There is a growing body of evidence suggesting that ethanol is used and abused for both its positive and negative reinforcing effects and that ethanol-mediated anxiolysis represents an important element of the negative reinforcement associated with ethanol drinking. Moreover, recent studies have suggested that ethanol's negative reinforcing effects gain salience with repeated ethanol exposure and withdrawal and may play an integral role in the development of, and relapse to, abusive drinking. Although much is known about the neurophysiological mechanisms responsible for the positive reinforcement associated with ethanol consumption, less is known about the neurocircuitry that contributes to many of ethanol's negative reinforcing effects. The overarching goal of this proposal is to integrate electrophysiological and behavioral approaches to begin to examine some of the neurophysiological mechanisms that may contribute to ethanol's anxiolytic effects. Specifically, these experiments will integrate electrophysiological and behavioral approaches to begin to address the central hypothesis that ethanol potentiation of GABAergic inhibition in the basolateral nucleus of the amygdala (BLA) contributes to specific measures of ethanol-mediated anxiolysis. Preliminary and published data suggest that there are two main GABAergic circuits within the BLA that mediate paracapsular, feedforward- and local, feedback-inhibition onto the principal output cells of this nucleus.
Aims 1 and 2 will test the working hypothesis that ethanol potentiates both circuits, albeit via distinct mechanisms. We also plan to take advantage of a genetically engineered mouse line with increased sensitivity to some acute anxiolytic effects of ethanol. By combining behavioral and ex vivo electrophysiological studies in these genetically engineered mice (Aim 3) and outbred rats (Aim 4), we will test the working hypothesis that there is a positive relationship between ethanol potentiation of local and/or paracapsular GABAergic inhibition in the BLA and specific measures of ethanol-mediated anxiolysis. Collectively, these studies will identify the mechanisms that mediate and regulate ethanol potentiation of local and paracapsular GABAergic inhibition in the BLA and provide initial insight into some of the synaptic mechanisms that may contribute to ethanol's anxiolytic effects.
The first two aims of this proposal seek to determine how ethanol enhances two distinct inhibitory circuits in the basolateral amygdala (BLA), a brain region that has long been thought to play an integral role in the regulation of anxiety-like behaviors. Aims 3 and 4 outline a novel strategy that integrates behavioral and electrophysiological approaches to begin to assess the relationship between ethanol potentiation of BLA GABAergic inhibition and measures of ethanol-mediated anxiolysis. The results of these studies may lead to a better understanding of some of the neurobiological mechanisms that contribute to ethanol's anxiolytic effects and potentially reveal novel synaptic elements that can be targeted for the development of more effective treatments for alcoholism.
|Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P et al. (2016) Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors. Neuroscience 333:54-64|
|Karkhanis, Anushree N; Alexander, Nancy J; McCool, Brian A et al. (2015) Chronic social isolation during adolescence augments catecholamine response to acute ethanol in the basolateral amygdala. Synapse 69:385-95|
|Adamah-Biassi, Ekue B; Almonte, Antoine G; Blagovechtchenski, Evgeny et al. (2015) Real time adenosine fluctuations detected with fast-scan cyclic voltammetry in the rat striatum and motor cortex. J Neurosci Methods 256:56-62|
|Karkhanis, Anushree N; Locke, Jason L; McCool, Brian A et al. (2014) Social isolation rearing increases nucleus accumbens dopamine and norepinephrine responses to acute ethanol in adulthood. Alcohol Clin Exp Res 38:2770-9|
|Gill, Kathryn E; Chappell, Ann M; Beveridge, Thomas J R et al. (2014) Chronic methylphenidate treatment during early life is associated with greater ethanol intake in socially isolated rats. Alcohol Clin Exp Res 38:2260-8|
|Skelly, Mary J; Weiner, Jeff L (2014) Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use. Brain Behav 4:468-83|
|Butler, Tracy R; Carter, Eugenia; Weiner, Jeffrey L (2014) Adolescent social isolation does not lead to persistent increases in anxiety- like behavior or ethanol intake in female long-evans rats. Alcohol Clin Exp Res 38:2199-207|
|Rau, Andrew R; Ariwodola, Olusegun J; Weiner, Jeff L (2014) Presynaptic adenosine AÃ½Ã½Ã½ receptors modulate excitatory transmission in the rat basolateral amygdala. Neuropharmacology 77:465-74|
|Butler, T R; Chappell, A M; Weiner, J L (2014) Effect of *3 adrenoceptor activation in the basolateral amygdala on ethanol seeking behaviors. Psychopharmacology (Berl) 231:293-303|
|Abrahao, Karina Possa; Ariwodola, Olusegun J; Butler, Tracy R et al. (2013) Locomotor sensitization to ethanol impairs NMDA receptor-dependent synaptic plasticity in the nucleus accumbens and increases ethanol self-administration. J Neurosci 33:4834-42|
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