Mechanisms in ethanol modulation of GABA release onto dopaminergic neurons of the ventral tegmental area

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Title: Mechanisms in ethanol modulation of GABA release onto dopaminergic neurons of the ventral tegmental area
Author: Theile, Jonathan William
Abstract: 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 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 .
URI: http : / /hdl .handle .net /2152 /ETD -UT -2009 -12 -491
Date: 2010-08-27

Citation

Mechanisms in ethanol modulation of GABA release onto dopaminergic neurons of the ventral tegmental area. Doctoral dissertation, The University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /ETD -UT -2009 -12 -491 .

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