Noradrenaline modulates central amygdala GABA transmission and alcohol drinking in female rats

Background: Alcohol use disorder (AUD) is a chronic relapsing disorder and a leading preventable cause of death worldwide. The central nucleus of the amygdala (CeA) is a hub for stress and AUD. Noradrenaline (norepinephrine; NE) regulates the brain's response to stress and alcohol. We previously reported that α1 adrenergic receptors drive moderate alcohol intake, while β receptors contribute to excessive drinking associated with dependence in male rats. Methods: Here, we determined that alcohol dependence and withdrawal alter the CeA noradrenergic system in female rats using ex vivo electrophysiology, in situ hybridization, site-specific behavioral pharmacology, and RNA-sequencing data from postmortem CeA samples obtained from female donors with and without AUD. Results: NE bidirectionally (increase and decrease) modulated CeA GABAergic transmission via both α1 and β receptors. Prazosin, an α1 receptor antagonist, reduced moderate alcohol intake in non-dependent female rats and excessive drinking in dependent females, while propranolol, a β receptor antagonist, only reduced excessive drinking in dependent females. While withdrawal produced a partial functional recovery of the NE modulation of the CeA, some of the cellular patterns of adrenergic receptor mRNA expression persist. Although we did not observe any differences in adrenergic receptor gene expression in the CeA from our human AUD donors, we found a downregulation of ADRA1A in the basolateral amygdala and the dorsolateral prefrontal cortex, compared to controls. Conclusions: Amygdalar α1 and β adrenergic receptors are key neural substrates of AUD. Our results support ongoing development of receptor-specific medication for AUD and highlight promising efficacy in females.