Alcohol abuse is an enormous public health problem and while there have been significant gains in our knowledge of this disorder, there remains a gap in our knowledge of the fundamental biological mechanisms that contribute to its chronic relapsing nature. It has been hypothesized that alcohol exposure modifies function in brain regions critical for regulation of emotion, and that these changes underlie the persistent alterations in behavior. The 5HT system has been implicated in the pathophysiology of a range of psychiatric conditions, most notably anxiety disorders and depression. In keeping with the co-morbidity of these conditions, the 5HT system is proposed to be involved in the development of alcoholism. Altered 5HT signaling has been suggested to contribute to cravings and relapses as well as the increased negative affect, manifested as increased anxiety-like behavior and dysphoria, that is associated with alcohol abuse. The BNST is a structure that has been proposed to be a site of neuroadaptations underlying these behavioral alterations. Further, 5HT signaling within the BNST has been associated with anxiety-like behavior. The ability of 5HT to modulate synaptic transmission in the BNST, and the possibility that this modulation may be altered following ethanol exposure, however, has not been studied in depth. A thorough understanding of the effects of alcohol exposure on 5HT function in the BNST will provide critical mechanistic insight in to alcohol-withdrawal induced anxiety. In preliminary studies, we show that 5HT modulates synaptic transmission in the BNST via activation of 5HT2C-R and that alcohol exposure alters 5HT levels and receptor expression in the BNST. These results support our central hypothesis that: Dysregulation of 5HT2C-R signaling in the BNST following chronic ethanol exposure is associated with alcohol withdrawal induced behavioral deficits. The following three separate but integrated Specific Aims are proposed to test our central hypothesis: SA#1. Test the hypothesis that 5HT2C-R increases GABA release on to an important population of feed- forward inhibitory neurons. SA#2. Test the hypothesis that alcohol exposure enhances 5HT2C-R function in the BNST. SA#3. Test the hypothesis that anxiety-like behavior is increased following alcohol exposure through activation of 5HT2C-R. In total, the proposed research will provide essential information concerning the role that the 5HT2C-R plays in alcohol-induced dysregulation of neuronal function and behavior. Further, given the ability of the 5HT2 agonist, mCPP, to increase craving in alcoholics, this study could shed important light on both craving and relapse. Understanding molecular mechanisms that underlie these processes could lead to more effective therapeutic interventions.
The focus of this project is to understand how alcohol exposure alters emotional behavior. Successful completion of this project will result in a greater understanding of how alcohol changes brain function. Further, these studies may provide insight as to how to develop more useful treatments for alcoholism and anxiety disorders. The focus of this project is to understand how alcohol exposure alters emotional behavior. Successful completion of this project will result in a greater understanding of how alcohol changes brain function. Further, these studies may provide insight as to how to develop more useful treatments for alcoholism and anxiety disorders.
|Hwa, Lara S; Neira, Sofia; Pina, Melanie M et al. (2018) Predator odor increases avoidance and glutamatergic synaptic transmission in the prelimbic cortex via corticotropin-releasing factor receptor 1 signaling. Neuropsychopharmacology :|
|Mazzone, C M; Pati, D; Michaelides, M et al. (2018) Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. Mol Psychiatry 23:143-153|
|Yu, Waylin; Hwa, Lara S; Makhijani, Viren H et al. (2018) Chronic inflammatory pain drives alcohol drinking in a sex-dependent manner for C57BL/6J mice. Alcohol :|
|Jury, Nicholas J; Radke, Anna K; Pati, Dipanwita et al. (2018) NMDA receptor GluN2A subunit deletion protects against dependence-like ethanol drinking. Behav Brain Res 353:124-128|
|Radke, Anna K; Jury, Nicholas J; Kocharian, Adrina et al. (2017) Chronic EtOH effects on putative measures of compulsive behavior in mice. Addict Biol 22:423-434|
|Hwa, Lara; Besheer, Joyce; Kash, Thomas (2017) Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective. F1000Res 6:298|
|Salling, Michael C; Faccidomo, Sara P; Li, Chia et al. (2016) Moderate Alcohol Drinking and the Amygdala Proteome: Identification and Validation of Calcium/Calmodulin Dependent Kinase II and AMPA Receptor Activity as Novel Molecular Mechanisms of the Positive Reinforcing Effects of Alcohol. Biol Psychiatry 79:430-42|
|Navarro, Montserrat; Olney, Jeffrey J; Burnham, Nathan W et al. (2016) Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli. Neuropsychopharmacology 41:1505-12|
|Crowley, Nicole A; Bloodgood, Daniel W; Hardaway, J Andrew et al. (2016) Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit. Cell Rep 14:2774-83|
|Hardaway, J Andrew; Jensen, Jennifer; Kim, Michelle et al. (2016) Nociceptin receptor antagonist SB 612111 decreases high fat diet binge eating. Behav Brain Res 307:25-34|
Showing the most recent 10 out of 32 publications