Pharmacology, Toxicology and Environmental Health Commons^™

The Biobehavioral Effects Of Embryonic Exposure To Neural Inflammation And Oxidative Stress In Zebrafish, Dalton J. Anderson

Honors College Theses

The purpose of this research is to improve understanding of the neurodevelopmental effects of embryonic exposure to elevated inflammation and oxidative stress induced by the antipyretic drug acetaminophen (APAP). Our study was the first to examine the interactive effects of APAP and inflammation in zebrafish embryos and how the treatments affect brain development and larval behavior. Experimental groups of zebrafish larvae were exposed to lipopolysaccharide (LPS) to induce inflammation, APAP, or LPS + APAP and larval behavior was analyzed using Ethovision automated behavioral tracking software. We also measured changes in whole-brain Glycogen Synthase Kinase 3 Beta (GSK3B) and GSK3B phosphorylation, …

Using A Toxic Aging Coin To Assess Hexavalent Chromium-Induced Neurotoxicity., Samuel Thomas Vielee

Electronic Theses and Dissertations

We are facing an aging crisis, with 20% of the U.S. population projected to be geriatric (65+) by 2030 and live another 40+ years. Age-related diseases accompany a growing geriatric population, emphasizing the need to understand their etiology. Environmental pollutants compound this crisis by: 1) geriatrics are more susceptible, exacerbating age-related diseases and comorbidities, and 2) they accelerate biological aging, inducing age-related diseases at younger ages. We address this crisis using a ‘toxic aging coin’ approach; heads examines how age impacts toxicity, tails examines how chemicals accelerate aging. This thesis applies the heads side for Cr(VI)-induced neurotoxicity across ages. We …

Neuroinflammatory And Metabolomic Temporal Dynamics From Inhaled Wildfire Smoke With Attenuation Via Pharmacological Intervention, David Scieszka, David Scieszka

Biomedical Sciences ETDs

Wildfire smoke is a global issue affecting nearly all humans on the surface of this Earth. Smoke dispersion from wildfires can span continents and cross oceans with amazing ease. Furthermore, total acres of land burned per year in the United States has roughly doubled since 1980, meaning this issue will persist for an indeterminate amount of time. Exposure to wildfire smoke is hazardous and promotes aging-associated events in the cardiopulmonary systems. Yet long- and short-term effects on the brain remain relatively unknown. From these, it is critically important to understand the neurological impacts from wildfire smoke exposure; to compare these …

Vapourized Cannabis Extract Administration Impairs Memory And Alters Neural Activity In Laboratory Rats, Megan Chladny

Theses and Dissertations (Comprehensive)

Although people have smoked cannabis for millennia, administration of cannabis by heating the dried plant material or distilled extracts to a temperature just below the combustion point (i.e., vapourization or "vaping") has rapidly increased over the past few years (Javadi-Payder, Cole, and Taffe, 2018; Manwell, Charchoglyan, Brewer, Matthews, Heipel, and Mallet, 2014). Conversely, most of the cannabinoid research using rodent models has used parenteral routes of administration to examine the effects of purified cannabis extracts such as ∆⁹-tetrahydrocannabinol (THC), making it difficult to directly compare laboratory research to human drug use. Building on previous studies showing that THC …

A Polypharmacological Approach To Relapse Prevention In An Animal Model Of Heroin Addiction, Scott T. Ewing

Dissertations, Theses, and Capstone Projects

Chemical compounds that target dopamine (DA) D1 or D3 receptors have shown promise as potential interventions in animal models of cue-induced relapse. However, undesirable side effects or pharmacodynamic profiles have limited the advancement of new compounds in preclinical studies when administered as independent treatments. In this series of experiments, we explored the effects of co-administration of a D1-recepter partial agonist (SKF 77434) and a D3-receptor antagonist (NGB 2904) in heroin-seeking rats within a ‘conflict’ model of abstinence and cue-induced relapse. Rats were first trained to press a lever to self-administer heroin and drug delivery was paired contingently with cues (e.g., …

Sex-Specific Effects Of Chaperone And Glial Defenses On Experimental Lewy Body Disease, Tarun Bhatia

Electronic Theses and Dissertations

Lewy body disorders are a group of neurodegenerative conditions characterized by the pathological misfolding and aggregation of the abundant protein, α-synuclein. The most common Lewy body disorders are Parkinson’s disease and dementia with Lewy bodies. Apart from ageing, male sex is a major risk factor for Lewy body disorders, as men are at ~1.5-fold higher risk for these diseases than women. Yet, preclinical studies on Lewy body disorders rarely examine sex as a biological variable, and the mechanisms underlying sex-skewedness in disease risk remain undetermined.

Here, we developed a sex-stratified model of Lewy body disorders by exposing primary neurons harvested …

Behavioral Effects And Neurobiological Mechanisms Of 3-Aminobenzimide In A Rodent Model Of Chronic Psychological Stress, Liza Wills

Electronic Theses and Dissertations

Major depressive disorder (MDD) is a leading cause of disability worldwide, with a lifetime prevalence rate of approximately 20%. Inadequate pharmacological treatment methods for MDD are a significant debilitating factor. Patient estimates suggest that the treatment resistance rate for pharmacological interventions is over 30%. Postmortem analyses of human tissue of individuals diagnosed with MDD have shown an increase in Poly (ADP-ribose) polymerase 1 (PARP-1) mRNA gene expression in prefrontal cortical white matter when compared to psychiatrically normal brain tissue. In order to further investigate this issue, the present study used the social defeat stress/chronic unpredictable stress (SDS + CUS) rodent …

Early Detection Of Atypical Motor And Neurobehavior Of Infants At Risk Secondary To Opioid Exposure: A Prospective Study, Kara Boynewicz

Electronic Theses and Dissertations

Prenatal opioid exposure has been studied in relation to infants' medical outcomes. However, large gaps exist in the literature supporting early identification of atypical neurobehavior and motor development of infants with prenatal opioid exposure. The purpose of the study was to investigate whether prenatal opioid exposure has a negative influence on a newborn infant’s neurobehavior and motor development to aid in the early identification of potential delays. Using a prospective quasi experimental design, infants motor development using the Test of Infant Motor Performance (TIMP) and neurobehavior using the NICU Neonatal Network Scale (NNNS) was assessed on 58 infants in a …

Psychedelics Can Save: The Scientific And Social Case For Rescheduling Psychedelic Compounds, Galen M. Fader

Chancellor’s Honors Program Projects

No abstract provided.

Investigating Cannabinoid Type-1 Receptor (Cb1r) Positive Allosteric Modulators (Pams) In Mouse Models Of Overt Cannabimimetic Activity, Subjective Drug Effects, And Neuropathic Pain, Jayden Elmer

Theses and Dissertations

Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model …

Hiv-1 Tat Interactions With Opioids Are Modulated By Progesterone And Estradiol, Dejun Jackson

Honors Theses

HIV infection and combined substance abuse are comorbid epidemics. Previous studies show that concurrent opioid drug use may potentiate HIV-1-mediated neurotoxicity partly via interactions with opioids. Preclinical studies suggest that the HIV-1 trans-activator of transcription (Tat), an HIV regulatory protein, can synergize with opioids to exacerbate its already neurotoxic effects. However, its interactions with clinical opioids, such as oxycodone, have yet to be elucidated. Additionally, Tat disrupts a number of systems including the dopaminergic system, which contribute to its capacity to potentiate the rewarding effects of abused drugs. Although the neurotoxic effects of Tat may be inhibited by gonadal steroids …

Activation Of The Sonic Hedgehog Effector Smoothened Counteracts L-Dopa Induced Dyskinesia By Restoring Cholinergic Interneuron Function, Lauren Malave

Dissertations, Theses, and Capstone Projects

Many types of neurons act as multimodal signaling centers. Yet, we have only limited insight into the regulation and functional consequences of neuronal co-transmission. For example, dopamine (DA) neurons, whose degeneration causes motor deficits characteristic of Parkinson’s Diseases (PD), communicate with all their targets by DA but only a selective subset of their targets using GABA, Glutamate, and the secreted cell signaling protein Sonic Hedgehog (Shh). It is unknown whether Levo-dopamine (L-Dopa) induced dyskinesia (LIDs), a severely debilitating side effect of DA supplementation in PD, might appear because DA neuron targets are exposed to high DA- but low Shh- signaling …

Molecular Targets Of Psychedelics And Their Role In Behavioral Models Of Hallucinogenic Action, Hiba Z. Vohra

Theses and Dissertations

Psychedelics are a subset of hallucinogenic drugs that exert their characteristic effects through agonist activity at the serotonin receptor 2A (5-HT_2A). In this study, I aimed to characterize the modulatory role of the metabotropic glutamate subtype 2 receptor (mGluR2) in the 5-HT_2A-specific rodent model of hallucinogenic action, head-twitch response (HTR). Secondly, I aimed to explore if 5-HT_2A agonist-induced deficits in prepulse inhibition (PPI) of the startle response, an additional model of hallucinogenic action, could be produced in mice. Though 5-HT_2A agonist-induced PPI deficits, which represent interruptions in normal sensorimotor gating, have been described in …

Exploring The Role Of Insulin Receptor Signaling In Hippocampal Learning And Memory, Neuronal Calcium Dysregulation, And Glucose Metabolism, Hilaree N. Frazier

Theses and Dissertations--Pharmacology and Nutritional Sciences

In the late 90’s, emerging evidence revealed that the brain is insulin-sensitive, highlighted by broad expression of brain-specific insulin receptors and reports of circulating brain insulin. Contemporary literature robustly supports the role of insulin signaling in normal brain function and suggests that insulin-related processes diminish with aging, evidenced by decreased signaling markers, reduced insulin receptor density, and lower levels of insulin transport across the blood-brain barrier. In the context of pathological cognitive decline, clinical trials using intranasal insulin delivery have reported positive outcomes on memory and learning in patients with mild cognitive decline or early-stage Alzheimer’s disease. However, while the …

Effort-Related Motivational Dysfunctions: Behavioral And Neurochemical Studies Of The Wistar-Kyoto Rat Model Of Depression, Brendan Abbott

Masters Theses

Depression and related disorders are characterized by motivational dysfunctions, including deficits in behavioral activation and exertion of effort. Animal models of relevance to depression represent a critical starting point in elucidating the neurobiological mechanisms underlying motivational dysfunctions. The present study explored the use of the Wistar-Kyoto (WKY) animal model of depression to examine effort-related functions as measured by voluntary wheel running and performance on a mixed fixed ratio 5/progressive ratio (FR5/PR) operant task. Given the known link between activational aspects of motivation and the mesocorticolimbic dopamine (DA) system, the behavioral effects of d-amphetamine (0.5 and 1.0 mg/kg, IP), a psychostimulant …

Defining The Radioresponse Of Mossy Cells, Devon Ivy

Electronic Theses, Projects, and Dissertations

Clinical radiotherapy is used to treat a variety of brain tumors within the central nervous system. While effective, it can result in progressive and debilitating cognitive impairment that can diminish quality of life. These impairments have been linked to hippocampal dysfunction and corresponding deficits in spatial learning and memory. Mossy cells are a major population of excitatory neurons located within the dentate hilus and highly involved in hippocampal circuitry. They play critical roles in spatial navigation, neurogenesis, memory, and are particularly vulnerable to a variety of neurotoxic insults. However, their sensitivity to ionizing radiation has yet to be investigated in …

Complexities Of Chronic Opioid Exposure, Maciej Gonek

Theses and Dissertations

Studies on repeated exposure to opioids have been carried out for decades yet the mechanisms for certain phenomena such as tolerance are still not fully understood. Furthermore, different medications, such as frequently prescribed benzodiazepines, or different disease states, such as HIV, have their own effects and interactions with chronic opioid exposure that are not fully understood. The overall objective of this dissertation was to investigate the complexities of chronic opioid exposure and how different disease states and medications may modulate the effects of chronic opioids. Our findings demonstrate that the administration of diazepam, at doses that are not antinociceptive or …

Potential Candidates For Treating Deficits Associated With Developmental Ethanol Exposure In A Rodent Model: Solidago Nemoralis & Dimethoxybenzylidene-Anabasine, Logan James Fields

Theses and Dissertations--Psychology

Prenatal alcohol exposure (Fetal Alcohol Syndrome [FAS] and Fetal Alcohol Spectrum Disorders [FASD’s]) represents the leading preventable cause of intellectual disabilities in the western world, with FASDs estimated to affect approximately 2-5% of live births in the United States at an approximate annual cost of $3.6 billion (CDC, 2015; May et al., 2009). Ethanol (ETOH) exposure during development can lead to a variety of long-term behavioral impairments including problems with executive functioning, motor coordination, spatial learning, attention, and hyperactivity (Jones, 2011; Mattson & Riley, 1998). Much research has been conducted to develop pharmacological and/or environmental interventions to reduce these deficits, …

Insulin Modulates The Strong Reinforcing Effects Of Nicotine And Changes In Insulin Biomarkers In A Rodent Model Of Diabetes, Bryan Cruz

Open Access Theses & Dissertations

This study examined whether the strong reinforcing effects of nicotine and changes in insulin biomarkers observed in diabetic rats are modulated via insulin. A model of diabetes was employed involving administration of streptozotocin (STZ), which produces hypoinsulinemia in rats. The present study included vehicle- or STZ-treated rats that received sham surgery or an insulin pellet. Two-weeks later, the rats were given extended access to intravenous self-administration (IVSA) of saline or nicotine. Concomitant changes in food intake, water responses, and body weight were assessed during 12 days of IVSA. After the last session, plasma levels of insulin, leptin, amylin, and glucagon-like …

Test Of Bpa's Estrogenic Effects On Brain Aromatase Expression, Neural Activity, And Locomotive Behavior In Zebrafish Larvae, Ryan J. Mcauley

Cal Poly Humboldt theses and projects

Bisphenol A (BPA) is a well-known endocrine disrupting chemical that mimics the effects of estrogens. Aromatase B (Cyp19a1b) is a brain-specific enzyme that converts testosterone to estrogen and is highly upregulated in response to estrogen receptor activation localized to radial glial cells. During embryonic zebrafish development, there is a small window of time denoted by an increase in neurogenesis and estrogen receptor activity. Previous studies have demonstrated that a low dose BPA exposure (0.1µM) during this window causes hyperlocomotion in larval zebrafish, yet no further explanation for this behavior change has been described. The purpose of this study was to …

Effects Of Chromium On Mouse Splenic T Lymphocytes And Effects Of Ethanol Exposure During Early Neurodevelopment On Behaviors In Mice, Lu Dai

Theses and Dissertations--Toxicology and Cancer Biology

The dissertation consists of three major projects with the focus on the immunotoxicity of chromium and the behavior disorders caused by early ETOH exposure respectively.

Hexavalent chromium [Cr(VI)] is widely used in various industrial processes and has been recognized as a carcinogen. As the first line of host defense system, the immune system can be a primary target of Cr(VI). T cell population represents a major arm of the immune system that plays a critical role in host anti-tumor immunity. Dysfunction of T cells compromises host anti-tumor immunity resulting in oncogenesis. Using mouse splenic T cells as an in vitro …

Characterization Of Sex Differences In The Reinforcing Effects Of Nicotine, Rodolfo Jesus Flores Garcia

Open Access Theses & Dissertations

It is presently unclear whether ovarian hormones, such as estradiol (E2) promote the reinforcing effects of nicotine in females. Thus, we compared extended access to nicotine intravenous self-administration (IVSA) in intact male, intact female, and OVX female rats (Study 1) as well as OVX females that received vehicle or E2 supplementation (Study 2). The E2 supplementation procedure involved a 4-day procedure involving 2 days of vehicle administration and 2 days of E2 administration. Two doses of E2 (25 or 250 ug) were assessed in separate groups of OVX females in order to examine the dose-dependent effects of this hormone on …

Role Of Mitochondrial Beta-Oxidation In Ethanol Response: A Candidate Gene Study Using Caenorhabditis Elegans, Harini Pallikarana Tirumala

Theses and Dissertations

Alcohol use disorder (AUD) is the fourth leading cause of preventable death in the United States, and the fifth leading risk factor for premature death and disability, globally. There are currently very few treatment options for AUD and there is a need for effective preventive and treatment strategies for this condition. AUD risk has a significant hereditary component, with the contribution of genetic factors being estimated to be about 50%. The Davies-Bettinger laboratory uses C. elegans as a model organism to study the contribution of genetic factors in modulating neuronal responses to ethanol. In this project, we examined the role …

Target Validation And Pharmacological Characterization Of Novel Nmdar Modulators, Kiran Sapkota

Theses & Dissertations

The N-methyl-D aspartate receptors (NMDARs) are ligand-gated ion channels, which play important roles in learning and memory. Excessive activity of NMDARs is implicated in damage due to stroke and neurodegenerative diseases, whereas hypoactivity of NMDARs contributes to schizophrenia. The initial goal of my dissertation is to evaluate the potential role of the GluN2D-containing NMDARs in neuropathological, behavioral and cognitive alterations associated with schizophrenia and characterize the pharmacology and mechanisms of action of NMDAR modulators which could potentially be used to modulate these receptors in schizophrenia.

A subanesthetic dose of the NMDAR antagonist ketamine elicits symptoms of schizophrenia. This property led …

Acute And Chronic Effects Of Inhalants In Intracranial Self-Stimulation, Matthew Tracy

Theses and Dissertations

Inhalants are a loosely defined diverse group of volatile substances which people abuse. Despite widespread misuse of inhalants, there are limited preclinical methods available to study the reinforcement-like properties of inhalants. One procedure which has demonstrated substantial promise as a tool to investigate inhalant pharmacology is the intracranial self-stimulation (ICSS) procedure. ICSS utilizes pulses of electrical stimulation to the mesolimbic reward pathway to serve as a temporally defined and controlled operant reinforcer with a highly adjustable efficacy. The first aim of the project was to characterize the effects of commonly abused inhalants: including toluene, trichloroethane, nitrous oxide, isoflurane and R134a …

Compensatory Mechanisms And T Cell Migration In Mouse Models Of Dopaminergic Loss, Kristi M. Anderson

Theses & Dissertations

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and second most common neurodegenerative disorder. PD is characterized by the selective loss of dopaminergic neurons and dopamine neurotransmitter within the substantia nigra and termini in the striatum. Progressive loss of dopaminergic neurons occurs over many years in PD, and by the time movement disorder symptoms manifest, up to 50-70% of dopaminergic neurons have been lost. Several aspects of PD pathology have been described in detail, but a better understanding of PD progression is needed to develop more efficient treatments.

Motor symptoms associated with PD do not manifest until significant …

An Analysis Of The Interaction Of Methylphenidate And Nicotine In Adolescent Rats: Effects On Bdnf, Elizabeth D. Freeman

Electronic Theses and Dissertations

This investigation was an analysis of the interaction of adolescent exposure to methylphenidate (MPH; trade name: Ritalin) on nicotine sensitization and conditioned place preference (CPP) in a rodent model and underlying mechanisms of this effect. Animals were treated IP with 1 mg/kg MPH or saline using a ―school day‖ regimen of five days on, two days off, from postnatal day (P) 28-50. During the final two weeks of MPH treatment, animals were either behaviorally sensitized to nicotine (0.5 mg/kg free base) or saline for 10 days, or conditioned to nicotine or saline using the CPP behavioral paradigm. In addition, three …

Elucidation Of Pharmacologically Manipulated Responding In The Delay Discounting Task In High Alcohol Preferring Mice, Meredith Halcomb

Open Access Dissertations

Impulsive behavior is the hallmark of many psychopathologies. Uncovering the neurobiological mechanisms driving impulsivity is paramount in the development of through the delay discounting (DD) task in both human and animal models. The present study is an examination of the predictive validity of the two primary types of DD procedures in animals, the Adjusting Amounts (AA) and within session Increasing Delays (ID) tasks. Methods:Subjects were administered either1.25 mg/kg d-amphetamine (AMP), 1.5 g/kg ethanol (EtOH) or saline and tested in either the AA or ID method for 15 days to evaluate drug effects on impulsive behavior. Results: Stimulant administration resulted …

Recovery From Acute Toluene Intoxication Is Facilitated By The Nmda Receptor Co-Agonist D-Serine, But Not The Gabaa Receptor Antagonist Picrotoxin, Susan R. Samuel-Herter

Theses and Dissertations (Comprehensive)

Toluene is a volatile solvent found in many household products and when intentionally inhaled results in intoxication. In rats, acute inhalation of toluene results in sedation and neurological impairments, with marked increases in ambulation and vertical behaviour during the recovery period. Previous in vitro research has shown that toluene may exert its effects by inhibiting NMDA receptors, and / or by activating GABA_A receptors. To test whether modulation of these receptors are also implicated in the changes in motor behaviour and neurological impairments resulting from toluene vapour inhalation, rats were injected with the NMDA receptor co-agonist D-serine (1000 mg/kg …

Diet-Induced Obesity: Dopaminergic And Behavioral Mechanisms As Outcomes And Predictors, Vidya Narayanaswami

Theses and Dissertations--Pharmacy

Obesity and drug abuse share common neural circuitries including the mesocoticolimbic and striatal dopamine reward system. In the current study, a rat model of diet-induced obesity (DIO) was used to determine striatal dopamine function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. For the outcome study, rats were randomly assigned a high-fat (HF) or a low-fat (LF) diet for 8 wk. Following the 8-wk HF-diet exposure, rats were segregated into obesity-prone and obesity-resistant groups based on maximum and minimum body weight gain, respectively, and neurobehavioral outcomes were evaluated. For the predictor study, neurobehavioral antecedents were evaluated prior to …