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  • Although the findings detailed above provide


    Although the findings detailed above provide ample evidence that the activity of the CRF1 receptor in the amygdala plays a role in the acute and chronic effects of alcohol exposure, several important areas of investigation remain understudied. The majority of the work on CRF1-alcohol interactions has been studied in the CeA, but the BLA clearly plays an important role in alcohol-related behaviors and undergoes significant molecular adaptations following alcohol exposure. Future work should examine the effects of alcohol on CRF1+ and CRF1− Cycloheximide within the BLA to complement the existing work from the CeA. At present, work on the CRF system and alcohol in the amygdala has focused on three discrete facets of this system: CRF peptide, the CRF1/CRF2 receptors, and CRF1-containing cell populations. It will be critical for future work to establish clear roles for these various components of the CRF system in alcohol-related behaviors, and to understand how they interact with one another to produce alterations in amygdala activity and behavior. Additionally, a functional role for CRF1 activity on alcohol-induced alterations in CeA glutamatergic activity has not yet been established. Lastly, two studies (Herman, Contet et al., 2013, Roberto et al., 2010) provide initial evidence of the impact of chronic alcohol exposure on the CRF system of the CeA, but specific circuit dissection and the identification of mechanisms behind this effect have not been performed. Recently, PKCε has emerged as an important regulator of CeA GABAergic transmission, CRF1 activity, and alcohol effects in acute alcohol models. Studies utilizing systemic knockout and intra-amygdala knockdown of PKCε have resulted in reduced alcohol intake, reduced alcohol intoxication, and altered GABAergic transmission both at baseline and in response to alcohol (Choi et al., 2008, Lesscher et al., 2009). Binge-like alcohol drinking, in which non-dependent subjects achieve a high blood-alcohol concentration during a limited window of alcohol access, has been shown to increase expression of PKCε in the CeA, and inhibition of PKCε specifically within the CeA reduced alcohol consumption in the binge model (Cozzoli et al., 2016). Given that PKCε has been shown to mediate some of the effects of CRF and alcohol on CeA GABAergic activity (Bajo et al., 2008, Blasio et al., 2018), the relationship between PKCε, CRF1 signaling, and alcohol consumption warrants further investigation. If indeed native PKCε serves to inhibit GABAergic activity in the CeA, the acute increase in PKCε expression following subchronic alcohol exposure may represent a compensatory mechanism to offset the acute enhancement of GABAergic signaling induced by alcohol. However, the effect of chronic alcohol on PKCε expression or activity, and the potential functions of PKCε in models of alcohol dependence, remain to be explored. PKC has also been implicated in the stress-inducing effects of intra-ventricular CRF infusion (Toth, Gresack, Hauger, Halberstadt, & Risbrough, 2013) and has a well-established role in learning and memory (Sun & Alkon, 2014). These features make PKCε a particularly attractive target for investigation of the overlap, or lack thereof, of amygdalar signaling mechanisms in anxiety and alcoholism. Inhibitors that are selective for PKCε may also represent a more fine-tuned approach to pharmacological intervention in AUD, given the failure of systemic CRF1 antagonists to reduce alcohol craving in human participants (Kwako et al., 2015, Schwandt et al., 2016). Another important consideration in the ongoing quest to clarify the role of CRF1 signaling in alcoholism and anxiety is the role of developmental stage. Adolescence is a time of heightened emotionality and stress responsivity (Casey et al., 2010), accompanied by alterations in the HPA axis generally and the cortisol system specifically (Apter, Pakarinen, Hammond, & Vihko, 1979). Findings from studies utilizing models of adolescent social isolation stress have demonstrated alterations in alcohol intake, amygdala function, and anxiety-like behaviors (Butler et al., 2016, Karkhanis et al., 2015, Rau et al., 2015, Skelly et al., 2015), suggesting the potential for overlapping circuitry for these behaviors during adolescent brain development. Exposure to alcohol (Grant & Dawson, 1997) and stress (Burke & Miczek, 2014) during adolescence has also been shown to substantially enhance the lifetime risk for alcoholism in human participants and increase adult alcohol consumption in rodent models. However, the specific molecular and cellular mechanisms responsible for this increased risk remain unclear. CRF represents a system where stress and alcoholism converge, and therefore may play a role in mediating the long-lasting effects of adolescent alcohol exposure. To date, this possibility has received relatively little investigation. Adolescent alcohol exposure has been shown to both increase (Karanikas et al., 2013) and decrease (Allen et al., 2011) CRF immunoreactivity in the CeA. Additionally, age and sex differences in the ontogeny of the CRF1 receptor have been cataloged in many limbic brain regions, including the hypothalamus, ventral tegmental area, nucleus accumbens, and hippocampus (Lukkes et al., 2016, Weathington et al., 2014), but the development of this receptor in the amygdala has not been studied. Age differences in sensitivity to CRF1 antagonist effects on alcohol consumption and GABAergic neurotransmission in brain regions relevant Cycloheximide to addiction and anxiety have also not been explored. Such studies would provide important insight into the progression of alcohol use disorders over the lifespan and may reveal potential molecular mechanisms underlying age differences in alcohol intake and lifetime risk of AUD.