Pharmacology & Toxicology Department Theses and Dissertations

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The advanced degree programs at the Indiana University of Medicine Department of Pharmacology and Toxicology prepare scientists for careers across the spectrum of biomedical research. The Master of Science (M.S.) degree is a thesis research degree that gives a student the intellectual background to understand and participate in ongoing research projects. The Doctor of Philosophy (Ph.D.) degree is offered for the student who wants to pursue an independent career in research. Students with the Ph.D. degree are prepared for an academic career combining research with teaching or for a career in industrial pharmaceutical research. A combined M.D./Ph.D. degree is open to qualified individuals who ultimately seek to direct biomedical research with a clinical emphasis.

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Browsing Pharmacology & Toxicology Department Theses and Dissertations by Author "Atwood, Brady K."

Now showing 1 - 3 of 3
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    A New Mechanism of Serotonin Transporter Regulation by Simvastatin and the Isoprenylation Pathway
    (2021-07) Deveau, Carmen Marie; Yamamoto, Bryan K.; Sheets, Patrick L.; Sullivan, William J., Jr.; Atwood, Brady K.; Brustovetsky, Nickolay
    The serotonergic system in the brain is necessary for neurophysiological processes related to mood, sleep, and cognitive regulation. This system is primarily regulated through the transport of extracellular serotonin (5-HT) into neuron terminals by the serotonin transporter (SERT). The activity of SERT is thought to be modulated in part by cholesterol and lipid rich microdomains within the plasma membrane where SERT localizes. However, experiments related to the mechanism of membrane cholesterol on SERT function in the brain has yielded conflicting results and no studies have examined the contribution of cholesterol biosynthetic intermediates in regulating SERT function. To address this knowledge gap, this dissertation examined the neuropharmacological effects of the highly prescribed cholesterol-lowering statin drugs on SERT-dependent 5- HT uptake into neurons. Unexpectedly, statin treatment increased SERT-dependent 5-HT uptake in a neuron cell model, and increased in vivo 5-HT content in synaptosomes. The mechanistic findings demonstrated that (1) statins enhanced activity of SERT rather than altered distribution at the membrane, (2) statins increased 5-HT uptake in a manner that is independent of cholesterol per se but is mediated in part by the cholesterol biosynthetic intermediates of the isoprenylation pathway, namely farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), (3) direct inhibition of the isoprenylation pathway through inhibition of GGPP enzyme geranylgeranyl transferase (GGT) also increased 5-HT uptake in a SERT-dependent manner, and (4) increased 5-HT uptake by statins or GGT inhibition was dependent on Ca2+/calmodulin-dependent protein kinase (CAMKII). Our results provide a novel role for lipid signaling in regulating SERT and a newly identified function of the isoprenylation pathway in the brain. These results also provide a possible explanation for the adverse neurological effects associated with the widely prescribed statin drugs.
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    The Role of Inflammation in Mediating Different Cognitive and Behavioral Functions
    (2023-03) El Jordi, Omar; Atwood, Brady K.; McKinzie, David L.; Oblak, Adrian L.; Block, Michelle L.; Sheets, Patrick L.
    Inflammation, specifically brain inflammation, can be both neuroprotective as well as detrimental in multiple neuropathic diseases. We investigated the inflammatory profile in two different receptor systems, opioids, and estrogens. Microglia, brain immune cells, can influence the neuron’s microenvironment and regulate neuronal activity via multiple signaling mediators. We investigated the role of microglia in opioid withdrawal in an oxycodone dependence paradigm. We found that microglial reduction had no effect on opioid withdrawal symptoms, glial activation markers, body temperature dysregulation, or select inflammatory cytokines. Interestingly, we found them involved in the acquisition of analgesic tolerance potentially mediated by the chemokine KC/GRO. This suggests that microglia modulate neuron adaptations to repetitive opioid dosing through chemokines or alternatively through direct interaction (cell-to-cell), indirect interaction through cytokines, or neurotransmitters that were not measured. In a different experiment, we investigated the effect of Raloxifene, a selective estrogen receptor modulator, in a model of lower back pain/spinal damage precipitated by intervertebral disc degeneration. Raloxifene’s therapeutic effect at the molecular level, verified by collaborators and evident by regeneration of healthy intervertebral disc tissue and reduction of pain signaling molecules (Substance P), did not translate to behavior. Our behavioral measures evaluating motor and psychological deficit, and ataxia were not altered by treatment. Interestingly, we found that hedonic behavior improved by the end of the treatment suggesting that Raloxifene may have a therapeutic effect on adverse sensory signals such as back pain resulting in reward-seeking behavior.
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    Treatment During Abstinence from Methamphetamine in a Rat Model of Methamphetamine Use Disorder
    (2022-12) Baek, James Jaewoo; Sheets, Patrick L.; Yamamoto, Bryan K.; Atwood, Brady K.; Fehrenbacher, Jill C.; Ma, Yao-Ying; Yoder, Karmen K.
    Methamphetamine (METH) is a psychostimulant with high abuse potential. Currently there are no pharmacological treatments specific for relapse to METH use disorder. Chronic METH abuse has been associated with changes to the dopamine and glutamate neurotransmitter systems, as well as inflammation. Phosphodiesterase-4 inhibitors are known to affect cAMP involved in dopaminergic and glutamatergic neurotransmission, as well as having anti-inflammatory action. In pre-clinical models, phosphodiesterase inhibitors can reduce behaviors associated with the self-administration of drugs of abuse if given directly before tests of relapse-like behavior. However, they have not been examined in the more clinically relevant context as a treatment for use during abstinence from drugs of abuse. To address this gap, a METH self-administration model in the rat was used in which roflumilast, a phosphodiesterase 4 inhibitor, was administered during the abstinence period before a relapse test. The overarching hypothesis was that roflumilast inhibited inflammation associated with METH self-administration abstinence to reduce subsequent relapse-like behaviors. A detailed behavioral analysis showed that the chronic treatment with roflumilast during 7 days of forced abstinence reduced relapse-like behavior to METH seeking and METH taking. Roflumilast treatment during 7 days of forced abstinence did not affect subsequent sucrose seeking and sucrose taking behaviors. Biochemical analyses of proteins related to dopamine and glutamate neurotransmission did not reveal changes in these neurotransmitter systems, nor was there evidence of overt inflammation. These data suggest that roflumilast may be a treatment for METH use disorder that is effective when taken during abstinence, but further studies related to the mechanism of action of roflumilast are needed.