Sophia KHOM -AddRess Colloquia

"Sexually dimorphic regulation of central amygdala signaling in rodent models of alcohol use disorder"

Alcohol use disorder (AUD) is a chronic, relapsing disease marked by loss of control over alcohol intake and a negative emotional state during abstinence. The negative affect associated with AUD is primarily mediated by aberrant activity of the central nucleus of the amygdala (CeA).¹ The CeA is mainly composed of GABAergic neurons, and increased GABA transmission in males with AUD is considered as the characteristic feature of AUD conserved across species, including humans.^2,3 However, more recent findings suggest that many CeA-related mechanisms central to AUD progression and negative emotional states are either absent or differently regulated in females.⁴ Here, we will discuss sex-specific effects of acute and chronic alcohol exposure on CeA GABAergic activity in distinct rodent models of AUD. In addition, AUD compromises the balance of stress-enhancing and stress-reducing neuropeptide systems in the CeA shifting the balance towards hyperactive stress systems.¹ Notably, two key players in AUD pathogenesis - CRF and more recently Substance P (SP)- display sexually dimorphic regulation of CeA function. Therefore, this talk will highlight emerging novel evidence of sex-specific mechanisms in the CeA- and beyond- underlying AUD-related behaviors, emphasizing how these differences may inform the development of novel therapeutic strategies.

1. Koob, G. F. et al. Addiction as a stress surfeit disorder. Neuropharmacology 76 Pt B, 370–382 (2014).
2. Augier, E. et al. A molecular mechanism for choosing alcohol over an alternative reward. Science 360, 1321–1326 (2018).
3. Roberto, M., Kirson, D. & Khom, S. The Role of the Central Amygdala in Alcohol Dependence. Cold Spring Harb. Perspect. Med. 11, a039339 (2021).
4. Kirson, D. et al. Sex Differences in Acute Alcohol Sensitivity of Naïve and Alcohol Dependent Central Amygdala GABA Synapses. Alcohol Alcohol. Oxf. Oxfs. 56, 581–588 (2021).

Host: Harald SITTE and Matthaeus WILLEIT