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.

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: 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: Many studies used the older ActiGraph (7164) for physical activity measurement, but this model has been replaced with newer ones (e.g., GT3X+). The assumption that new generation models are more accurate has been questioned, especially for measuring lower intensity levels. The low-frequency extension (LFE) increases the low-intensity sensitivity of newer models, but its comparability with older models is unknown. This study compared step counts and physical activity collected with the 7164 and GT3X + using the Normal Filter and the LFE (GT3X+N and GT3X+LFE, respectively).

Findings: Twenty-five adults wore 2 accelerometer models simultaneously for 3Âdays and were instructed to engage in typical behaviors. Average daily step counts and minutes per day in nonwear, sedentary, light, moderate, and vigorous activity were calculated. Repeated measures ANOVAs with post-hoc pairwise comparisons were used to compare mean values. Means for the GT3X+N and 7164 were significantly different in 4 of the 6 categories (p < .05). The GT3X+N showed 2041 fewer steps per day and more sedentary, less light, and less moderate than the 7164 (+25.6, -31.2, -2.9 mins/day, respectively). The GT3X+LFE showed non-significant differences in 5 of 6 categories but recorded significantly more steps (+3597 steps/day; p < .001) than the 7164.

Conclusion: Studies using the newer ActiGraphs should employ the LFE for greater sensitivity to lower intensity activity and more comparable activity results with studies using the older models. Newer generation ActiGraphs do not produce comparable step counts to the older generation devices with the Normal filter or the LFE.

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.

Background: Advancements in geographic information systems over the past two decades have increased the specificity by which an individual’s neighborhood environment may be spatially defined for physical activity and health research. This study investigated how different types of street network buffering methods compared in measuring a set of commonly used built environment measures (BEMs) and tested their performance on associations with physical activity outcomes.

Methods: An internationally-developed set of objective BEMs using three different spatial buffering techniques were used to evaluate the relative differences in resulting explanatory power on self-reported physical activity outcomes. BEMs were developed in five countries using ‘sausage,’ ‘detailed-trimmed,’ and ‘detailed,’ network buffers at a distance of 1 km around participant household addresses (n = 5883).

Results: BEM values were significantly different (p < 0.05) for 96% of sausage versus detailed-trimmed buffer comparisons and 89% of sausage versus detailed network buffer comparisons. Results showed that BEM coefficients in physical activity models did not differ significantly across buffering methods, and in most cases BEM associations with physical activity outcomes had the same level of statistical significance across buffer types. However, BEM coefficients differed in significance for 9% of the sausage versus detailed models, which may warrant further investigation.

Conclusions: Results of this study inform the selection of spatial buffering methods to estimate physical activity outcomes using an internationally consistent set of BEMs. Using three different network-based buffering methods, the findings indicate significant variation among BEM values, however associations with physical activity outcomes were similar across each buffering technique. The study advances knowledge by presenting consistently assessed relationships between three different network buffer types and utilitarian travel, sedentary behavior, and leisure-oriented physical activity outcomes.

Background: The World Health Organization recommends strategies to improve urban design, public transportation, and recreation facilities to facilitate physical activity for non-communicable disease prevention for an increasingly urbanized global population. Most evidence supporting environmental associations with physical activity comes from single countries or regions with limited variation in urban form. This paper documents variation in comparable built environment features across countries from diverse regions.

Methods: The International Physical Activity and the Environment Network (IPEN) study of adults aimed to measure the full range of variation in the built environment using geographic information systems (GIS) across 12 countries on 5 continents. Investigators in Australia, Belgium, Brazil, Colombia, the Czech Republic, Denmark, China, Mexico, New Zealand, Spain, the United Kingdom, and the United States followed a common research protocol to develop internationally comparable measures. Using detailed instructions, GIS-based measures included features such as walkability (i.e., residential density, street connectivity, mix of land uses), and access to public transit, parks, and private recreation facilities around each participant’s residential address using 1-km and 500-m street network buffers.

Results: Eleven of 12 countries and 15 cities had objective GIS data on built environment features. We observed a 38-fold difference in median residential densities, a 5-fold difference in median intersection densities and an 18-fold difference in median park densities. Hong Kong had the highest and North Shore, New Zealand had the lowest median walkability index values, representing a difference of 9 standard deviations in GIS-measured walkability.

Conclusions: Results show that comparable measures can be created across a range of cultural settings revealing profound global differences in urban form relevant to physical activity. These measures allow cities to be ranked more precisely than previously possible. The highly variable measures of urban form will be used to explain individuals’ physical activity, sedentary behaviors, body mass index, and other health outcomes on an international basis. Present measures provide the ability to estimate dose–response relationships from projected changes to the built environment that would otherwise be impossible.

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated thattype 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability toenhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.

Background: To more accurately quantify the potential impact of the neighbourhood environment on adults’ physical activity (PA), it is important to compare environment-PA associations between periods of the day or week when adults are more versus less likely to be in their neighbourhood and utilise its PA resources. We examined whether, among adults from 10 countries, associations between objectively-assessed neighbourhood environment attributes and moderate-to-vigorous physical activity (MVPA) varied by time of the day and day of the week. The secondary aim was to examine whether such associations varied by employment status, gender and city.

Methods: This cross-sectional study included 6,712 adults from 14 cities across 10 countries with ≥1 day of valid accelerometer-assessed MVPA and complete information on socio-demographic and objectively-assessed environmental characteristics within 0.5 and 1 km street-network buffers around the home. Accelerometer measures (MVPA min/h) were created for six time periods from early morning until late evening/night, for weekdays and weekend days separately. Associations were estimated using generalized additive mixed models.

Results: Time of the day, day of week, gender and employment status were significant moderators of environment-MVPA associations. Land use mix was positively associated with MVPA in women who were employed and in men irrespective of their employment status. The positive associations between MVPA and net residential density, intersection density and land use mix were stronger in the mornings of weekdays and the afternoon/evening periods of both weekdays and weekend days. Associations between number of parks and MVPA were stronger in the mornings and afternoon/evenings irrespective of day of the week. Public transport density showed consistent positive associations with MVPA during weekends, while stronger effects on weekdays were observed in the morning and early evenings.

Conclusions: This study suggests that space and time constraints in adults’ daily activities are important factors that determine the impact of neighbourhood attributes on PA. Consideration of time-specific associations is important to better characterise the magnitude of the effects of the neighbourhood environment on PA. Future research will need to examine the contribution of built environment characteristics of areas surrounding other types of daily life centres (e.g., workplaces) to explaining adults’ PA at specific times of the day.

Background: An evidence-based steps/day translation of U.S. federal guidelines for youth to engage in ≥60 minutes/day of moderate-to-vigorous physical activity (MVPA) would help health researchers, practitioners, and lay professionals charged with increasing youth’s physical activity (PA). The purpose of this study was to determine the number of free-living steps/day (both raw and adjusted to a pedometer scale) that correctly classified children (6–11 years) and adolescents (12–17 years) as meeting the 60-minute MVPA guideline using the 2005–2006 National Health and Nutrition Examination Survey (NHANES) accelerometer data, and to evaluate the 12,000 steps/day recommendation recently adopted by the President’s Challenge Physical Activity and Fitness Awards Program.

Methods: Analyses were conducted among children (n = 915) and adolescents (n = 1,302) in 2011 and 2012. Receiver Operating Characteristic (ROC) curve plots and classification statistics revealed candidate steps/day cut points that discriminated meeting/not meeting the MVPA threshold by age group, gender and different accelerometer activity cut points. The Evenson and two Freedson age-specific (3 and 4 METs) cut points were used to define minimum MVPA, and optimal steps/day were examined for raw steps and adjusted to a pedometer-scale to facilitate translation to lay populations.

Results: For boys and girls (6–11 years) with ≥ 60 minutes/day of MVPA, a range of 11,500–13,500 uncensored steps/day for children was the optimal range that balanced classification errors. For adolescent boys and girls (12–17) with ≥60 minutes/day of MVPA, 11,500–14,000 uncensored steps/day was optimal. Translation to a pedometer-scaling reduced these minimum values by 2,500 step/day to 9,000 steps/day. Area under the curve was ≥84% in all analyses.

Conclusions: No single study has definitively identified a precise and unyielding steps/day value for youth. Considering the other evidence to date, we propose a reasonable ‘rule of thumb’ value of ≥ 11,500 accelerometer-determined steps/day for both children and adolescents (and both genders), accepting that more is better. For practical applications, 9,000 steps/day appears to be a more pedometer-friendly value.