There is a growing body of evidence that endogenous opioid peptides, including proopiomelanocortin (POMC)- derived b-endorphin, can modulate the neurobiological responses to ethanol and that administration of ethanol alters the expression of POMC and b-endorphin. Given that ethanol has direct effects on POMC activity, it is possible that the other POMC-derived peptides, namely the melanocortins (MCs), are also involved with neurobiological responses to ethanol. MC peptides include a-melanocyte stimulating hormone (a-MSH), which is synthesized in the arcuate nucleus of the hypothalamus and projects to many brain regions of known relevance to alcoholism. Agouti-related protein, synthesized in the arcuate nucleus and secreted in the same terminals as a-MSH, is a natural MC receptor (MCR) antagonist. Consistent with a role in modulating neurobiological responses to ethanol, recent work has shown that MCR agonists reduce, and MCR antagonists increase, ethanol consumption in rodents, and that the MC-4 receptor (MC4R) modulates the effects of MCR compounds on ethanol drinking. Additionally, exposure to ethanol significantly reduces central a-MSH immunoreactivity (IR), and increases central AgRP IR, indicating that these endogenous MCR ligands modulate neurobiological responses to ethanol.
The specific aims proposed below will extend our recent findings by testing the guiding hypothesis that MC4R signaling modulates the reinforcing properties of ethanol and ethanol relapse-like behaviors, in a brain-region-specific and protein kinase A (PKA)- dependent fashion. Specifically, we will determine if operant self-administration of ethanol alters a-MSH, AgRP, MC3R and/or MC4R IR in specific brain regions (Specific Aim 1), if a MC4R agonist modulates ethanol self-administration in brain regions implicated in ethanol reinforcement (Specific Aim 2), if MC4R signaling requires normal PKA activity to modulate operant self-administration of ethanol (Specific Aim 3), and if MC4R signaling modulates relapse-like behaviors (Specific Aim 4). These studies will provide important insight into the mechanisms by which MC4R signaling modulates the reinforcing properties of ethanol and relapse of ethanol-seeking behaviors.
Despite years of research and a wealth of important information, the neurobiological factors that leave some individuals vulnerable to alcohol abuse and alcoholism remain unclear. One hypothesis is that some individuals show increased sensitivity to the reinforcing properties of alcohol, leading to increased early use and a subsequent increased risk of dependence. The work that is outlined in the current proposal will show that melanocortin neuropeptides modulate the reinforcing properties of alcohol and relapse of alcohol-seeking behavior following abstinence.
|Olney, Jeffrey J; Marshall, S Alex; Thiele, Todd E (2018) Assessment of depression-like behavior and anhedonia after repeated cycles of binge-like ethanol drinking in male C57BL/6J mice. Pharmacol Biochem Behav 168:1-7|
|Companion, Michel A; Thiele, Todd E (2018) Assessment of ventral tegmental area-projecting GABAergic neurons from the bed nucleus of the stria terminalis in modulating binge-like ethanol intake. Eur J Neurosci 48:3335-3343|
|Burnham, Nathan W; Thiele, Todd E (2017) Voluntary Binge-like Ethanol Consumption Site-specifically Increases c-Fos Immunoexpression in Male C57BL6/J Mice. Neuroscience 367:159-168|
|Carvajal, Francisca; Lerma-Cabrera, José M; Alcaraz-Iborra, Manuel et al. (2017) Nucleus Accumbens MC4-R Stimulation Reduces Food and Ethanol Intake in Adult Rats Regardless of Binge-Like Ethanol Exposure during Adolescence. Front Behav Neurosci 11:167|
|Olney, Jeffrey J; Navarro, Montserrat; Thiele, Todd E (2017) The Role of Orexin Signaling in the Ventral Tegmental Area and Central Amygdala in Modulating Binge-Like Ethanol Drinking Behavior. Alcohol Clin Exp Res 41:551-561|
|Marshall, S Alex; McKnight, Kyle H; Blose, Allyson K et al. (2017) Modulation of Binge-like Ethanol Consumption by IL-10 Signaling in the Basolateral Amygdala. J Neuroimmune Pharmacol 12:249-259|
|Rinker, Jennifer A; Marshall, S Alex; Mazzone, Christopher M et al. (2017) Extended Amygdala to Ventral Tegmental Area Corticotropin-Releasing Factor Circuit Controls Binge Ethanol Intake. Biol Psychiatry 81:930-940|
|Marshall, S Alex; Casachahua, John D; Rinker, Jennifer A et al. (2016) IL-1 receptor signaling in the basolateral amygdala modulates binge-like ethanol consumption in male C57BL/6J mice. Brain Behav Immun 51:258-67|
|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|
|Sprow, Gretchen M; Rinker, Jennifer A; Lowery-Gointa, Emily G et al. (2016) Lateral hypothalamic melanocortin receptor signaling modulates binge-like ethanol drinking in C57BL/6J mice. Addict Biol 21:835-46|
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