A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies

Abstract

For many years, research from around the world has suggested that the neuroactive steroid (3a,5a)-3hydroxypregnan-20-one (allopregnanolone or 3a,5a-THP) may have therapeutic potential for treatment of various symptoms of alcohol use disorders (AUDs). In this critical review, we systematically address all the evidence that supports such a suggestion, delineate the etiologies of AUDs that are addressed by treatment with allopregnanolone or its precursor pregnenolone, and the rationale for treatment of various components of the disease based on basic science and clinical evidence. This review presents a theoretical framework for understanding how endogenous steroids that regulate the effects of stress, alcohol, and the innate immune system could play a key role in both the prevention and the treatment of AUDs. We further discuss cautions and limitations of allopregnanolone or pregnenolone therapy with suggestions regarding the management of risk and the potential for helping millions who suffer from AUDs.

Neurosteroid allopregnanolone (3α,5α-THP) inhibits inflammatory signals induced by activated MyD88-dependent toll-like receptors

“…In summary, the ability of 3α,5α-THP to inhibit MyD88-dependent TLR signals suggests a wide applicability to many inflammatory conditions that involve TLR activation of pro-inflammatory pathways 27 , 28 , 31 . Since neurosteroids, like immune factors, circulate in the bloodstream, cross the blood brain barrier, diffuse between different cell types, and exhibit paracrine effects in many cells, it is likely that neurosteroids are endogenous modulators of TLR activation and may contribute to inflammatory disease susceptibility and recovery.…”

“…It acts upon synaptic and extrasynaptic γ-aminobutyric acid type A (GABA A ) receptors to mediate phasic and tonic inhibition 19 , 20 , has anesthetic, anticonvulsant, sedative, and anxiolytic effects 21 , and modulates the hypothalamic pituitary adrenal axis to reduce stress activation 22 . Significantly, 3α,5α-THP and/or its precursors progesterone and pregnenolone, were shown to be effective in clinical studies of traumatic brain injury 23 , schizophrenia 24 , cocaine craving 25 , and post-partum depression 26 , identifying them as promising therapeutics 27 , 28 . Remarkably, these diverse conditions all exhibit pro-inflammatory immune and neuroimmune activation.…”

Adolescent Alcohol and Stress Exposure Rewires Key Cortical Neurocircuitry

“…These maturational changes are susceptible to exposure to alcohol or stress during this period, with behavioral and structural changes often becoming permanent. Promising targets for future research may include populations of GABAergic neurons, as alcohol and stress both impact this system ( Morrow et al, 2020 ; Woodward and Coutellier, 2021 ). Further investigation into behavioral effects of adolescent alcohol or stress may uncover potential factors influencing individual sensitivity to these insults, as there is often variability in outcomes in human studies.…”

“…Administration of neuroactive steroids has reduced voluntary alcohol consumption in male rats exposed to ethanol during adolescence ( Gurkovskaya et al, 2009 ). Because of this demonstrated effect, neuroactive steroids have emerged as a potential treatment strategy for AUD ( Morrow et al, 2020 ); however, studies testing the efficacy of neuroactive steroids across sex and broader age ranges are limited.…”

Epigenetic Regulation of GABAergic Neurotransmission and Neurosteroid Biosynthesis in Alcohol Use Disorder

“…Since acute alcohol stimulates neurosteroidogenesis ( Korpi et al, 2001 ; Khisti et al, 2002 ), the dampened response we observed after long-term chronic alcohol consumption may be related to an adaptive mechanism leading to alcohol dependence. This may provide a rationale for the use of synthetic neurosteroids (e.g., allopregnanolone) in the treatment of AUD ( Morrow et al, 2020 ). Our previous work showed similar effects in the hippocampus of rats exposed to chronic intermittent ethanol administration ( Cagetti et al, 2004 ).…”