Individuals with major depressive disorder (MDD) have double the risk of alcohol use disorders (AUDs) and vice versa, and it has previously been proposed that some people with MDD may use alcohol to self-medicate. Though alcohol can become depressant if used chronically, alcohol initially has an antidepressant effect, though the underlying mechanisms have not been identified. Findings reported in September 2016 in Nature Communications begin to elucidate the basis of this action.
Behavioral and molecular evidence of the rapid antidepressant activity of NMDA receptor (NMDAR) antagonists, which have been found to be effective within 2 hours of administration and remain so for 2 weeks, represents a significant advance in depression treatment. Antidepressant efficacy involves the induction phase and the sustained phase.
The sustained phase of rapid antidepressants requires “both new protein synthesis and an increase in protein stability… for the GABABR shift in function necessary to increase” the activity of mTORC1, a mechanistic target of rapamycin complex 1, the authors explained in their paper. Rapamycin (mTOR) is a “serine/threonine kinase essential for messenger RNA translation” and is required for the sustained impact off rapid antidepressants.
Citing previous findings that ethanol (EtOH) also blocks NMDARs in the hippocampus, scientists at the University of Texas at Austin and Wake Forest University School of Medicine in Winston-Salem, North Carolina, aimed to determine whether EtOH and NMDAR antagonists exert rapid antidepressant effects via the same synaptic pathways in rodents. They hypothesized that EtOH “has lasting antidepressant efficacy, shares the same downstream molecular signaling events as rapid antidepressants, and requires de novo protein synthesis.”
First, they found that acute exposure to EtOH led to antidepressant and anxiolytic behaviors in rodents for up to 24 hours. They then discovered that, like NMDAR antagonists, EtOH alters the expression and signaling of GABABR, increases dendritic calcium, and leads to the synthesis of new GABABRs. This synthesis requires fragile-X mental retardation protein (FMRP), an RNA-binding protein of which precise levels are needed for normal neuronal functioning.
The antidepressant effects and the changes in GABABR expression and dendritic calcium were not observed in in Fmr1-knockout (KO) mice, supporting the concept that FMRP has in important role in regulating protein synthesis after EtOH exposure, and thereby facilitating its antidepressant efficacy.
These results point to a shared molecular pathway for the antidepressant activity of EtOH and rapid antidepressants, and highlight a mechanism involved in the initial antidepressant action of alcohol. “A shift in GABABR signaling is observed with both rapid antidepressants and acute EtOH treatment, which may provide insight into the molecular basis for the high comorbidity between major depressive disorder and AUD,” the authors concluded.
Wolfe SA, Workman ER, Heaney CF, et al. FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties. Nature Communications. 2016; doi:10.1038/ncomms12867