Browsing by Subject "GABA"
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Item Open Access GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen.(Frontiers in molecular neuroscience, 2022-01) Demchenko, Ivan T; Suliman, Hagir B; Zhilyaey, Sergey Y; Alekseeva, Olga S; Platonova, Tatyana F; Makowski, Matthew S; Piantadosi, Claude A; Gasier, Heath GOxygen breathing at elevated partial pressures (PO2's) at or more than 3 atmospheres absolute (ATA) causes a reduction in brain γ-aminobutyric acid (GABA) levels that impacts the development of central nervous system oxygen toxicity (CNS-OT). Drugs that increase brain GABA content delay the onset of CNS-OT, but it is unknown if oxidant damage is lessened because brain tissue PO2 remains elevated during hyperbaric oxygen (HBO2) exposures. Experiments were performed in rats and mice to measure brain GABA levels with or without GABA transporter inhibitors (GATs) and its influence on cerebral blood flow, oxidant damage, and aspects of mitochondrial quality control signaling (mitophagy and biogenesis). In rats pretreated with tiagabine (GAT1 inhibitor), the tachycardia, secondary rise in mean arterial blood pressure, and cerebral hyperemia were prevented during HBO2 at 5 and 6 ATA. Tiagabine and the nonselective GAT inhibitor nipecotic acid similarly extended HBO2 seizure latencies. In mice pretreated with tiagabine and exposed to HBO2 at 5 ATA, nuclear and mitochondrial DNA oxidation and astrocytosis was attenuated in the cerebellum and hippocampus. Less oxidant injury in these regions was accompanied by reduced conjugated microtubule-associated protein 1A/1B-light chain 3 (LC3-II), an index of mitophagy, and phosphorylated cAMP response element binding protein (pCREB), an initiator of mitochondrial biogenesis. We conclude that GABA prevents cerebral hyperemia and delays neuroexcitation under extreme HBO2, limiting oxidant damage in the cerebellum and hippocampus, and likely lowering mitophagy flux and initiation of pCREB-initiated mitochondrial biogenesis.Item Open Access Revisiting the monoamine hypothesis of depression: a new perspective.(Perspect Medicin Chem, 2014) Goldberg, Joel S; Bell, Clifton E; Pollard, David AAs the incidence of depression increases, depression continues to inflict additional suffering to individuals and societies and better therapies are needed. Based on magnetic resonance spectroscopy and laboratory findings, gamma aminobutyric acid (GABA) may be intimately involved in the pathophysiology of depression. The isoelectric point of GABA (pI = 7.3) closely approximates the pH of cerebral spinal fluid (CSF). This may not be a trivial observation as it may explain preliminary spectrophotometric, enzymatic, and HPLC data that monoamine oxidase (MAO) deaminates GABA. Although MAO is known to deaminate substrates such as catecholamines, indoleamines, and long chain aliphatic amines all of which contain a lipophilic moiety, there is very good evidence to predict that a low concentration of a very lipophilic microspecies of GABA is present when GABA pI = pH as in the CSF. Inhibiting deamination of this microspecies of GABA could explain the well-established successful treatment of refractory depression with MAO inhibitors (MAOI) when other antidepressants that target exclusively levels of monoamines fail. If further experimental work can confirm these preliminary findings, physicians may consider revisiting the use of MAOI for the treatment of non-intractable depression because the potential benefits of increasing GABA as well as the monoamines may outweigh the risks associated with MAOI therapy.Item Open Access Selected Gamma Aminobutyric Acid (GABA) Esters may Provide Analgesia for Some Central Pain Conditions.(Perspect Medicin Chem, 2010-08-03) Goldberg, Joel SCentral pain is an enigmatic, intractable condition, related to destruction of thalamic areas, resulting in likely loss of inhibitory synaptic transmission mediated by GABA. It is proposed that treatment of central pain, a localized process, may be treated by GABA supplementation, like Parkinson's disease and depression. At physiologic pH, GABA exists as a zwitterion that is poorly permeable to the blood brain barrier (BBB). Because the pH of the cerebral spinal fluid (CSF) is acidic relative to the plasma, ion trapping may allow a GABA ester prodrug to accumulate and be hydrolyzed within the CSF. Previous investigations with ester local anesthetics may be applicable to some GABA esters since they are weak bases, hydrolyzed by esterases and cross the BBB. Potential non-toxic GABA esters are discussed. Many GABA esters were investigated in the 1980s and it is hoped that this paper may spark renewed interest in their development.Item Open Access Stimulation of GABAergic neurons of the lateral septum and its effect on movement speed(2016-06-06) Stackmann, MichelleThe lateral septum is associated with the regulation of innate behavior, motivation, and locomotion. Its complex interconnections with cognitive and affective regions such as the hippocampus, hypothalamus, and medial septum have made it an attractive region for studying how motivation regulates behavior in context-specific settings. This GABAergic brain region’s main output is the lateral hypothalamus, which provides downstream signaling of motor commands. Even though stimulation of lateral septum projections to the hypothalamus have shown to decrease running speed in free behaving mice, characterizing movement kinematics due to LS activation has not been studied. GABAergic medium spiny neurons of the lateral septum were selectively activated through the use of optogenetic techniques in transgenic mice. Photostimulation of the lateral septum at theta frequencies caused a non-significant decrease in head and back speed. 3D motion analysis of body movement under photostimulation was quantified, revealing a slow, linear decrease of body speed as photostimulation progressed. These results support the role of lateral septum activation in movement regulation and shed light on the specific manner in which stimulation of the LS gradually decreases movement speed.Item Embargo Synaptic Control of Dopamine as a Driver of Reward Learning(2023) Burwell, Sasha Carmelle VeraVentral tegmental area dopamine (VTADA) neurons fire in a manner consistent with Reward Prediction Error, with better-than-expected and worse-than-expected outcomes correlating with bursts and pauses, respectively. Burst and pause firing dynamics are believed to be responsible for driving associative learning, yet interrogating this causality, and understanding how these firing patterns are synaptically created within endogenous neural circuits, has been technically difficult. Utilizing a novel tool, DART (drug acutely restricted by tethering), paired with a multiplexed cue-reward associative learning task and in vivo neural recordings, I explore which classes of endogenous synaptic inputs to VTADA neurons create their canonical firing dynamics, and their role in the associated reward learning behaviors. My key finding is that antagonizing GABAA receptors on VTADA neurons decreases the pauses in firing these cells exhibit, but also accelerates extinction learning in response to unexpected reward omission. In the same mice, the manipulation had no impact on conditioning to a novel cue-reward pairing, indicating that positive-valence learning was unperturbed. This dissertation work provides critical insight into the neural circuitry underlying adaptive behaviors by creating a new framework for understanding conditioning and extinction as anti-correlated behaviors, and by establishing a novel role for direct inhibitory GABAA signaling to VTADA cells in conditioned conviction.