Methods: We analyzed a large series of laboratory-confirmed pandemic A/H1N1 influenza cases from a prospective surveillance system maintained by the Mexican Social Security system, April-December 2009. We considered a spectrum of disease severity encompassing outpatient visits, hospitalizations, and deaths, and recorded demographic and geographic information on individual patients. We assessed the impact of neuraminidase inhibitor treatment and hospital admission delay (≤ > 2 days after disease onset) on the risk of death by multivariate logistic regression.

Results: Approximately 50% of all A/H1N1-positive patients received antiviral medication during the Spring and Summer 2009 pandemic waves in Mexico while only 9% of A/H1N1 cases received antiviral medications during the fall wave (P < 0.0001). After adjustment for age, gender, and geography, antiviral treatment significantly reduced the risk of death (OR = 0.52 (95% CI: 0.30, 0.90)) while longer hospital admission delays increased the risk of death by 2.8-fold (95% CI: 2.25, 3.41).

Conclusions: Our findings underscore the potential impact of decreasing admission delays and increasing antiviral use to mitigate the mortality burden of future influenza pandemics.

Domestic poultry serve as intermediates for transmission of influenza A virus from the wild aquatic bird reservoir to humans, resulting in influenza outbreaks in poultry and potential epidemics/pandemics among human beings. To combat emerging avian influenza virus, an inexpensive, heat-stable, and orally administered influenza vaccine would be useful to vaccinate large commercial poultry flocks and even migratory birds. Our hypothesized vaccine is a recombinant attenuated bacterial strain able to mediate production of attenuated influenza virus in vivo to induce protective immunity against influenza. Here we report the feasibility and technical limitations toward such an ideal vaccine based on our exploratory study. Five 8-unit plasmids carrying a chloramphenicol resistance gene or free of an antibiotic resistance marker were constructed. Influenza virus was successfully generated in avian cells transfected by each of the plasmids. The Salmonella carrier was engineered to allow stable maintenance and conditional release of the 8-unit plasmid into the avian cells for recovery of influenza virus. Influenza A virus up to 10⁷ 50% tissue culture infective doses (TCID₅₀)/ml were recovered from 11 out of 26 co-cultures of chicken embryonic fibroblasts (CEF) and Madin-Darby canine kidney (MDCK) cells upon infection by the recombinant Salmonella carrying the 8-unit plasmid. Our data prove that a bacterial carrier can mediate generation of influenza virus by delivering its DNA cargoes into permissive host cells. Although we have made progress in developing this Salmonella influenza virus vaccine delivery system, further improvements are necessary to achieve efficient virus production, especially in vivo.

Natural killer (NK) cells are a critical part of the innate immune defense against viral infections and for the control of tumors. Much less is known about how NK cells contribute to anti-bacterial immunity. NK cell-produced interferon gamma (IFN-γ) contributes to the control of early exponential replication of bacterial pathogens, however the regulation of these events remains poorly resolved. Using a mouse model of invasive Salmonellosis, here we report that the activation of the intracellular danger sensor NLRC4 by Salmonella-derived flagellin within CD11c⁺ cells regulates early IFN-γ secretion by NK cells through the provision of interleukin 18 (IL-18), independently of Toll-like receptor (TLR)-signaling. Although IL18-signalling deficient NK cells improved host protection during S. Typhimurium infection, this increased resistance was inferior to that provided by wild-type NK cells. These findings suggest that although NLRC4 inflammasome-driven secretion of IL18 serves as a potent activator of NK cell mediated IFN-γ secretion, IL18-independent NK cell-mediated mechanisms of IFN-γ secretion contribute to in vivo control of Salmonella replication.

The 1918 influenza pandemic was a major epidemiological event of the twentieth century resulting in at least twenty million deaths worldwide; however, despite its historical, epidemiological, and biological relevance, it remains poorly understood. Here we examine the relationship between annual pneumonia and influenza death rates in the pre-pandemic (1910–17) and pandemic (1918–20) periods and the scaling of mortality with latitude, longitude and population size, using data from 66 large cities of the United States. The mean pre-pandemic pneumonia death rates were highly associated with pneumonia death rates during the pandemic period (Spearman ρ = 0.64–0.72; P<0.001). By contrast, there was a weak correlation between pre-pandemic and pandemic influenza mortality rates. Pneumonia mortality rates partially explained influenza mortality rates in 1918 (ρ = 0.34, P = 0.005) but not during any other year. Pneumonia death counts followed a linear relationship with population size in all study years, suggesting that pneumonia death rates were homogeneous across the range of population sizes studied. By contrast, influenza death counts followed a power law relationship with a scaling exponent of ∼0.81 (95%CI: 0.71, 0.91) in 1918, suggesting that smaller cities experienced worst outcomes during the pandemic. A linear relationship was observed for all other years. Our study suggests that mortality associated with the 1918–20 influenza pandemic was in part predetermined by pre-pandemic pneumonia death rates in 66 large US cities, perhaps through the impact of the physical and social structure of each city. Smaller cities suffered a disproportionately high per capita influenza mortality burden than larger ones in 1918, while city size did not affect pneumonia mortality rates in the pre-pandemic and pandemic periods.

Background: The historical Japanese influenza vaccination program targeted at schoolchildren provides a unique opportunity to evaluate the indirect benefits of vaccinating high-transmitter groups to mitigate disease burden among seniors. Here we characterize the indirect mortality benefits of vaccinating schoolchildren based on data from Japan and the US.

Methods: We compared age-specific influenza-related excess mortality rates in Japanese seniors aged ≥65 years during the schoolchildren vaccination program (1978–1994) and after the program was discontinued (1995–2006). Indirect vaccine benefits were adjusted for demographic changes, socioeconomics and dominant influenza subtype; US mortality data were used as a control.

Results: We estimate that the schoolchildren vaccination program conferred a 36% adjusted mortality reduction among Japanese seniors (95%CI: 17–51%), corresponding to ∼1,000 senior deaths averted by vaccination annually (95%CI: 400–1,800). In contrast, influenza-related mortality did not change among US seniors, despite increasing vaccine coverage in this population.

Conclusions: The Japanese schoolchildren vaccination program was associated with substantial indirect mortality benefits in seniors.

The low pH of the stomach serves as a barrier to ingested microbes and must be overcome or bypassed when delivering live bacteria for vaccine or probiotic applications. Typically, the impact of stomach acidity on bacterial survival is evaluated in vitro, as there are no small animal models to evaluate these effects in vivo. To better understand the effect of this low pH barrier to live attenuated Salmonella vaccines, which are often very sensitive to low pH, we investigated the value of the histamine mouse model for this application. A low pH gastric compartment was transiently induced in mice by the injection of histamine. This resulted in a gastric compartment of approximately pH 1.5 that was capable of distinguishing between acid-sensitive and acid-resistant microbes. Survival of enteric microbes during gastric transit in this model directly correlated with their in vitro acid resistance. Because many Salmonella enterica serotype Typhi vaccine strains are sensitive to acid, we have been investigating systems to enhance the acid resistance of these bacteria. Using the histamine mouse model, we demonstrate that the in vivo survival of S. Typhi vaccine strains increased approximately 10-fold when they carried a sugar-inducible arginine decarboxylase system. We conclude that this model will be a useful for evaluating live bacterial preparations prior to clinical trials.

Leucine-responsive regulatory protein (Lrp) is known to be an indirect activator of type 1 fimbriae synthesis in Salmonella enterica serovar Typhimurium via direct regulation of FimZ, a direct positive regulator for type 1 fimbriae production. Using RT-PCR, we have shown previously that fimA transcription is dramatically impaired in both lrp-deletion (Δlrp) and constitutive-lrp expression (lrp^C) mutant strains. In this work, we used chromosomal P_fimA-lacZ fusions and yeast agglutination assays to confirm and extend our previous results. Direct binding of Lrp to P_fimA was shown by an electrophoretic mobility shift assay (EMSA) and DNA footprinting assay. Site-directed mutagenesis revealed that the Lrp-binding motifs in P_fimA play a role in both activation and repression of type 1 fimbriae production. Overproduction of Lrp also abrogates fimZ expression. EMSA data showed that Lrp and FimZ proteins independently bind to P_fimA without competitive exclusion. In addition, both Lrp and FimZ binding to P_fimA caused a hyper retardation (supershift) of the DNA-protein complex compared to the shift when each protein was present alone. Nutrition-dependent cellular Lrp levels closely correlated with the amount of type 1 fimbriae production. These observations suggest that Lrp plays important roles in type 1 fimbriation by acting as both a positive and negative regulator and its effect depends, at least in part, on the cellular concentration of Lrp in response to the nutritional environment.