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.

Stone-tipped weapons were a significant innovation for Middle Pleistocene hominins. Hafted hunting technology represents the development of new cognitive and social learning mechanisms within the genus Homo, and may have provided a foraging advantage over simpler forms of hunting technology, such as a sharpened wooden spear. However, the nature of this foraging advantage has not been confirmed. Experimental studies and ethnographic reports provide conflicting results regarding the relative importance of the functional, economic, and social roles of hafted hunting technology. The controlled experiment reported here was designed to test the functional hypothesis for stone-tipped weapons using spears and ballistics gelatin. It differs from previous investigations of this type because it includes a quantitative analysis of wound track profiles and focuses specifically on hand-delivered spear technology. Our results do not support the hypothesis that tipped spears penetrate deeper than untipped spears. However, tipped spears create a significantly larger inner wound cavity that widens distally. This inner wound cavity is analogous to the permanent wound cavity in ballistics research, which is considered the key variable affecting the relative ‘stopping power’ or ‘killing power’ of a penetrating weapon. Tipped spears conferred a functional advantage to Middle Pleistocene hominins, potentially affecting the frequency and regularity of hunting success with important implications for human adaptation and life history.

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.

Background:
Ketogenic diets are high fat and low carbohydrate or very low carbohydrate diets, which render high production of ketones upon consumption known as nutritional ketosis (NK). Ketosis is also produced during fasting periods, which is known as fasting ketosis (FK). Recently, the combinations of NK and FK, as well as NK alone, have been used as resources for weight loss management and treatment of epilepsy.

Methods:
A crossover study design was applied to 11 healthy individuals, who maintained moderately sedentary lifestyle, and consumed three types of diet randomly assigned over a three-week period. All participants completed the diets in a randomized and counterbalanced fashion. Each weekly diet protocol included three phases: Phase 1 - A mixed diet with ratio of fat: (carbohydrate + protein) by mass of 0.18 or the equivalence of 29% energy from fat from Day 1 to Day 5. Phase 2- A mixed or a high-fat diet with ratio of fat: (carbohydrate + protein) by mass of approximately 0.18, 1.63, or 3.80 on Day 6 or the equivalence of 29%, 79%, or 90% energy from fat, respectively. Phase 3 - A fasting diet with no calorie intake on Day 7. Caloric intake from diets on Day 1 to Day 6 was equal to each individual’s energy expenditure. On Day 7, ketone buildup from FK was measured.

Results:
A statistically significant effect of Phase 2 (Day 6) diet was found on FK of Day 7, as indicated by repeated analysis of variance (ANOVA), F(2,20) = 6.73, p < 0.0058. Using a Fisher LDS pair-wise comparison, higher significant levels of acetone buildup were found for diets with 79% fat content and 90% fat content vs. 29% fat content (with p = 0.00159**, and 0.04435**, respectively), with no significant difference between diets with 79% fat content and 90% fat content. In addition, independent of the diet, a significantly higher ketone buildup capability of subjects with higher resting energy expenditure (R[superscript 2] = 0.92), and lower body mass index (R[superscript 2] = 0.71) was observed during FK.

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.

The Middle Stone Age (MSA) is associated with early evidence for symbolic material culture and complex technological innovations. However, one of the most visible aspects of MSA technologies are unretouched triangular stone points that appear in the archaeological record as early as 500,000 years ago in Africa and persist throughout the MSA. How these tools were being used and discarded across a changing Pleistocene landscape can provide insight into how MSA populations prioritized technological and foraging decisions. Creating inferential links between experimental and archaeological tool use helps to establish prehistoric tool function, but is complicated by the overlaying of post-depositional damage onto behaviorally worn tools. Taphonomic damage patterning can provide insight into site formation history, but may preclude behavioral interpretations of tool function. Here, multiple experimental processes that form edge damage on unretouched lithic points from taphonomic and behavioral processes are presented. These provide experimental distributions of wear on tool edges from known processes that are then quantitatively compared to the archaeological patterning of stone point edge damage from three MSA lithic assemblages—Kathu Pan 1, Pinnacle Point Cave 13B, and Die Kelders Cave 1. By using a model-fitting approach, the results presented here provide evidence for variable MSA behavioral strategies of stone point utilization on the landscape consistent with armature tips at KP1, and cutting tools at PP13B and DK1, as well as damage contributions from post-depositional sources across assemblages. This study provides a method with which landscape-scale questions of early modern human tool-use and site-use can be addressed.

We formulate an in silico model of pathogen avoidance mechanism and investigate its impact on defensive behavioural measures (e.g., spontaneous social exclusions and distancing, crowd avoidance and voluntary vaccination adaptation). In particular, we use SIR(B)S (e.g., susceptible-infected-recovered with additional behavioural component) model to investigate the impact of homo-psychologicus aspects of epidemics. We focus on reactionary behavioural changes, which apply to both social distancing and voluntary vaccination participations. Our analyses reveal complex relationships between spontaneous and uncoordinated behavioural changes, the emergence of its contagion properties, and mitigation of infectious diseases. We find that the presence of effective behavioural changes can impede the persistence of disease. Furthermore, it was found that under perfect effective behavioural change, there are three regions in the response factor (e.g., imitation and/or reactionary) and behavioural scale factor (e.g., global/local) factors ρ–α behavioural space. Mainly, (1) disease is always endemic even in the presence of behavioural change, (2) behavioural-prevalence plasticity is observed and disease can sometimes be eradication, and (3) elimination of endemic disease under permanence of permanent behavioural change is achieved. These results suggest that preventive behavioural changes (e.g., non-pharmaceutical prophylactic measures, social distancing and exclusion, crowd avoidance) are influenced by individual differences in perception of risks and are a salient feature of epidemics. Additionally, these findings indicates that care needs to be taken when considering the effect of adaptive behavioural change in predicting the course of epidemics, and as well as the interpretation and development of the public health measures that account for spontaneous behavioural changes.

Many drugs are effective in the early stage of treatment, but patients develop drug resistance after a certain period of treatment, causing failure of the therapy. An important example is Herceptin, a popular monoclonal antibody drug for breast cancer by specifically targeting human epidermal growth factor receptor 2 (Her2). Here we demonstrate a quantitative binding kinetics analysis of drug-target interactions to investigate the molecular scale origin of drug resistance. Using a surface plasmon resonance imaging, we measured the in situ Herceptin-Her2 binding kinetics in single intact cancer cells for the first time, and observed significantly weakened Herceptin-Her2 interactions in Herceptin-resistant cells, compared to those in Herceptin-sensitive cells. We further showed that the steric hindrance of Mucin-4, a membrane protein, was responsible for the altered drug-receptor binding. This effect of a third molecule on drug-receptor interactions cannot be studied using traditional purified protein methods, demonstrating the importance of the present intact cell-based binding kinetics analysis.

Neuropharmacological effects of psychedelics have profound cognitive, emotional, and social effects that inspired the development of cultures and religions worldwide. Findings that psychedelics objectively and reliably produce mystical experiences press the question of the neuropharmacological mechanisms by which these highly significant experiences are produced by exogenous neurotransmitter analogs. Humans have a long evolutionary relationship with psychedelics, a consequence of psychedelics' selective effects for human cognitive abilities, exemplified in the information rich visionary experiences. Objective evidence that psychedelics produce classic mystical experiences, coupled with the finding that hallucinatory experiences can be induced by many non-drug mechanisms, illustrates the need for a common model of visionary effects. Several models implicate disturbances of normal regulatory processes in the brain as the underlying mechanisms responsible for the similarities of visionary experiences produced by psychedelic and other methods for altering consciousness. Similarities in psychedelic-induced visionary experiences and those produced by practices such as meditation and hypnosis and pathological conditions such as epilepsy indicate the need for a general model explaining visionary experiences. Common mechanisms underlying diverse alterations of consciousness involve the disruption of normal functions of the prefrontal cortex and default mode network (DMN). This interruption of ordinary control mechanisms allows for the release of thalamic and other lower brain discharges that stimulate a visual information representation system and release the effects of innate cognitive functions and operators. Converging forms of evidence support the hypothesis that the source of psychedelic experiences involves the emergence of these innate cognitive processes of lower brain systems, with visionary experiences resulting from the activation of innate processes based in the mirror neuron system (MNS).