Allopregnanolone is an inhibitory pregnane neurosteroid. It is a metabolite, or breakdown product, of the hormone progesterone, produced both in the brain and in the peripheral nervous system. This molecule is widely regarded as a positive mood regulator due to its tranquilizing and stress-reducing properties. Allopregnanolone helps the brain maintain emotional balance and regulate the effects of stress.
Mechanism of Action in the Brain
The function of allopregnanolone is tied to the brain’s main inhibitory network, governed by the neurotransmitter gamma-aminobutyric acid (GABA). The GABA system acts as the brain’s braking mechanism, reducing neuronal excitability to promote calmness. Allopregnanolone exerts its effects by targeting the GABA-A receptor, the primary docking site for GABA on nerve cells.
The neurosteroid functions as a positive allosteric modulator. This means allopregnanolone binds to a separate site on the receptor, enhancing the effects of the GABA already present. By binding to this site, allopregnanolone increases the frequency and duration that the chloride ion channel within the receptor remains open. The influx of negatively charged chloride ions hyperpolarizes the neuron, making it less likely to fire an electrical impulse, which translates to a calming effect.
Allopregnanolone is particularly effective at modulating a subset of GABA-A receptors containing the delta subunit, known as extrasynaptic receptors. These receptors mediate a sustained, low-level inhibition of the neuron, referred to as tonic inhibition. Potentiating this tonic current allows allopregnanolone to exert an anxiolytic effect at low concentrations, distinct from the focal effects of traditional sedatives.
Natural Roles in Stress and Reproduction
Allopregnanolone helps the body cope with stress. Following an acute stressor, the body rapidly increases production of this neurosteroid. This surge acts as a fast-acting anxiolytic, dampening the over-activation of the hypothalamic-pituitary-adrenal (HPA) axis, the body’s main stress response system. By inhibiting HPA axis activity, allopregnanolone helps restore emotional and physiological equilibrium after a stressful event.
The molecule’s concentrations fluctuate during the menstrual cycle, peaking in the luteal phase alongside the rise in its precursor, progesterone. The most significant physiological change occurs during pregnancy. Plasma progesterone levels increase substantially throughout gestation, leading to high allopregnanolone production, which can reach up to 100 milligrams per day.
This high concentration, which peaks during the third trimester, is thought to be neuroprotective for both the mother and the developing fetus. The sustained, elevated levels help protect the maternal brain from stress and promote the development of the fetal brain, preparing the maternal brain for the demands of the postpartum period.
Clinical Significance of Low Levels
A reduction in allopregnanolone is strongly associated with the onset of several mood and anxiety disorders. The most studied link is with Postpartum Depression (PPD), a condition that affects many women following childbirth. The prevailing theory is that the brain’s GABA-A receptors become accustomed to the high allopregnanolone levels present during the final months of pregnancy.
Following delivery, the placental source of progesterone and allopregnanolone is removed, causing levels to plummet rapidly, often within hours. This withdrawal is believed to destabilize the neural circuits that regulate mood, leading to the depressive and anxious symptoms characteristic of PPD. Research suggests that women who develop PPD may have had lower allopregnanolone levels earlier in their pregnancy, indicating a pre-existing vulnerability.
Beyond PPD, low concentrations of allopregnanolone have been observed in individuals with other stress-related mood conditions, including generalized anxiety disorder, major depressive disorder, and Post-Traumatic Stress Disorder (PTSD). This suggests that a failure to synthesize or utilize this neurosteroid contributes to mood dysregulation.
Therapeutic Applications
The discovery of allopregnanolone led to the development of fast-acting medications designed to mimic its function. These synthetic analogs are structurally similar to the natural neurosteroid and act on the GABA-A receptor site. Brexanolone, which is molecularly identical to allopregnanolone, was the initial therapeutic breakthrough.
Brexanolone (Zulresso) was the first FDA-approved drug specifically for PPD. It is administered as a continuous intravenous infusion over 60 hours to restore neurosteroid function. This enables rapid improvement in depressive symptoms, often within the 60-hour window, offering a significant advantage over traditional antidepressants.
Zuranolone is a subsequent development, offering a more convenient oral analog. Also indicated for PPD, Zuranolone works by the same positive allosteric modulation of the GABA-A receptor. Its oral delivery and two-week course of treatment eliminate the need for an inpatient stay required by intravenous Brexanolone. Research continues into the potential use of these analogs for other neurological conditions, including seizure disorders and essential tremor.