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  • Finally the recent work to

    2021-04-08

    Finally, the recent work to define the microcircuitry of the central amygdala and the role of specific cell populations in fear conditioning can stand as a useful model for advances in preclinical alcohol research. To date, the role of the amygdala in alcohol-related behaviors, and reward-related behaviors in general, has focused on projections between the amygdala and other limbic circuitry. For instance, several studies have identified a role for an excitatory projection from the BLA to the NAc in behavior related to both natural and drug reward. Stuber et al. (2011) characterized this cell population and demonstrated that activation of this projection was sufficient to maintain self-administration of optical stimulation. Further, inhibiting this pathway reduced cued sucrose intake. Two recent papers have established a role for this pathway in alcohol-related behaviors. Keistler et al. (2017) found that selective ablation of cells in the BLA to NAc projection reduces reinstatement of alcohol seeking in rats. Millan, Kim, and Janak (2017) demonstrated that activation of this pathway reduced alcohol drinking and cue-induced alcohol seeking. These findings provide compelling evidence of the central role the amygdala plays in the regulation of downstream brain regions and the expression of alcohol-related behaviors. However, the role of intra-amygdala microcircuits on the overall activity of amygdalar subnuclei and the ways in which this circuitry modulates alcohol seeking, consumption, and withdrawal behaviors have not been assessed. The recent work to characterize local microcircuits within the CeA in the context of fear conditioning has identified several important cell populations, including the CRF1+, SOM+, and PKCδ+ cells of the CeAM and CeAL, whose sensitivity to acute and chronic alcohol has received limited investigation. Differences in the functional role of these populations on alcohol-related behaviors remain to be studied. Engagement of this circuitry by alcohol may drive changes in amygdala activity associated with anxiety and stress, and conversely activation of some or all of these populations by stress may alter their sensitivity to the effects of alcohol. With the identification of these discrete cell populations within the amygdala, both in the context of fear conditioning and alcohol exposure, the stage is set for the thorough mechanistic evaluation of the functional role of the intra-amygdala architecture in the cellular, regional, and behavioral effects of alcohol.
    Funding This work was supported by the Bowles Center for Alcohol Studies and the National Institute of Health [grants # AA023002 and R13AA017581].
    Introduction Nicotine dependence drives the habit of smoking, which causes a heavy load of disease and death, as smoking is one of the largest contributors to preventable morbidity and mortality (GBD 2015 Risk Factors Collaborators, 2016; World Health Organization(WHO), 2017). Inhaled nicotine reaches the brain, where it binds and activates nicotinic Mexiletine HCl receptors (Hurst et al., 2013; Zoli et al., 2015) in several brain regions, including the mesocorticolimbic regions involved in the reward system (Picciotto and Kenny, 2013). Nicotine stimulates dopamine release from neurons originating in the ventral tegmental area (VTA) and terminating in the nucleus accumbens and prefrontal cortex (PFCx). Repeated nicotine exposure causes long-lasting adaptations of dopaminergic transmission that mediate the motivation to maintain nicotine self-administration despite the known harmful effects. The long-term effects of nicotine that support compulsive use require the activation, desensitization, and up-regulation of the nicotinic receptor to mediate alterations in the activity of the neuronal circuitry of the mesocorticolimbic system (De Biasi and Dani, 2011; Pistillo et al., 2015). The changes in synaptic function are based on the regulation of transcriptional and epigenetic modulations that sustain the onset of addiction (Pistillo et al., 2015). Among the systems which mediate the neurobiological adaptations supporting addiction, a role has been proposed for the corticotropin releasing factor (CRF) system (Koob, 2010; Zorrilla et al., 2014). CRF (also known as CRH) is a 41-amino acid neuropeptide that has a role in coordinating the endocrine, autonomic, and behavioural response to stress through the regulation of the hypothalamic-pituitary-adrenal stress system (Bale and Vale, 2004). In addition to the stress-response regulation related to its hypothalamic expression, a wider set of functions were discovered in association with CRF expression in numerous brain areas which demonstrate its relevance in anxiety, depression, and addiction (Bale and Vale, 2004; Hauger et al., 2006; Zorrilla et al., 2014). The CRF family includes three additional members called urocortin 1, urocortin 2 and urocortin 3, which show a more confined expression ocurring mainly in hypothalamic and brainstem structures (Hauger et al., 2006). CRF released from synaptic vesicles plays a neuromodulatory role that varies depending on whether the neuropeptide and its receptor are expressed on glutamatergic or GABAergic neurons, which leads to different responses in distinct brain regions (Henckens et al., 2016). CRF binds to two G-protein-coupled receptors, CRF1R and CRF2R, with a 4- to 20-fold higher affinity towards CRF1R, thus activating signal transduction pathways including cyclic AMP–protein kinase A, mitogen-activated protein kinases, and other pathways. These signals result in modulating the transcription of downstream target genes, synaptic transmission, and plasticity, thus mediating short- and long-term effects (Hauger et al., 2006; Henckens et al., 2016). Within the conceptual three-stage framework for addiction, comprising of Mexiletine HCl binge/intoxication, reward, and withdrawal (Koob and Volkow, 2016, 2010), a role for the CRF system has been mainly proposed in the withdrawal phase in association with negative affect, dysphoria, and anxiety feelings (Baiamonte et al., 2014; Bruijnzeel et al., 2012, 2009; Cohen et al., 2015; George et al., 2007; Koob, 2010; Marcinkiewcz et al., 2009; Zhao-Shea et al., 2015). However, a significant role in the reward component cannot be ruled out (Brielmaier et al., 2012; Lemos et al., 2012; Peciña et al., 2006).