Pharmacology Commons^™

Effects Of Limb Dominance On Dopaminergic Neurodegeneration In A 6-Ohda Rat Model Of Parkinson’S Disease Assessed By Immunoblotting, Jasin Aziz Porshia, Deanna Chaialee, Dipesh Pokharel, Kala Venkiteswaran, Thyagarajan Subramanian, Dilshan Beligala

ONU Student Research Colloquium

Effects of Limb Dominance on Dopaminergic Neurodegeneration in a 6-OHDA Rat Model of Parkinson’s Disease Assessed by Immunoblotting

Jasin Porshia^a , Deanna Chaialee^a , Dipesh Pokharel^b,c , Kala Venkiteswaran^{b, c, d} , Thyagarajan Subramanian^{b, c, d}, Dilshan Beligala^a

^aDepartment of Biological Sciences, Ohio Northern University, Ada, OH, USA

^bDepartment of Neurosciences and Psychiatry, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

^cDepartment of Neurology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

^dDepartment of Neurology, Howard University, Washington, DC, …

Design And Advancement Of Analytical Frameworks For In Vivo Single-Photon Calcium Imaging To Characterize Temporal- And Treatment-Dependent Neural Adaptations To Opioid Exposure And Withdrawal In The Medial Prefrontal Cortex, Alexia R. Alsum Dr.

Theses and Dissertations--Pharmacy

Despite the availability of several approved medications for opioid use disorder (OUD), it remains a significant public health concern characterized by persistent neurobiological adaptations that drive relapse and impede successful recovery. The medial prefrontal cortex (mPFC), a region critical for executive control and decision-making, undergoes pronounced functional changes during chronic opioid exposure and withdrawal, yet the cellular mechanisms underlying these adaptations remain poorly understood. This dissertation aims to investigate longitudinal alterations in mPFC neural activity across opioid exposure and withdrawal using in vivo single-photon calcium imaging and newly developed computational frameworks.

Following standard preprocessing to extract and normalize calcium traces, …

Identifying Rna Splicing Changes During Alcohol Withdrawal Using An Optimized Rna-Seq Analysis Pipeline, Yasaswi Veera, Luana Martins De Carvalho, Amy Lasek

Undergraduate Research Posters

Alcohol use disorder (AUD) causes long-lasting changes in brain gene expression and RNA splicing, particularly in the ventral hippocampus. This study analyzes RNA-Seq data from rats exposed to chronic alcohol and withdrawal to identify transcript-level and splicing alterations. An optimized RNA-Seq pipeline using STAR, FeatureCounts, edgeR, and WGCNA improved efficiency by 25-40% while maintaining consistency across 25 datasets. Results reveal changes in neural signaling and stress-response pathways associated with withdrawal. This work provides both biological insight into AUD and a reproducible computational framework for transcriptomic analysis.

Investigating Prefrontal Cortex Neuronal Signatures Of Opioid-Induced Risk-Taking Behavior, Cana Quave

Dissertations and Theses (Open Access)

Opioid use disorder occurs alongside impaired risk-related decision-making, but the underlying neural correlates are unclear. We developed an approach-avoidance conflict task using a modified conditioned place preference procedure to study neural signals of risky opioid seeking in the prefrontal cortex, a region implicated in executive decision-making. Following morphine conditioned place preference, rats underwent a conflict test in which fear-inducing cat odor was introduced in the previously drug-paired side of the apparatus. While the saline-exposed control group avoided cat odor, the morphine group included two subsets of rats that either maintained a preference for the paired side despite the presence of …

Investigating The Role Of The Hypocretin/Orexin System In A Novel Model Of Polysubstance Dependence, Tyler Zarin

Electronic Theses and Dissertations

Substance use disorders (SUD) in the United States are steadily increasing. Potent and dangerous substances such as methamphetamine (MA) and fentanyl (FEN) are often co-used as a polysubstance (POLY), either intentionally or unknowingly as FEN is a common adulterant. SUD is characterized by physiological and psychological dependence involving the negative reinforcement of anhedonia and withdrawal which drive hypermotivated drug-taking behaviors. Current theory suggests that recruitment of hypocretin/orexin (HCRT) neuropeptide in reward and stress associated brain regions contributes to drug dependence. Despite strong evidence for HCRT’s role in mono-drug dependence, a relevant model for POLY dependence has yet to be developed, …

Assessing The Behavioral Impact Of Pyridostigmine Bromide In Rats, Noah A. Martin

Honors Theses

Pyridostigmine bromide (PB) is an organophosphate (OP) nerve agent prophylactic used to protect warfighters against chemical warfare agents. OPs inhibit the neural enzyme acetylcholinesterase (AChE) in the brain. This leads to the buildup of acetylcholine, causing respiratory failure, seizures, and death. PB functions by inhibiting ~30% of peripheral AChE temporarily, protecting the enzymes so that the body is able to restore sufficient cholinergic function post-exposure. PB does not cross the blood-brain barrier, though it may still indirectly affect toxicity in the brain due to repeated AChE inhibition throughout treatment, or by inhibition of non-target ChE’s in the blood. The aim …

Psilocybin Impairs The Extinction Of Contextual Fear In Adult Female, But Not Male, Rats, Lillianna P. Puppel, Aleece K. Al-Olimat, Kylie M. King, Marisa J. Savini, Claire E. Miller, Colin R. Del Valle, Heather R. Sparkman, Brooke E. Bramlage, Phillip R. Zoladz

ONU Student Research Colloquium

Fear-related disorders are often treated with exposure therapy, a technique based on the concept of extinction. However, this type of therapy is ineffective for many individuals, so finding a pharmacological adjunct that augments the extinction of fear could lead to better treatment outcomes. In recent preclinical work, investigators have shown that psychedelics can accelerate the extinction of fear, potentially through their impact on neurotrophic signaling. We previously found that psilocybin exerted sex-dependent effects on the extinction of conditioned fear to an isolated cue (i.e., a tone). Specifically, psilocybin enhanced the extinction of cue fear in male rats but impaired it …

Effect Of Paxlovid On Neurodevelopmental Disorder Diagnosis Outcomes In Offspring Of Mothers Infected With Sars-Cov-2 During Pregnancy, Simone Rogers

CMC Senior Theses

The onset of the 2020 COVID-19 pandemic brought concern over the effects that this virus would have on pregnancy and fetal outcomes, specifically neurodevelopmental outcomes. Maternal immune activation (MIA), caused by infection during pregnancy, is known to result in neurodevelopmental disorder (NDD) diagnosis in offspring, typically autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). This effect has already been observed in mothers who were infected with COVID-19 during pregnancy. However, in 2023, Paxlovid, the COVID-19 antiviral drug, became available to patients experiencing symptoms of the virus, including pregnant women. Consequently, this study seeks to determine whether the risk of …

Investigating The Role Of Dynamic Signaling Of Nrg3-Erbb4 In The Prefrontal Cortex In Mediating Nicotine Withdrawal Phenotypes, Emily Prantzalos

Theses and Dissertations--Pharmacy

While several pharmacotherapies are currently available for nicotine use disorder (NUD), smoking cessation success rates remain below 10% each year. The molecular mechanisms underlying failed quit attempts continue to represent a critical gap in our knowledge. However, recent advances in understanding the genetic contributions to nicotine dependence offer a promising avenue for developing more effective cessation therapies. Prior research has identified genetic variation in Neuregulin 3 (Nrg3) and its cognate receptor ErbB4 as potential contributors to affective nicotine withdrawal (WD) phenotypes and cessation outcomes. Therefore, this dissertation aims to systematically investigate the region-specific, functional role of the Neuregulin Signaling Pathway …

Weighted Family History Density Of Substance Use: Influence On Participant Substance Use Onset, Escalation, And Duration, Carleigh A. Litteral

Theses and Dissertations--Psychology

Substance use disorders impose a staggering toll on the United States (U.S.), straining healthcare systems, destabilizing communities, and profoundly impacting both individuals and families. Approximately one in six Americans aged 12 and older had a past-year substance use disorder in 2022 (Key Substance Use, 2022), and nearly one-third of adults experience a substance use disorder in their lifetime (Wu, 2010), contributing to an economic burden exceeding $400 billion annually (National Drug Threat Assessment, 2011). Family history of substance use disorders is a key predictor of vulnerability, with individuals who have affected relatives being 2–8 times more …

The Multipurpose Dna Repair/Redox Protein Ape1 In Rodent And Human Lewy Body Disease, Kristin Marie Miner

Electronic Theses and Dissertations

Lewy body disorders are a family of neurodegenerative conditions characterized by proteostatic and redox disequilibrium, leading to deposition of the abundant protein α-synuclein in hallmark inclusions and oxidative damage to DNA. Sublethal oxidative DNA damage in neurons is repaired predominantly by the base excision repair pathway, which involves the coordinated activity of several enzymes, including apurinic/apyrimidinic endonuclease 1 (APE1). Despite emerging connections between α-synuclein, oxidative stress, and DNA damage/repair, along with evidence demonstrating the multifunctional nature of APE1, the link between APE1 and α-synuclein has not yet been explored.

Here, we conducted a broad investigation of APE1 in the context …

The Effect Of Novel Microtubule Modulators On Experimental Lewy Body Disease, Anuj S. Jamenis

Electronic Theses and Dissertations

In Lewy body disorders, α-synuclein aggregates are believed to destabilize the microtubular framework. However, microtubules are a challenging therapeutic target, as excessive rigidity or flexibility afforded by microtubule modulators may be neurotoxic. Thus, the objective of the present study was to evaluate dual-acting microtubule- stabilizing/destabilizing agents in cellular and animal models of early-stage Lewy body disease.

In Aim 1 we tested the dual-acting tricylic pyrimido[4,5-b]indole analogs AG161-47 and AG161-41 in an in vitro preformed fibril induced model of Lewy body disease. We found that both compounds reduced preformed fibril-seeded α-synucleinopathy without toxicity in primary hippocampal cultures. AG161-47 subtly impacted microtubule …

Pipecolic Acid And Novel Insights Into Cerebral Malaria, Akua E. Mensah

Theses and Dissertations

Cerebral malaria (CM), a severe manifestation of Plasmodium infection, prompts our investigation into the nuanced role of pipecolic acid in its pathophysiology. To unravel the molecular intricacies, we conducted in vitro lysine labeling techniques of mice infected with P. berghei ANKA parasites, and human P. falciparum grown in vitro, aiming to discern the impact of Plasmodium on pipecolic acid production. Previous observations indicated an elevation in pipecolic acid levels correlating with neurological decline in children with CM. In our study, confirming elevated pipecolic acid presence in the plasma and brain tissues of CM patients and the animal model of CM, …

Differential Behavioral Responses In Male And Female Mice Lacking Either Rgs2 Or Rgs4 Proteins After Acute Administration Of Antidepressants And Anxiolytics, Hiroyoshi Matsui, Sarah Seeley, Manoranjan S. D'Souza

ONU Student Research Colloquium

The overall objective of the study was to assess the acute behavioral effects of currently used antidepressants and anxiolytics in male and female mice lacking regulator of G protein-signaling (RGS) proteins 2 and 4 and their wild-type counterparts. RGS 2 and 4 proteins negatively modulate signaling pathways of G protein-coupled receptors (GPCRs), which play an important role in mediating the effects of monoamine neurotransmitters such as dopamine, norepinephrine, and serotonin. These neurotransmitters in turn play an important role in the action of antidepressant and anxiolytic medications. The study was undertaken because no studies till date have systematically assessed the behavioral …

Effects Of Kappa Opioid Receptor Manipulation On Methamphetamine-Induced Behavioral Sensitization In Adolescent Male And Female Rats, Hiroyoshi Matsui Mr, Sarah Seeley, Manoranjan S. D'Souza

ONU Student Research Colloquium

Methamphetamine abuse amongst adolescents has been on the rise in the United States. In this study, we assessed the effects of manipulation of KORs on methamphetamine-induced behavioral sensitization in adolescent male and female rats. Methamphetamine-induced behavioral sensitization is an animal model to study methamphetamine addiction. Behavioral sensitization usually occurs in animals who have been treated with methamphetamine followed by a period of withdrawal. It is hypothesized that brain circuits are altered during the period of withdrawal after methamphetamine exposure resulting in sensitized (increased) responses to methamphetamine at the end of the withdrawal period. The experiment was conducted over 28 days. …

The Effect Of The Glucocorticoid Receptor Modulator, Safit, On Acute Stress Reactivity In A Rat Model Of Abusive Head Trauma, Brielle Coe

Tower Health Research Day

No abstract provided.

In Silico Identification Of Small Molecule Agonist Binding Sites On Kcc2, Kenyon Mitchell, Alfred Amendolara, Ruth Hunter, Jaden Miner, Andrew Payne

Annual Research Symposium

Purpose: Potassium-Chloride Cotransporter 2 (KCC2) is a neuronal membrane protein specific to the central nervous system. It is responsible for removing Cl- ions from the intracellular space, maintaining a normal Cl- gradient essential for proper function at inhibitory synapses. Dysregulation causes an upward shift in the Cl- reversal potential resulting in a hyperexcitable state of the postsynaptic neuron. Existing literature indicates that KCC2 may be involved in the addiction pathway of a variety of drugs of abuse, including opioids and alcohol. This makes KCC2 an attractive potential drug target when treating substance use disorders. A novel direct KCC2 agonist, VU0500469, …

The Effect Of Caffeine On Bee Behavior: A Progressive Ratio Study, Kayle Cohen, Becky Hansis-O'Neill, Aimee Dunlap Dr

Undergraduate Research Symposium

This presentation focuses on the effect of caffeine on bee behavior using behavioral pharmacology methodologies. Researchers trained bumblebees to drink out of artificial flowers, then administered sucrose nectar or caffeinated sucrose nectar during a schedule of progressive and fixed ratios. The finding suggests that caffeine did increase the number of rewards during the fixed ratio, but not in the progressive ratio. However, research is still ongoing as bees continue to be tested..

Examining The Effects Of Artemisia Annua On Neuro2a Cells, Wesley Lim

Honors Undergraduate Theses

Artemisia annua L. is a well-known medicinal herb used in Traditional Chinese Medicine for many centuries and contains artemisinin, which exhibits antimalarial properties [1] and is a potential treatment for SARS-CoV-2 [2]. However, the neurological effect of A. annua and its compounds are poorly understood. We hypothesize that A. annua extracts and artemisinin will provide protection against oxidative stress in mouse neuronal Neuro2A cells. Superoxide dismutase 1 (SOD1) is an anti-oxidant enzyme that protects against oxidative damage [3]. Growth Arrest and DNA Damage-inducible 45 alpha (Gadd45a) is involved in DNA repair and is a common biomarker for DNA damage[4]. SOD1 …

Enhancing Translation: A Need To Leverage Complex Preclinical Models Of Addictive Drugs To Accelerate Substance Use Treatment Options, Christa Corley, Ashley Craig, Safiyah M. Sadek, Julie A. Marusich, Samar N. Chehimi, Ashley M. White, Lexi J. Holdiness, Benjamin C. Reiner, Cassandra D. Gipson

Markey Cancer Center Faculty Publications

Preclinical models of addictive drugs have been developed for decades to model aspects of the clinical experience in substance use disorders (SUDs). These include passive exposure as well as volitional intake models across addictive drugs and have been utilized to also measure withdrawal symptomatology and potential neuro- behavioral mechanisms underlying relapse to drug seeking or taking. There are a number of Food and Drug Administration (FDA)-approved medications for SUDs, however, many demonstrate low clinical efficacy as well as potential sex differences, and we also note gaps in the continuum of care for certain aspects of clinical ex- periences in individuals …

Impacts Of Xylazine On Fentanyl Demand, Body Weight, And Acute Withdrawal In Rats: A Comparison To Lofexidine, Safiyah M. Sadek, Shailesh N. Khatri, Zachary A. Kipp, Kelly E. Dunn, Joshua S. Beckmann, William W. Stoops, Terry D. Hinds, Jr., Cassandra D. Gipson

Markey Cancer Center Faculty Publications

The opioid use landscape has recently shifted to include xylazine, a veterinary anesthetic, as an adulterant in the fentanyl supply. The health impacts of xylazine as an emerging fentanyl adulterant has raised alarm regarding xylazine as a public health threat, warranting research on the impacts of xylazine on fentanyl’s behavioral effects. No prior studies have evaluated the effects of xylazine on fentanyl consumption at various unit doses, fentanyl demand, or withdrawal as compared to the Food and Drug Administration-approved opioid withdrawal medication, lofexidine (Lucemyra®). This is important because lofexidine and xylazine are both adrenergic α2a (A2aR) agonists, however, lofexidine is …

Oxycodone Withdrawal Is Associated With Increased Cocaine Self-Administration And Aberrant Accumbens Glutamate Plasticity In Rats, Shailesh N. Khatri, Hanaa Ulangkaya, Erin E. Maher, Safiyah M. Sadek, Mei Hong, Andrea M. Woodcox, William W. Stoops, Cassandra D. Gipson

Markey Cancer Center Faculty Publications

Individuals with opioid use disorder (OUD) frequently use other substances, including cocaine. Opioid with- drawal is associated with increased likelihood of cocaine use, which may represent an attempt to ameliorate opioid withdrawal effects. Clinically, 30% of co-using individuals take opioids and cocaine exclusively in a sequential manner. Preclinical studies evaluating mechanisms of drug use typically study drugs in isolation. However, polysubstance use is a highly prevalent clinical issue and thus, we established a novel preclinical model of sequential oxycodone and cocaine self-administration (SA) whereby rats acquired oxycodone and cocaine SA in an A-B-A-B design. Somatic signs of withdrawal were evaluated …

The Reinforcement Enhancing Effects Of Delta-9-Tetrahyrdrocannabinol (Thc) In Male And Female Rats, Kynah Walston

Electronic Theses and Dissertations

Cannabis is widely consumed by humans for pharmacological effects that are mediated by THC, though there is little evidence that THC is a primary reinforcer in non-human animal models. We hypothesized that THC may have potent reinforcement enhancing effects, comparable to other drugs (e.g., nicotine and caffeine) which are also widely consumed by humans, but difficult to establish as primary reinforcers in non-humans. In three experiments with male and female rats saccharin (SACC) or a visual stimulus (VS) served as reinforcers for operant behavior. We explored several pharmacological parameters of THC on responding for SACC or VS, including THC dose, …

Antibody-Dependent Enhancement Activity Of A Plant-Made Vaccine Against West Nile Virus, Amber M. Paul, Haiyan Sun, Dhiraj Acharya, Huafang Lai, Junyun He, Fengwei Bai, Qiang Chen

Publications

West Nile virus (WNV) causes annual outbreaks globally and is the leading cause of mosquito-borne disease in Unite States. In the absence of licensed therapeutics, there is an urgent need to develop effective and safe human vaccines against WNV. One of the major safety concerns for WNV vaccine development is the risk of increasing infection by related flaviviruses in vaccinated subjects via antibody-dependent enhancement of infection (ADE). Herein, we report the development of a plant-based vaccine candidate that provides protective immunity against a lethal WNV challenge mice, while minimizes the risk of ADE for infection by Zika (ZIKV) and dengue …

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 …

The Impact Of Hiv-1 Tat And Morphine On Spatial Distribution Of Drugs In The Brain., Austin M. Jones

Theses and Dissertations

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, the central nervous system (CNS) remains affected by the virus. Approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND) or neuroHIV. Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, viral replication, and potentially altering the antiretroviral concentrations within the brain.

Using a transgenic mouse that expresses the HIV-1 Tat protein, we examined the effects of Tat and morphine on antiretroviral accumulation and distribution and the effects of Tat on morphine accumulation within the brain using infrared matrix-assisted laser desorption electrospray ionization with mass spectrometry imaging (IR-MALDESI-MSI). …

Selective Gsk3b Overexpression In Medial Prefrontal Cortex Camkiia Cells Produces Sex-Specific Changes In Ethanol Self-Administration, Anxiety-Like Behavior, And Working Memory, Sam Gottlieb, Zachary Tatom, Michael F. Miles

Graduate Research Posters

Background: Glycogen synthase kinase 3 beta (Gsk3b) is central in a gene network regulated by ethanol in mouse medial prefrontal cortex (mPFC). GSK3B abundance/activity modulations regulate ethanol consumption, suggesting GSK3B could be a target in treating alcohol use disorder. However, the critical cell type in this ethanol response is not yet known, nor have sex differences in GSK3B modulations been fully investigated. Here we report results of GSK3B overexpression selectively in CamKIIa⁺ mPFC cells on multiple behaviors.

Methods: Mice underwent stereotaxic injections to overexpress GSK3B in mPFC CamKIIa⁺ cells or control virus (n=4-6/sex/virus). We assayed working …

Morphine-Induced Tolerance Is Reduced By The Consumption Of A Ketogenic Diet, But Not A High Fat/High Carbohydrate Diet, Nina Beltran

Open Access Theses & Dissertations

Opioid drugs like morphine are used medicinally for pain relief, but also have abuse liability that can lead to opioid use disorder (OUD), which contributes to nearly 70% of drug overdose deaths in the United States. Another rising health concern is the global obesity epidemic, and new evidence suggests that obesity and OUD might converge to impact individuals. For example, high body mass index (BMI) is associated with greater reports of pain among women. Further, opioid overdose risk is increased among individuals diagnosed with obesity, suggesting a potential relationship that might convey enhanced vulnerability among some populations. Given the high …

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., …

Novel Therapeutic Strategies For Alzheimer’S Disease: Prostaglandin D2 Signaling And Its Human Polymorphisms As Well As A Polypharmacological Approach, Charles H. Wallace

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is an age related neurodegenerative disease with pathology that includes amyloid plaques, neurofibrillary tangles and non-resolving neuroinflammation. Non-resolving neuroinflammation lasts the entire course of the disease and has deleterious effects and is often thought to accelerate AD pathology. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) have commonly been used as therapeutics to treat pain, inflammation and vascular. NSAIDs work by altering the cyclooxygenase (COX) mediated biosynthesis of prostaglandins which are lipid mediators that have many physiological functions, for example nociception, inflammation and vasodilation. Epidemiological studies support the notion that NSAIDs could be used to treat AD. Yet, clinical trials using …