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.

Although insulin resistance in skeletal muscle is well-characterized, the role of circulating whole blood in the metabolic syndrome phenotype is not well understood. We set out to test the hypothesis that genes involved in inflammation, insulin signaling and mitochondrial function would be altered in expression in the whole blood of individuals with metabolic syndrome. We further wanted to examine whether similar relationships that we have found previously in skeletal muscle exist in peripheral whole blood cells. All subjects (n=184) were Latino descent from the Arizona Insulin Resistance registry. Subjects were classified based on the metabolic syndrome phenotype according to the National Cholesterol Education Program’s Adult Treatment Panel III. Of the 184 Latino subjects in the study, 74 were classified with the metabolic syndrome and 110 were without. Whole blood gene expression profiling was performed using the Agilent 4x44K Whole Human Genome Microarray. Whole blood microarray analysis identified 1,432 probes that were altered in expression ≥1.2 fold and P<0.05 after Benjamini-Hochberg in the metabolic syndrome subjects. KEGG pathway analysis revealed significant enrichment for pathways including ribosome, oxidative phosphorylation and MAPK signaling (all Benjamini-Hochberg P<0.05). Whole blood mRNA expression changes observed in the microarray data were confirmed by quantitative RT-PCR. Transcription factor binding motif enrichment analysis revealed E2F1, ELK1, NF-kappaB, STAT1 and STAT3 significantly enriched after Bonferroni correction (all P<0.05). The results of the present study demonstrate that whole blood is a useful tissue for studying the metabolic syndrome and its underlying insulin resistance although the relationship between blood and skeletal muscle differs.

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.

In spite of well-documented health benefits of vegetarian diets, less is known regarding the effects of these diets on athletic performance. In this cross-sectional study, we compared elite vegetarian and omnivore adult endurance athletes for maximal oxygen uptake (VO2 max) and strength. Twenty-seven vegetarian (VEG) and 43 omnivore (OMN) athletes were evaluated using VO2 max testing on the treadmill, and strength assessment using a dynamometer to determine peak torque for leg extensions. Dietary data were assessed using detailed seven-day food logs. Although total protein intake was lower among vegetarians in comparison to omnivores, protein intake as a function of body mass did not differ by group (1.2 ± 0.3 and 1.4 ± 0.5 g/kg body mass for VEG and OMN respectively, p = 0.220). VO2 max differed for females by diet group (53.0 ± 6.9 and 47.1 ± 8.6 mL/kg/min for VEG and OMN respectively, p < 0.05) but not for males (62.6 ± 15.4 and 55.7 ± 8.4 mL/kg/min respectively). Peak torque did not differ significantly between diet groups. Results from this study indicate that vegetarian endurance athletes’ cardiorespiratory fitness was greater than that for their omnivorous counterparts, but that peak torque did not differ between diet groups. These data suggest that vegetarian diets do not compromise performance outcomes and may facilitate aerobic capacity in athletes.

Background: Use of synthetic cathinones, which are designer stimulants found in “bath salts,” has increased dramatically in recent years. Following governmental bans of methylenedioxypyrovalerone, mephedrone, and methylone, a second generation of synthetic cathinones with unknown abuse liability has emerged as replacements.

Methods: Using a discrete trials current intensity threshold intracranial self-stimulation procedure, the present study assessed the effects of 2 common second-generation synthetic cathinones, α‐pyrrolidinopentiophenone (0.1–5mg/kg) and 4-methyl-N-ethcathinone (1–100mg/kg) on brain reward function. Methamphetamine (0.1–3mg/kg) was also tested for comparison purposes.

Results: Results revealed both α‐pyrrolidinopentiophenone and 4-methyl-N-ethcathinone produced significant intracranial self-stimulation threshold reductions similar to that of methamphetamine. α‐Pyrrolidinopentiophenone (1mg/kg) produced a significant maximal reduction in intracranial self-stimulation thresholds (~19%) most similar to maximal reductions produced by methamphetamine (1mg/kg, ~20%). Maximal reductions in intracranial self-stimulation thresholds produced by 4-methyl-N-ethcathinone were observed at 30mg/kg (~15%) and were comparable with those observed with methamphetamine and α‐pyrrolidinopentiophenone tested at the 0.3-mg/kg dose (~14%). Additional analysis of the ED50 values from log-transformed data revealed the rank order potency of these drugs as methamphetamine ≈ α‐pyrrolidinopentiophenone>4-methyl-N-ethcathinone.

Conclusions: These data suggest that the newer second-generation synthetic cathinones activate the brain reward circuitry and thus may possess a similar degree of abuse potential as prototypical illicit psychostimulants such as methamphetamine as well as the first generation synthetic cathinone methylenedioxypyrovalerone, as previously reported.

Background: Peanut consumption favorably influences satiety. This study examined the acute effect of peanut versus grain bar preloads on postmeal satiety and glycemia in healthy adults and the long-term effect of these meal preloads on body mass in healthy overweight adults.

Methods: In the acute crossover trial (n = 15; 28.4 ± 2.9 y; 23.1 ± 0.9 kg/m²), the preload (isoenergetic peanut or grain bar with water, or water alone) was followed after 60 min with ingestion of a standardized glycemic test meal. Satiety and blood glucose were assessed immediately prior to the preload and to the test meal, and for two hours postmeal at 30-min intervals. In the parallel-arm, randomized trial (n = 44; 40.5 ± 1.6 y, 31.8 ± 0.9 kg/m²), the peanut or grain bar preload was consumed one hour prior to the evening meal for eight weeks. Body mass was measured at 2-week intervals, and secondary endpoints included blood hemoglobin A1c and energy intake as assessed by 3-d diet records collected at pre-trial and trial weeks 1 and 8.

Results: Satiety was elevated in the postprandial period following grain bar ingestion in comparison to peanut or water ingestion (p = 0.001, repeated-measures ANOVA). Blood glucose was elevated one hour after ingestion of the grain bar as compared to the peanut or water treatments; yet, total glycemia did not vary between treatments in the two hour postprandial period. In the 8-week trial, body mass was reduced for the grain bar versus peanut groups after eight weeks (−1.3 ± 0.4 kg versus −0.2 ± 0.3 kg, p = 0.033, analysis of covariance). Energy intake was reduced by 458 kcal/d in the first week of the trial for the grain bar group as compared to the peanut group (p = 0.118). Hemoglobin A1c changed significantly between groups during the trial (−0.25 ± 0.07% and −0.18 ± 0.12% for the grain bar and peanut groups respectively, p = 0.001).

Conclusions: Compared to an isoenergetic peanut preload, consumption of a grain bar preload one hour prior to a standardized meal significantly raised postmeal satiety. Moreover, consumption of the grain bar prior to the evening meal was associated with significant weight loss over time suggesting that glycemic carbohydrate ingestion prior to meals may be a weight management strategy.

Background: Height is an important health assessment measure with many applications. In the medical practice and in research settings, height is typically measured with a stadiometer. Although lasers are commonly used by health professionals for measurement including facial imaging, corneal thickness, and limb length, it has not been utilized for measuring height. The purpose of this feasibility study was to examine the ease and accuracy of a laser device for measuring height in children and adults.

Findings: In immediate succession, participant height was measured in triplicate using a stadiometer followed by the laser device. Measurement error for the laser device was significantly higher than that for the stadiometer (0.35 and 0.20 cm respectively). However, the measurement techniques were highly correlated (r² = 0.998 and 0.990 for the younger [<12 y, n = 25] and older [≥12 y, n = 100] participants respectively), and the estimated reliability between measurement techniques was 0.999 (ICC; 95 % CI: 0.998,1.000) and 0.995 (ICC; 95 % CI: 0.993,0.997) for the younger and older groups respectively. The average differences between the two styles of measurement (e.g., stadiometer minus laser) were significantly different from zero: +0.93 and +0.45 cm for the younger and older groups respectively.

Conclusions: These data demonstrate that laser technology can be adapted to measure height in children and adults. Although refinement is needed, the laser device for measuring height merits further development.

Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10^-4) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10^-60) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10[superscript -9]), BMI (5.4 x 10^-6), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.

The group I metabotropic glutamate receptors (mGluR1a and mGluR5) are important modulators of neuronal structure and function. Although these receptors share common signaling pathways, they are capable of having distinct effects on cellular plasticity. We investigated the individual effects of mGluR1a or mGluR5 activation on dendritic spine density in medium spiny neurons in the nucleus accumbens (NAc), which has become relevant with the potential use of group I mGluR based therapeutics in the treatment of drug addiction. We found that systemic administration of mGluR subtype-specific positive allosteric modulators had opposite effects on dendritic spine densities. Specifically, mGluR5 positive modulation decreased dendritic spine densities in the NAc shell and core, but was without effect in the dorsal striatum, whereas increased spine densities in the NAc were observed with mGluR1a positive modulation. Additionally, direct activation of mGluR5 via CHPG administration into the NAc also decreased the density of dendritic spines. These data provide insight on the ability of group I mGluRs to induce structural plasticity in the NAc and demonstrate that the group I mGluRs are capable of producing not just distinct, but opposing, effects on dendritic spine density.