Medicine and Health Sciences Commons^™

Design And Synthesis Of Substituted N,3,3-Triphenylpropanamide And 1-Benzhydryl-N-Phenylazetidine-3-Carboxamide Analogs And Their Biological Evaluation, Michael Dorogan

Theses and Dissertations

As D₁R agonism has significant implications in the treatment of cognitive deficits, we sought to develop novel D₁R PAMs, through the derigidification of BMS D₁R PAM hit compound. While we were able to synthesize derigidified analogs of the BMS hit compound, derigidification did not produce active D₁R ligands.

Exploring The Dopamine Transporter Utilizing A Two-Pronged Approach With Novel Cathinone Analogs And Mutant Dopamine Transporters, Charles B. Jones Iii

Theses and Dissertations

The dopamine transporter (DAT) is responsible for the removal of the neurotransmitter from the synaptic gap and a therapeutic target for a multitude of drugs. While the ortholog Drosophila melanogaster dopamine transporter (dDAT) and human serotonin transporter (hSERT) have resolved structures, the human dopamine transporter (hDAT) does not. A 3-D computational homology model of hDAT was constructed for the study of molecular interactions with agents within the central binding site (S1) of the transporter.

Synthetic cathiones are a class of abused stimulant drugs that primarily target DAT. Greater than 150 cathinones have been identified on the clandestine market but there …

Astrocyte Sensitivity To Dopamine In Culture And Ex Vivo, Ashley L. Galloway

Theses and Dissertations

Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well established. This thesis illustrates effects of dopamine on cultured astrocytes and astrocytes in brain slices (ex vivo). In striatal cultures, extracellular dopamine triggered changes in astrocytic Ca²⁺ signaling and rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation, but instead relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. To isolate possible mechanisms underlying these structural and functional changes, whole-genome RNA sequencing was …

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the …

Morphogenic Effects Of Dopamine In Cultured Rat Hippocampal Astrocytes, Ashley L. Galloway

Theses and Dissertations

Dopamine is critical for processing of reward and addictive behaviors brought about by drugs of abuse. Scientific investigation of drugs of abuse and their effects on CNS function has traditionally been directed at understanding the role of neurons. However, astrocytes, which constitute approximately half of all human brain cells, play a dynamic role in many essential nervous system functions, including neurotransmission, ion homeostasis, and immune defense. Dopamine effects on astrocytes have been historically understudied, yet research indicates that astrocytes express dopamine receptors and are sensitive to dopaminergic activity. Importantly, astrocytes, comprise a morphologically heterogeneous population of cells, and a distinction …

Metabotropic Receptor Modulation Of Kainate Receptors In The Hippocampus, C'Iana Patrice Cooper

Theses and Dissertations

Kainate receptors (KARs) are glutamate-gated ion channels that mediate synaptic transmission, modulate transmitter release, and mediate excitation in the brain. Potentiation in their function predisposes the hippocampus to hyperexcitability and seizures. These receptors are widely expressed throughout the central nervous system as tetramers composed of various combinations of GluK1-5 subunits. In the hippocampus (a brain region commonly associated with seizure initiation), GluK2-, GluK4-, and GluK5-containing receptors are highly expressed in the CA3 pyramidal cell layer, whereas GluK1 is barely detectable. The lack of pharmacological tools hinders identifying the functional contribution of each kainate receptor subtype in normal CA3 synaptic transmission. …

Activation Of Microglia In The Rotenone Lymnaea Stagnalis Model Of Parkinson's Disease, Xiomara Galvan

Theses and Dissertations

Parkinson’s disease (PD) is the most common irreversible neurodegenerative movement disorder affecting approximately ten million people worldwide. In the central nervous system (CNS), PD is known by the selective loss of Dopamine (DA) cells of the substantia nigra pars compacta. Although the disease has been very widely studied, the underlying mechanisms are not yet understood. Several hypotheses have arisen as result of injury of the mitochondria, some experiments include microglia activation, microtubule damage, and reactive oxidative species, which all result in the death of DA cells. The theory of microglia activation upon inflammation was explored in this study. Using the …

Conduction States Of The Human Dopamine Transporter, Krasnodara Cameron

Theses and Dissertations

Dysregulation of dopaminergic homeostasis has been established as the primary source of numerous neurological disorders including Parkinson’s and drug addiction. A tonic increase of dopamine (DA) in the nucleus accumbens is required for associating everyday events and behaviors with rewards. Yet many addictive exogenous compounds such as amphetamine (AMPH) and cocaine (COC) produce a much greater augmentation of synaptic DA levels that are linked to euphoria and a shift in behavior towards drug seeking. The protein responsible for maintaining extracellular levels of DA is the dopamine transporter (DAT). It is primarily located in the perisynaptic area at terminals of pre-synaptic …

Determinants Of Abuse-Related Effects Of Monoamine Releasers In Rats, Clayton T. Bauer

Theses and Dissertations

Monoamine releasers constitute a class of compounds that promote release of dopamine, serotonin, and/or norepinephrine. These compounds have a range of different uses in the medical setting, including treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity. A major limitation of many of these compounds (i.e. amphetamine, methamphetamine, phenmetrazine) is their propensity for abuse; however, not all monoamine releasers are abused (i.e. fenfluramine). The goal of this dissertation was to examine pharmacological determinants of abuse-related effects produced by monoamine releasers in two preclinical assays in rats: intracranial self-stimulation (ICSS) and drug discrimination. First, this work confirmed and expanded upon previous …

Characterization Of The Zona Incerta, Heather Joyce Green

Theses and Dissertations

Parkinson's Disease affects more than 1 million people in the United States with 60,000 new cases being diagnosed each year. Currently, there is no cure for Parkinson's Disease, but there are several treatment options available. Currently the most popular surgical option is Deep Brain Stimulation. Microelectrode recording helps identify nuclei as the microelectrode passes through them. While the firing frequencies of the target nuclei are well defined, other nuclei are not. This study will attempt to characterize the Zona Incerta, which is the structure directly above the Subthalamic Nucleus, a target nucleus. Characterization of the firing frequency of the Zona …