Alcohol use disorder (AUD) is a major public health problem. The central nucleus of the amygdala (CeA)
functions as a hub of stress and anxiety processing and plays a crucial role in the negative affect associated
with alcohol dependence and abstinence/withdrawal. Rodent studies attribute negative, reinforcement–driven
compulsive behaviors associated with alcohol dependence to an “imbalance” between neurotransmitters in the
brain pro-stress and anti-stress systems. Both corticotropin-releasing factor (CRF) and norepinephrine (NE)
pro-stress systems are critical in behavioral aspects of addiction, including the anxiogenic effects of drug
withdrawal. We have characterized the cellular mechanisms involved in the actions of alcohol and CRF on
GABA and glutamate signaling, and the neuroadaptations induced by alcohol dependence in CeA of male rats.
In addition, we found that NE, like CRF, strongly modulates CeA GABAergic transmission in naive, alcohol
dependent, and withdrawn male rats, and identified specific adrenergic receptors that mediate these effects.
However, it is unknown whether similar functional alterations occur in female rats. Notably, our preliminary data
identified compelling sex-specific differences showing that CeA GABAergic synapses differ in their sensitivity to
the acute effects of alcohol, CRF, NE and nociceptin/orphanin FQ (nociceptin). Concerning the latter, the
opioid-like peptide nociceptin exerts anti-stress effects by counteracting the function of endogenous CRF in the
brain, and our preliminary data show that nociceptin may also counteract NE functions. Surprisingly, no studies
have examined the effects of these neurotransmitter systems on CeA signaling in a sex-dependent manner.
Capitalizing on these recent preliminary findings, the main objective of this project is to test the hypothesis that
1) adaptive changes in pro-stress (CRF and NE) and anti-stress (nociceptin) systems in the CeA circuits are
differentially and sex-specifically recruited or suppressed through alcohol dependence, and 2) the disrupted
balance between these systems leads to significant dysregulation of CeA activity that contributes to the
negative affect associated with alcohol dependence and abstinence, as well as the sex differences in alcohol
abuse patterns. We propose two specific aims with a multidisciplinary approach using in vitro
electrophysiology, molecular biology, and behavioral studies to provide essential mechanistic data that can
elucidate the cellular basis of the susceptibility of AUD to stress and relapse. A better understanding of the
neuroadaptations shaping the synaptic networks involved in alcohol dependence represents a challenge to
alcohol researchers and will be critical toward identifying new promising avenues for therapeutic purposes to
alleviate AUD.