Medicine and Health Sciences Commons^™

Behavioral Assessment Of Acute Inhibition Of System XC - In Rats, Victoria Lutgen, Jon M. Resch, Krista Qualmann, Nicholas J. Raddatz, Cristina Panhans, Ellen M. Olander, Linghai Kong, Sujean Choi, John R. Mantsch, David A. Baker

Biomedical Sciences Faculty Research and Publications

Rationale

Gaps in our understanding of glutamatergic signaling may be key obstacles in accurately modeling complex CNS diseases. System x_c ^- is an example of a poorly understood component of glutamate homeostasis that has the potential to contribute to CNS diseases.

Objectives

This study aims to determine whether system x_c ^- contributes to behaviors used to model features of CNS disease states.

Methods

In situ hybridization was used to map mRNA expression of xCT throughout the brain. Microdialysis in the prefrontal cortex was used to sample extracellular glutamate levels; HPLC was used to measure extracellular glutamate and tissue …

Augmented Cystine–Glutamate Exchange By Pituitary Adenylate Cyclase-Activating Polypeptide Signaling Via The Vpac1 Receptor, Jon M. Resch, Rebecca Albano, Xiaoqian Liu, Julie Hjelmhaug, Doug Lobner, David A. Baker, Sujean Choi

Biomedical Sciences Faculty Research and Publications

In the central nervous system, cystine import in exchange for glutamate through system x_c^- is critical for the production of the antioxidant glutathione by astrocytes, as well as the maintenance of extracellular glutamate. Therefore, regulation of system x_c^- activity affects multiple aspects of cellular physiology and may contribute to disease states. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuronally derived peptide that has already been demonstrated to modulate multiple aspects of glutamate signaling suggesting PACAP may also target activity of cystine–glutamate exchange via system x_c^-. In this study, 24-h treatment of primary cortical …

Phosphate And Acidosis Act Synergistically To Depress Peak Power In Rat Muscle Fibers, Cassandra R. Nelson, Edward P. Debold, Robert H. Fitts

Biomedical Sciences Faculty Research and Publications

Skeletal muscle fatigue is characterized by the buildup of H⁺ and inorganic phosphate (P_i), metabolites that are thought to cause fatigue by inhibiting muscle force, velocity, and power. While the individual effects of elevated H⁺ or P_i have been well characterized, the effects of simultaneously elevating the ions, as occurs during fatigue in vivo, are still poorly understood. To address this, we exposed slow and fast rat skinned muscle fibers to fatiguing levels of H⁺ (pH 6.2) and P_i (30 mM) and determined the effects on contractile properties. At 30°C, elevated P_{i …}

Stress-Induced Cocaine Seeking Requires A Beta-2 Adrenergic Receptor-Regulated Pathway From The Ventral Bed Nucleus Of The Stria Terminalis That Regulates Crf Actions In The Ventral Tegmental Area, Oliver Vranjkovic, Paul J. Gasser, Clayton H. Gerndt, David A. Baker, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

The ventral bed nucleus of the stria terminalis (vBNST) has been implicated in stress-induced cocaine use. Here we demonstrate that, in the vBNST, corticotropin releasing factor (CRF) is expressed in neurons that innervate the ventral tegmental area (VTA), a site where the CRF receptor antagonist antalarmin prevents the reinstatement of cocaine seeking by a stressor, intermittent footshock, following intravenous self-administration in rats. The vBNST receives dense noradrenergic innervation and expresses β adrenergic receptors (ARs). Footshock-induced reinstatement was prevented by bilateral intra-vBNST injection of the β-2 AR antagonist, ICI-118,551, but not the β-1 AR antagonist, betaxolol. Moreover, bilateral intra-vBNST injection of …

Cyclic Ovarian Hormone Modulation Of Supraspinal Δ9-Tetrahydrocannabinol-Induced Antinociception And Cannabinoid Receptor Binding In The Female Rat, Alexa A. Wakley, Alisha A. Mcbride, Linda K. Vaughn, Rebecca M. Craft

Biomedical Sciences Faculty Research and Publications

Estrous cycle-related fluctuations in delta-9-tetrahydrocannabinol (THC)-induced antinociception have been observed in the rat. The aim of this study was to determine which major ovarian hormone modulates the antinociceptive effects of i.c.v. THC, and whether hormone modulation of THC's behavioral effects could be due to changes in brain cannabinoid receptors (CBr). Vehicle (oil) or hormones (estradiol or progesterone, or both) were administered to female rats on days 3 and 7 post-ovariectomy. On the morning or afternoon of day 8 or day 9, vehicle or THC (100 μg) was administered i.c.v. Paw pressure, tail withdrawal, locomotor activity and catalepsy tests were conducted …

Time Course Of Cocaine-Induced Behavioral And Neurochemical Plasticity, Victoria Lutgen, Linghai Kong, Kristen S. Kau, Aric Madayag, John Mantsch, David A. Baker

Biomedical Sciences Faculty Research and Publications

Factors that result in augmented reinstatement, including increased withdrawal period duration and high levels of cocaine consumption, may provide insight into relapse vulnerability. The neural basis of augmented reinstatement may arise from more pronounced changes in plasticity required for reinstatement and/or the emergence of plasticity expressed only during a specific withdrawal period or under specific intake conditions. In this study, we examined the impact of withdrawal period duration and cocaine intake on the magnitude of cocaine-primed reinstatement and extracellular glutamate in the nucleus accumbens, which has been shown to be required for cocaine-primed reinstatement. Rats were assigned to self-administer under …

Inhibition Of Food Intake By Pacap In The Hypothalamic Ventromedial Nuclei Is Mediated By Nmda Receptors, Jon M. Resch, Brian Maunze, Kailynn A. Phillips, Sujean Choi

Biomedical Sciences Faculty Research and Publications

Central injections of pituitary adenylate cyclase-activating polypeptide (PACAP) into the ventromedial nuclei (VMN) of the hypothalamus produce hypophagia that is dependent upon the PAC1 receptor; however, the signaling downstream of this receptor in the VMN is unknown. Though PACAP signaling has many targets, this neuropeptide has been shown to influence glutamate signaling in several brain regions through mechanisms involving NMDA receptor potentiation via activation of the Src family of protein tyrosine kinases. With this in mind, we examined the Src-NMDA receptor signaling pathway as a target for PACAP signaling in the VMN that may mediate its effects on feeding behavior. …

Nature Of The Neurotoxic Membrane Actions Of Amyloid-Β On Hippocampal Neurons In Alzheimer's Disease, Fernando J. Sepúlveda, Humberto Fierro, Eduardo Fernandez, Carolina Castillo, Robert W. Peoples, Carlos Opazo, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

The mechanism by which amyloid-β (Aβ) produces brain dysfunction in patients with Alzheimer's disease is largely unknown. According to previous studies, Aβ might share perforating properties with gramicidin, a well-accepted membrane-disrupting peptide. Therefore, we hypothesize that the key steps leading to synaptotoxicity by Aβ and gramicidin involve peptide aggregation, pore formation, and calcium dysregulation. Here, we show that Aβ and gramicidin form aggregates enriched in β-sheet structures using electron microscopy, and Thioflavin and Congo Red staining techniques. Also, we found that Aβ and gramicidin display fairly similar actions in hippocampal cell membranes, i.e. inducing Ca²⁺ entry and synaptoxicity characterized …

Fgf-2 Induces Neuronal Death Through Upregulation Of System Xc-, Xiaoqian Liu, Rebecca Albano, Doug Lobner

Biomedical Sciences Faculty Research and Publications

The cystine/glutamate antiporter (system xc-) transports cystine into cell in exchange for glutamate. Fibroblast growth factor-2 (FGF-2) upregulates system xc- selectively on astrocytes, which leads to increased cystine uptake, the substrate for glutathione production, and increased glutamate release. While increased intracellular glutathione can limit oxidative stress, the increased glutamate release can potentially lead to excitotoxicity to neurons. To test this hypothesis, mixed neuronal and glial cortical cultures were treated with FGF-2. Treatment with FGF-2 for 48 h caused a significant neuronal death in these cultures. Cell death was not observed in neuronal-enriched cultures, or astrocyte-enriched …

Neurobiological Mechanisms That Contribute To Stress-Related Cocaine Use, John R. Mantsch, Oliver Vranjkovic, Robert C. Twining, Paul J. Gasser, Jayme R. Mcreynolds, Jordan M. Blacktop

Biomedical Sciences Faculty Research and Publications

The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the …