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Copyright by Jonathan William Theile 2009 Copyright by Jonathan William Theile 2009 The Dissertation Committee for Jonathan William Theile Certifies that this is the approved version of the following dissertation: MECHANISMS IN ETHANOL MODULATION OF GABA RELEASE ONTO DOPAMINERGIC NEURONS OF THE VENTRAL TEGMENTAL AREA Committee: ______________________________ Richard A. Morrisett, Supervisor ______________________________ Rueben A. Gonzales ______________________________ Hitoshi Morikawa ______________________________ R. Dayne Mayfield ______________________________ S. John Mihic MECHANISMS IN ETHANOL MODULATION OF GABA RELEASE ONTO DOPAMINERGIC NEURONS OF THE VENTRAL TEGMENTAL AREA by Jonathan William Theile, B.A. Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin December, 2009 Acknowledgements I would like to acknowledge my dissertation members: Richard A. Morrisett, Ph.D. Rueben A. Gonzales, Ph.D. Hitoshi Morikawa, Ph.D. R. Dayne Mayfield, Ph.D. S. John Mihic, Ph.D. I would also like to acknowledge current and past associates: Regina Maldve Ph.D., Adam Hendricson Ph.D., Tao Zhang Ph.D., Armando Salinas, Zach Jeanes, Tavanna Porter, Min Yang Ph.D. and Mark Harnett Ph.D. I would also like to thank my family and friends. iv MECHANISMS IN ETHANOL MODULATION OF GABA RELEASE ONTO DOPAMINERGIC NEURONS OF THE VENTRAL TEGMENTAL AREA Jonathan William Theile, Ph.D. The University of Texas at Austin, 2009 Supervisor: Richard A. Morrisett Activation of ventral tegmental area (VTA) dopaminergic (DA) neurons by ethanol has been implicated in the rewarding and reinforcing actions of ethanol. GABAergic transmission is thought to play an important role in regulating the activity of DA neurons. While at most central synapses ethanol generally increases inhibitory synaptic transmission, no studies have explored the effect of acute ethanol on GABAergic transmission in the VTA. Here we investigated how ethanol modulates GABAergic transmission in the VTA in relation to the overall action of ethanol on VTA-DA neuron activity. We demonstrated that ethanol dose-dependently enhances action potential-dependent and -independent GABA release onto VTA-DA neurons. Utilizing whole-cell voltage clamp recording techniques, ethanol increased both spontaneous and miniature inhibitory postsynaptic current (s/mIPSC) frequency while having minimal effect on s/mIPSC amplitude. The ethanol enhancement in GABA release was independent of GABAB auto-receptor inhibition of release. Intra-terminal calcium v levels regulate neurotransmitter release, thus we investigated how modulation of calcium levels would affect the ethanol-enhancement in GABA release. Ethanol enhanced mIPSC frequency in the presence of the voltage-gated calcium channel blockers, cadmium chloride and nicardipine. However, blockade of intracellular calcium stores with 2-APB and cyclopiazonic acid eliminated the ethanol-enhancement of mIPSC frequency. Intracellular calcium stores are regulated via Gq protein-coupled receptors such as the 5-HT2C receptor. 5-HT2C receptor activation robustly enhanced mIPSC frequency whereas blockade inhibited the ethanol-enhancement in mIPSC frequency. These observations suggest that increased calcium release from intracellular stores via 5-HT2C receptor activation is involved in the ethanol-enhancement of GABA release onto VTA-DA neurons. Utilizing cell-attached current-clamp recordings, we demonstrated that the ethanol-enhancement of VTA-DA neuron activity is modulated by the concurrent enhancement in GABA release. Blockade and activation of GABAA receptors enhanced and reversed, respectively, the stimulatory effect of ethanol on VTA-DA neurons. Mu-opioid receptors (MORs) on GABAergic interneurons have been demonstrated to modulate both basal and ethanol-enhanced VTA-DA activity in vivo, though we failed to demonstrate such an effect in vitro. Overall, the results of this study suggest that the 5-HT2C receptor and intra-terminal calcium-dependent ethanol enhancement in GABA release acts to regulate the overall stimulatory effect of ethanol on VTA-DA activity. vi Table of Contents List of Figures.....................................................................................................xi Abbreviations....................................................................................................xiii Chapter 1: Introduction.......................................................................................1 1-1. Alcohol dependence...................................................................................1 1-1-1. Definition…………………………………………………………....…....1 1-1-2. Economic/societal impact……………………………………….….......2 1-1-3. Current treatment…………………………………………………..…....3 1-2. Ventral Tegmental Area ...............................…………………….................3 1-2-1. Anatomy and connectivity………………………………………..….…3 1-2-2. Cell types and electrophysiological properties…………………...….6 1-2-3. Neural substrates of addiction……………………....………….…......8 1-2-3-1. Mesocorticolimbic system………………………..............….8 1-2-3-2. Dopamine and reward/reinforcement…...….…..............….8 1-2-4. Ethanol and the mesolimbic system...............................................10 1-2-4-1. Ethanol enhances dopamine release...............................10 1-2-4-2. Direct and indirect effects on VTA-DA cell excitation.......12 1-2-5. Neurotransmitter receptors...........................………....…………….14 1-2-5-1. GABA receptors................................................................14 1-2-5-1-1. Ethanol and GABAA receptors............................16 1-2-5-1-2. Ethanol and GABA release.................................18 1-2-5-1-2-1. Hippocampus........................................19 vii 1-2-5-1-2-2. Amygdala..............................................20 1-2-5-1-2-3. Cerebellum...........................................21 1-2-5-1-2-4. VTA and SN..........................................22 1-2-5-1-2-5. Other brain regions...............................23 1-2-5-2. 5-HT2C receptors……………………………………….....…24 1-2-5-2-1. Ethanol and 5-HT...............................................25 1-2-5-3. Opioid receptors.………………………………………….…26 1-2-5-3-1. Ethanol and opioids............................................27 1-3. Calcium and neurotransmitter release .....................................................30 1-3-1. Role of extracellular calcium and VGCCs.......................................30 1-3-1-1. Ethanol and VGCCs.........................................................31 1-3-2. Role of IP3- and ryanodine-sensitive intracellular calcium stores……………………………………………………………………….......31 1-3-2-1. Ethanol and intracellular Ca2+ stores................................32 1-4. Hypothesis and Aims................................................................................33 Chapter 2: Ethanol Enhances GABAergic Transmission onto Dopamine Neurons in the Ventral Tegmental Area of the Rat.........................................36 2-1. Introduction...............................................................................................37 2-2. Materials and Methods.............................................................................38 2-2-1. Slice preparation............................................................................38 2-2-2. Electrophysiological recordings.....................................................39 2-2-3. Data analysis.................................................................................41 2-3. Results......................................................................................................41 viii 2-3-1. Baseline parameters of sIPSCs on VTA Neurons..........................41 2-3-2. Ethanol enhances GABAergic transmission in the VTA.................42 2-3-3. Ethanol potentiation of sIPSCs does not involve GABAB receptors...................................................................................................51 2-3-4. Ethanol potentiates GABA release in the VTA...............................54 2-4. Discussion................................................................................................56 2+ Chapter 3: Role of 5-Hydroxytryptamine2C Receptors in Ca -dependent Ethanol Potentiation of GABA Release onto Ventral Tegmental Area Dopamine Neurons............................................................................................62 3-1. Introduction...............................................................................................63 3-2. Materials and Methods.............................................................................66 3-2-1. Slice preparation.............................................................................66 3-2-2. Electrophysiological recordings of VTA-DA neurons......................67 3-2-3. Data analysis..................................................................................69 3-3. Results......................................................................................................70 3-3-1. Ethanol enhances mIPSC frequency..............................................70 3-3-2. Extracellular Ca2+ influx is not required for the ethanol-induced increase in GABA release..............................................................74 3-3-3. Intracellular Ca2+ stores are required for ethanol-induced enhancement of GABA release......................................................78 3-3-4. The 5-HT2C agonist, Ro-60-0175, and 5-HT
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