Pharmacology Commons^™

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., …

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 …

Sex Differences In The Mechanisms That Modulate The Neurochemical Effects Of Nicotine, Kevin Uribe

Open Access Theses & Dissertations

Prior behavioral studies in our laboratory revealed that overexpression of the stress peptide, corticotrophin-releasing factor (CRF), in the mesocorticolimbic reward pathway enhanced the reinforcing effects of nicotine. The latter effect was greater in female versus male rats, suggesting that females are uniquely susceptible to the effects of stress on nicotine reinforcement. The goal of this dissertation was to examine the neurochemical mechanisms by which overexpression of CRF in the nucleus accumbens (NAc), a terminal region of the mesocorticolimbic pathway, modulates the behavioral effects of nicotine. Specifically, we examined whether nicotine-induced dopamine levels are altered by CRF overexpression via excitatory (glutamate) …

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 …

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 …

The Combined Neuropharmacology And Toxicology Of Major 'Bath Salts' Constituents Mdpv, Mephedrone, And Methylone, Serena Allen

Electronic Theses and Dissertations

The synthetic cathinones, 3,4- methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4- methylenedioxymethcathinone (methylone), gained worldwide notoriety as the psychoactive components of ‘bath salts;’ a marketing term used to circumvent federal drug laws and permit their legal sale. Previous studies have shown that these drugs share pharmacological characteristics with cocaine and the amphetamines, however, descriptions of their neurotoxic properties are limited. Moreover, while forensic analysis has revealed that the most frequently abused bath salts ‘brands’ contain binary and ternary mixtures of MDPV, mephedrone, and methylone, the majority of preclinical research has focused on explicating the individual effects of these drugs. Therefore, the …

Discriminative Stimulus Properties Of 1.25 Mg/Kg Clozapine In Rats: Mediation By Serotonin 5-Ht2 And Dopamine D4 Receptors, Adam J. Prus, Laura Wise, Alan L. Pehrson, Scott D. Philibin, Benny Bang-Andersen, Jørn Arnt, Joseph H. Porter

Journal Articles

The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug dis- crimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands …

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 Faculty Scholarship

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. …

Structural Determinants Of Abuse-Related Neurochemical And Behavioral Effects Of Para-Substituted Methcathinone Analogs In Rats, Julie S. Bonano

Theses and Dissertations

Methcathinone (MCAT) is the β-ketone analog of methamphetamine, and like its amphetamine analog, MCAT functions as a monoamine releaser that selectively promotes the release of dopamine (DA) and norepinephrine (NE) over serotonin (5-HT). MCAT produces amphetamine-like psychostimulant effects and is classified as a Schedule I drug of abuse by the United States Drug Enforcement Administration (DEA). Recently, synthetic MCAT analogs have emerged as designer drugs of abuse in Europe and the United States and have been marketed under deceptively benign names like “bath salts” in an attempt to evade legal restriction. These dangerous, recently emergent and novel drugs of abuse …

Effect Of Dichloromethane Fraction Of Areca Catechu Nut On Monoamines Associated Behaviors And Tyramine Pressor Sensitivity In Rodents, Shagufta Khan, Ghulam Abbas, Fahad Shabbir Ahmed, Attaur Rahman, Ahsana Dar

Department of Biological & Biomedical Sciences

The current study was aimed at investigating the effect of Areca catechu nut dichloromethane fraction (7 mg/kg) on monoamines (serotonin and dopamine) modulation (5-hydroxytryptophan-induced tremors and phenylethylamine-induced stereotypes) and its interaction with tyramine (cheese effect). The dichloromethane fraction caused pronounced increase in 5-HTP-induced tremors (50%) with negligible PEA-induced stereotypes (20%). Additionally, it did not produce a significant increase in the tyramine pressor effects. These results suggest that the dichloromethane fraction of A. catechu nut primarily elevates serotonin levels (probably via monoamine oxidase A inhibition) and does not induce cheese effect.

Selected Neuropharmacology Of Resurgence, Adam D. Pyszczynski

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

The reemergence of problem behavior (i.e., relapse) is a key concern in most behavioral interventions. Resurgence refers to the reappearance of a previously rewarded behavior when reward for an alternative behavior is also discontinued. It is especially relevant to the reappearance of problem behavior because many behavioral interventions discontinue reward for aberrant behavior while simultaneously rewarding an appropriate response.

Understanding the underlying neuropharmacology of behavioral phenomena such as resurgence is important because it helps elucidate the neural processes at the root of such behavior, and also has implications for pharmacotherapies. Existing information about the neuropharmacology of resurgence is scarce, but …

Tremulous Jaw Movements Induced By The Vmat2 Inhibitor Tetrabenazine, Samantha J. Podurgiel

Master's Theses

Parkinsonism is a movement disorder characterized by several cardinal motor symptoms: resting tremor, akinesia, bradykinesia, rigidity, and postural instability. Parkinsonian resting tremor can be modeled in rodents using the tremulous jaw movement model. Tremulous jaw movements (TJMs) are defined as “rapid vertical deflections of the lower jaw that resemble chewing but are not directed at any particular stimulus.” TJMs occur in a frequency range of 3-7 Hz and are induced by a number of pharmacological manipulations that parallel those seen in human Parkinsonism including dopamine (DA) depleting agents, DA antagonists, and cholinomimetic administration. Additionally, TJMs can be attenuated using antiparkinsonian …

Cocaine-Induced Reinstatement Of A Conditioned Place Preference In Developing Rats: Involvement Of The D2 Receptor, Kimberly A. Badanich, Cheryl L. Kirstein

Psychology Faculty Publications

Reinstatement of conditioned place preferences have been used to investigate physiological mechanisms mediating drug-seeking behavior in adolescent and adult rodents; however, it is still unclear how psychostimulant exposure during adolescence affects neuron communication and whether these changes would elicit enhanced drug-seeking behavior later in adulthood. The present study determined whether the effects of intra-ventral tegmental area (VTA) or intra-nucleus accumbens septi (NAcc) dopamine (DA) D2 receptor antagonist infusions would block (or potentiate) cocaine-induced reinstatement of conditioned place preferences. Adolescent rats (postnatal day (PND 28–39)) were trained to express a cocaine place preference. The involvement of D2 receptors on cocaine-induced reinstatement …

The Effects Of Extended Access To Methamphetamine Self-Administration On Dopaminergic Markers In The Striatum, Joe Luevano

Open Access Theses & Dissertations

Methamphetamine (METH) abuse is a persistent problem in the U.S. and abroad. Escalation of METH use among independent users occurs for a variety of physiological and psychological reasons. Methamphetamine dependence may be attributed to the rewarding effect of this drug via the dopaminergic systems of the central nervous system (CNS). The presence of METH in the CNS increases synaptic release of dopamine. This increase in dopaminergic neurotransmission is thought to be directly attributed to the rewarding effects of METH. Following METH use, compensatory changes have been found to occur in the dopaminergic system during various periods of abstinence. It is …

Parthenolide Blocks Cocaine’S Effect On Spontaneous Firing Activity Of Dopaminergic Neurons In The Ventral Tegmental Area, David Schwarz, Damaris Bloom, Rocío Castro, Oné R. Pagán, C. A. Jiménez-Rivera

Biology Faculty Publications

Chronic cocaine administration leads to catecholamine reuptake inhibition which enhances reward and motivational behaviors. Ventral Tegmental Area dopaminergic (VTA DA) neuronal firing is associated with changes in reward predictive signals. Acute cocaine injections inhibit putative VTA DA cell firing in vertebrates. Parthenolide, a compound isolated from the feverfew plant (Tanacetum parthenium), has been shown to substantially inhibit cocaine’s locomotion effects in a planarian animal model (Pagán et al., 2008). Here we investigated the effects of parthenolide on the spontaneous firing activity of putative VTA DA neurons in anesthetized male rats (250-300g). Single-unit recordings were analyzed after intravenous (i.v.) parthenolide administration …

Optimization Of Ion-Pair High Performance Liquid Chromatography For Separation Of Endogenous Amines And Their Metabolites In Rat Brain Tissue(การหาภาวะเหมาะที่สุดสำหรับการวิเคราะห..., Rungrudee Srisawat, Anan Srikiatkhachorn, Naiphinich Kotchabhakdi, Duangdeun Meksuriyen

The Thai Journal of Pharmaceutical Sciences

An improved, HPLC with electrochemical detection method for the isocratic separation and simultaneous determination of endogenous amines and their metabolites from post-mortem rat brain tissue is described. Optimal conditions that maximize stability, res...