Pharmacology, Toxicology and Environmental Health Commons^™

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 …

Synthetic And Biological Exploration Of (+)-Boldine - Identification Of Potential Cns Receptor Ligands, Sujay Joseph

Theses and Dissertations

(+)-Boldine, an aporphine alkaloid, is reported to be biologically active at various Central Nervous System(CNS) receptors. However, only a few Structure Activity Relationship(SAR) studies have been conducted using boldine’s aporphine scaffold. A library of novel analogs was synthesized from boldine to understand the effect of bisbenzylation at C2 and C9 positions on the affinity and selectivity at the serotonin receptors.

Molecular Mechanisms Involved In Neurotoxicity Mediated By Hiv Proteins And Drug Abuse, Yu Cai

Theses & Dissertations

While the advancement of highly active antiretroviral therapy (HAART) has transformed the course of HIV/AIDS from a death sentence to a manageable chronic condition, the prevalence of a constellation of neurological disorders collectively termed as HIV-associated neurocognitive disorders (HAND) continues to persist in these patients. HAND is characterized by cognitive dysfunction, depression, impaired memory and/or deficits in motor skills. The underlying factors leading to HAND have been the subject of extensive research and are thought to be associated with HIV infection in the CNS combined with robust immune activation of resident cells of the CNS. In addition, there is a …

Exploring The Effect Of Novel Small Molecules On Oligodendrocyte Precursor Proliferation, Sagune Sakya

University Scholar Projects

Gliomas, a type of brain tumor, can be difficult to treat and have a poor survival rate. One pathway that leads to glioma formation is excessive signaling by platelet derived growth factors (PDGF) through PDGF receptor α (PDGFRα). Through this research, I found that novel compounds that downregulate PDGFRα decrease proliferation of Oli-neu cells, an oligodendrocyte precursor cell model, and identified signaling pathways through which these compounds may exert their effect. Further investigation may identify targets for development of glioma treatments.

Glyphosate Induces Neurotoxicity In Zebrafish, Nicole M. Roy, Bruno Carneiro, Jeremy Ochs

Biology Faculty Publications

Glyphosate based herbicides (GBH) like Roundup^® are used extensively in agriculture as well as in urban and rural settings as a broad spectrum herbicide. Its mechanism of action was thought to be specific only to plants and thus considered safe and non-toxic. However, mounting evidence suggests that GBHs may not be as safe as once thought as initial studies in frogs suggest that GBHs may be teratogenic. Here we utilize the zebrafish vertebrate model system to study early effects of glyphosate exposure using technical grade glyphosate and the Roundup^® Classic formulation. We find morphological abnormalities including cephalic and …

Blockade Of Astrocytic Calcineurin/Nfat Signaling Helps To Normalize Hippocampal Synaptic Function And Plasticity In A Rat Model Of Traumatic Brain Injury, Jennifer L. Furman, Pradoldej Sompol, Susan D. Kraner, Melanie M. Pleiss, Esther J. Putman, Jacob Dunkerson, Hafiz Mohmmad Abdul, Kelly N. Roberts, Stephen William Scheff, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Increasing evidence suggests that the calcineurin (CN)-dependent transcription factor NFAT (Nuclear Factor of Activated T cells) mediates deleterious effects of astrocytes in progressive neurodegenerative conditions. However, the impact of astrocytic CN/NFAT signaling on neural function/recovery after acute injury has not been investigated extensively. Using a controlled cortical impact (CCI) procedure in rats, we show that traumatic brain injury is associated with an increase in the activities of NFATs 1 and 4 in the hippocampus at 7 d after injury. NFAT4, but not NFAT1, exhibited extensive labeling in astrocytes and was found throughout the axon/dendrite layers of CA1 and the dentate …

Role Of The Calcium Plateau In The Neuronal Injury And Behavioral Morbidities Following Organophosphate Intoxication, Laxmikant S. Deshpande, Robert E. Blair, Kristin F. Phillips, Robert J. Delorenzo

Neurology Publications

Organophosphate (OP) chemicals include nerve agents and pesticides, and there is a growing concern of OP based chemical attacks against civilians. Current antidotes are essential in limiting immediate mortality associated with OP exposure. However, further research is needed to identify molecular mechanisms underlying long-term neurological deficits following survival of OP toxicity in order to develop effective therapeutics. We have developed rat survival models of OP induced status epilepticus (SE) that mimic chronic mortality and morbidity following OP intoxication. We have observed significant elevations in hippocampal calcium levels after OP SE that persisted for weeks following initial survival. Drugs inhibiting intracellular …

Pharmacological Blockade Of The Calcium Plateau Provides Neuroprotection Following Organophosphate Paraoxon Induced Status Epilepticus In Rats, Laxmikant S. Deshpande, Robert E. Blair, Beverly A. Huang, Kristin F. Phillips, Robert J. Delorenzo

Neurology Publications

Organophosphate (OP) compounds which include nerve agents and pesticides are considered chemical threat agents. Currently approved antidotes are crucial in limiting OP mediated acute mortality. However, survivors of lethal OP exposure exhibit delayed neuronal injury and chronic behavioral morbidities. In this study, we investigated neuroprotective capabilities of dantrolene and carisbamate in a rat survival model of paraoxon (POX) induced status epilepticus (SE). Significant elevations in hippocampal calcium levels were observed 48-h post POX SE survival, and treatment with dantrolene (10 mg/kg, i.m.) and carisbamate (90 mg/kg, i.m.) lowered these protracted calcium elevations. POX SE induced delayed neuronal injury …

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 …

High Affinity Block Of Icl,Swell By Thiol-Reactive Small Molecules, Sung H. Park

Theses and Dissertations

Ebselen (Ebs) is considered as a glutathione peroxidase (GPx) mimetic and primarily thought to function by scavenging intracellular reactive oxygen species (ROS). Previous to our work, Deng et al. (2010a) demonstrated complete block of I_Cl,swell with 15 microM Ebs following endothelin-1 (ET-1) induced activation of the current in cardiomyocytes. This block was presumed to take effect mainly via the quenching of ROS. Nonetheless, our work with DI TNC1 astrocytes strongly emphasizes that Ebs might function by an alternative mechanism based on its kinetic profile in blocking I_Cl,swell. Our experiments showed that 45 nM Ebs can fully block …

The Role Of Oxidative Stress In The Mechanisms Of Ammonia-Induced Brain Swelling And Tolerance In The Goldfish (Carassius Auratus), David F. Jones Lisser Mr.

Theses and Dissertations (Comprehensive)

Toxic build-ups of ammonia can cause potentially fatal brain swelling in mammals, but such swelling is reversible in the anoxia- and ammonia-tolerant goldfish (Carassius auratus). The mechanisms of ammonia-induced brain swelling and tolerance remain elusive, but several studies have suggested a role for reactive oxygen species (ROS), which may damage proteins and lipids in the plasma membrane of astrocytes in the brain. As a result, osmotic gradients across cell membranes may be altered leading to water uptake by astrocytes and swelling. While a role for ROS has been proposed in mammals, no studies have addressed this question in …

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 …

The Cognition-Enhancing Effects Of Psychostimulants Involve Direct Action In The Prefrontal Cortex, Robert C. Spencer, David M. Devilbiss, Craig Berridge

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. The clinical efficacy of these drugs is strongly linked to their ability to improve cognition dependent on the prefrontal cortex (PFC) and extended frontostriatal circuit. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. …

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 …

The Effect Of Silver Nanoparticles On Synaptic Responses In The Lateral Giant Escape Circuit Of The Crayfish, Samantha N. Adkins

Theses, Dissertations and Capstones

The lateral giant neuron in the crayfish is a neuron that controls the reflexive escape response; the context and experience-dependent tuning of this response is critical for survival. Serotonin modulates synaptic responses in this neuron, and social experiences (stress) changes the modulatory role of serotonin. I investigated the mechanisms of induced synaptic response changes and serotonergic modulatory changes after silver nanoparticle exposure to ask if 1) contaminant induced stress changes serotonergic modulation in a manner consistent with social stress and 2) shed light on potential neurotoxic effects of widely used, but poorly understood nanomaterials. Our data show that stress induced …

A Quantitative Analysis Of The Value-Enhancing Effects Of Nicotine, Bupropion, And Varenicline In Male And Female Rats, Scott Barrett

Department of Psychology: Dissertations, Theses, and Student Research

Smoking and tobacco dependence are serious health concerns in the United States and globally. Reward via the pharmacological effects of nicotine are believed to be the principal motivating factor that drive tobacco dependence. Research reveals differences in sensitivity between males and females to the motivational effects of nicotine in tobacco use. Enhancement of reinforcement value of non-nicotine rewards contributes to overall nicotine reward. Similar value-enhancing effects have been observed by the two most commonly prescribed smoking cessation aids, bupropion and varenicline. The present dissertation investigated the value-enhancing effects of nicotine, bupropion and varenicline in both male and female rats using …

Discovery Of Thienoquinolone Derivatives As Selective And Atp Non-Competitive Cdk5/P25 Inhibitors By Structure-Based Virtual Screening, Arindam Chatterjee, Stephen J. Cutler, Robert J. Doerksen, Ikhlas A. Khan, John S. Williamson

Office for Research Publications and Presentations

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2- …

Possible Role Of Adrenergic Receptors In Epilepsy-Associated Depression, Hannah Marie Redwine

Honors Program Theses and Research Projects

Depression is one of the most frequent comorbidities of temporal lobe epilepsy. Rats subjected to pilocarpine-induced status epilepticus (SE), develop depressive impairments that may stem from the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and/or a decrease in central serotonin neurotransmission. Based on performance in the forced swim test and increased activity of the HPA axis, Post-SE animals were classified as those with Moderate and severe depressive impairments. In both moderately and severely impaired rats, raphe-to-hippocampus serotonergic neurotransmission is decreased and the function of post-synaptic 5-HTrA receptors in the hippocampus is diminished. However, in post-SE rats with severe depressive like behavior, …

The Characterization Of Pb2+ Toxicity In Rat Neural Development: An Assessment Of Pb2+ Effects On The Gaba Shift In Neural Networks And Implications For Learning And Memory Disruption, Lorenz Simon Neuwirth

Dissertations, Theses, and Capstone Projects

The toxic effects of Pb2+ on the developing rat nervous system has been investigated to assess early developmental GABAergic disruption and its implications with altering inhibitory learning and memory. This goal was achieved using a multi-systems approach: blood lead levels (clinical physiology), qRT-PCR (molecular genetics), brain and primary neuronal culture immunology (immunohistochemical and cellular approaches), physiological cellular components (synaptosomes and protein expression) and finally through learning and memory assessment with GABA mimetic drug manipulations in the intact animal (behavioral pharmacology). The influence of a 956ppm Pb2+ gestational diet (i.e. from birth to sacrifice) resulted in pup mean blood lead levels …

An Introduction To Drugs And The Neuroscience Of Behavior, Adam J. Prus

Books

This up-to-date text provides an introductory overview of the nervous system actions and behavioral effects of the major classes of psychoactive drugs, using pedagogy unique among pharmacology texts to make the topic approachable.

An Environmental Toxic Model Of Parkinson's Disease: The Fruit Fly, Jennene Lyda

Graduate Student Theses, Dissertations, & Professional Papers

Parkinson’s disease (PD) is the second most common neurodegenerative disorder with no known specific cause; although genetic risk factors and/or environmental exposure are thought to be involved. The etiology of PD is currently unknown, although the combination of non-genetic components such as environmental exposures, the accumulation of exposure, and gene-environment interactions are thought to play a major role. However, despite this knowledge it is important to develop better models that parallel PD pathophysiology to further understand the mechanisms underlying dopaminergic neuron (DaN) damage. The use of mammalian models to study the degenerative processes in PD has been the most common …

Characterizing A Novel Monoclonal Ampa Receptor 1/2/3 Antibody In The Hippocampus And Prefrontal Cortex Of Rat, Monkey, And Human, Sebastian Aguiar

Pitzer Senior Theses

The excitatory, ionotropic glutamatergic AMPA receptor is the most common membrane-bound receptor in the central nervous system. AMPARs and the NMDA receptors are central to synaptic plasticity, memory, and mechanisms of neurodegeneration. The AMPAR is an obligate heterotetramer, composed of subunits GluA1-4. Subunit permutation determines ion conductance, trafficking and other functional characteristics. Few available antibodies are subunit-specific, disabling researchers from accurately visualizing differential AMPAR subunit distribution in the nervous system. This study sought to visualize a novel monoclonal GluA1/2/3 antibody with functional avidity for three of four receptor subunits and to characterize the ultrastructural localization of these receptors using confocal …

Flavonoids With Novel Nicotinic Activity As Potential Pharmacotherapies To Treat Ethanol-Induced Neurotoxicity, Joseph A. Lutz

Theses and Dissertations--Pharmacy

Ethanol causes neurotoxicity via several mechanisms at different points in the cycle of dependence, including neuroinflammation and oxidative stress during ethanol exposure as well as excitotoxicity during ethanol withdrawal. The primary therapeutic implication is that ethanol-induced neurotoxicity requires multifunctional pharmacotherapies which reduce all mechanisms. Using an innovative pharmacological high throughput screening method on a large plant extract library we discovered flavonoids with alpha7 nicotinic acetylcholine receptor (nAChR) activity. In addition to their well-known anti-inflammatory and antioxidant properties, this novel activity means they can potentially reduce excitotoxicity and therefore makes them ideal for inhibition of ethanol-induced neurotoxicity. Rhamnetin, the candidate compound, …

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 …

Repeated Asenapine Treatment Produces A Sensitization Effect In Two Preclinical Tests Of Antipsychotic Activity, Rongyin Qin, Yingzhu Chen, Ming Li

Department of Psychology: Faculty Publications

Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and phencyclidine (PCP)- induced hyperlocomotion paradigms – two well established animal tests of antipsychotic drugs, whereas clozapine causes a tolerance effect. Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding sites and behavioral features with other atypical antipsychotic drugs. However, it is not clear what type of repeated effect (sensitization or tolerance) asenapine would induce, and whether such an effect is transferrable to other atypicals. In this study, …

Modulation Of Synaptic Transmission By Adenosine In Layer 2/3 Of The Rat Visual Cortex In Vitro, Nicholas M. Bannon

Master's Theses

No abstract provided.

The Effects Of Acute Nicotine Administration On Memory Formation And Neural Activity In The Hippocampus, Perirhinal Cortex, And Medial Septum: Implications For Neurodegenerative Disorders, Matthew Wishnoff

Behavioral Neuroscience Honors Papers

Within the general public, nicotine is commonly thought of as a harmful molecule due to its role in tobacco addiction. However, nicotinic stimulation of the cholinergic system has also been shown to enhance cognitive functioning. This enhancement is thought to be caused by an increase in the release of the neurotransmitter, acetylcholine (ACh), which is responsible for mediating a variety of cognitive processes, such as REM sleep and memory formation. Recent research by Melichercik and colleagues shows that systemic nicotine administration enhances memory acquisition for both object location and object recognition memory in rats, as assessed by a modified version …