PROJECT SUMMARY
Major depressive disorder (MDD) and alcohol use disorder (AUD) are comorbid. Acute alcohol decreases both
anxiety- and depressive-like behaviors. Chronic alcohol exposure increases both of these negative emotion-
like behaviors. In fact, decades of epidemiological data suggest that individuals use alcohol to alleviate a
negative affective state. Whether the negative emotional state is due to MDD or repeated alcohol exposure
(AUD), researchers are now beginning to examine how mechanisms that are initially positive and rewarding
shift toward negative affect/anhedonia during withdrawal. For example, much is known about the neural
circuitry and neurotransmitter/peptide systems underlying acute and chronic effects of alcohol on anxiety-like
behaviors. Surprisingly, much less attention has been directed at the negative affective (anhedonia)
component. Our preclinical work suggests that acute ethanol treatment produces an antidepressant-like effect
and hijacks the same biochemical pathway as NMDAR antagonists. Pivotal to ethanol and NMDAR
antagonists’ antidepressant efficacy is the dynamic expression of the RNA-binding protein Fragile X Mental
Retardation Protein (FMRP). Reduction in FMRP expression allows for the upregulation of transsynaptic
proteins that promote new synapse formation and antidepressant-like effects. Consistent with a shift from
positive to negative emotion-like behaviors, FMRP is upregulated during withdrawal in ethanol-dependent
animals. Using molecular, biochemical, and electrophysiological techniques, combined with a novel synapse
detection assay that we developed in our laboratory (DetectSyn), and the expertise of our collaborators in the
Weiner laboratory in preclinical models of alcohol dependence, we will determine in Specific Aim 1 if acute
ethanol regulates the binding of FMRP to transsynaptic mRNAs, regulates the synaptic protein synthesis of
these target mRNAs, and promotes new synapse formation. Moreover, in Specific Aim 2 we will determine if
the FMRP-regulated antidepressant signaling pathway is muted or suppressed during the WD/negative affect
state, and if acute ethanol treatment can reverse the biochemical and behavioral depressive phenotypes.
Furthermore, we will isolate and sequence FMRP target mRNAs that are repressed during WD but released
due to treatment with acute ethanol during WD. Using a computational/genomic approach such as the Library
of Integrated Network-Based Cellular Signatures – a method that has shown promise in AUD research – these
data will facilitate future studies using these targets to predict effective, repurposed FDA-approved drugs to
treat AUD and MDD. These studies will lay the foundation for future pharmacological intervention to treat
negative affect during WD in alcohol-dependent individuals with comorbid MDD.
