Allopregnanolone is a neurosteroid naturally produced in the body, synthesized from progesterone. This compound is produced in the adrenal glands, reproductive organs, and also directly within the brain. Its presence and function within the central nervous system have made it a point of interest in understanding mood and brain health. The concentration of this neurosteroid changes in response to various physiological states, influencing the brain’s internal environment.
The Role of Allopregnanolone in the Brain
Allopregnanolone is a neurosteroid synthesized within the brain that has rapid effects on neuronal excitability. Its primary mechanism of action involves the gamma-aminobutyric acid type A (GABA-A) receptor. GABA is the main inhibitory neurotransmitter in the brain, responsible for reducing neuronal excitability and producing a calming effect. Allopregnanolone functions as a positive allosteric modulator of this receptor, binding to a site distinct from GABA’s own binding site.
This binding enhances the receptor’s response to GABA. When allopregnanolone is present, the GABA-A receptor’s chloride ion channel opens more frequently or for a longer duration, allowing more chloride ions to enter the neuron. This influx makes the neuron less likely to fire an action potential, amplifying GABA’s natural inhibitory signal. This enhanced inhibition underlies its anxiolytic, sedative, and anticonvulsant properties.
The interaction is highly potent and affects various subtypes of GABA-A receptors, including those at the synapse and outside of it (extrasynaptic). The extrasynaptic receptors are particularly sensitive to allopregnanolone and mediate a constant, low-level inhibitory tone in the brain. By modulating both receptor types, allopregnanolone helps fine-tune the overall level of inhibition in the central nervous system.
Fluctuations During the Menstrual Cycle and Pregnancy
Allopregnanolone levels in the body are not constant, showing significant fluctuations that correspond with hormonal changes in women. During a menstrual cycle, its concentrations mirror those of progesterone. They remain low during the follicular phase and then rise significantly during the luteal phase after ovulation, contributing to the modulation of mood and nervous system excitability.
The most dramatic changes occur during pregnancy. As progesterone production from the placenta increases, so does the synthesis of allopregnanolone. Its concentration rises steadily throughout gestation, reaching peak levels in the third trimester that can be many times higher than those during the menstrual cycle. These elevated levels are thought to play a neuroprotective role for both the mother and fetus.
Following childbirth, the delivery of the placenta triggers an abrupt decline in both progesterone and allopregnanolone. Within hours to a few days, the levels of this neurosteroid crash from their pregnancy peak back to the low levels of the follicular phase. This sudden withdrawal of a powerful calming agent from the brain is a significant physiological event.
Connection to Mood and Neurological Conditions
The drop in allopregnanolone after childbirth is a leading theory for the development of postpartum depression (PPD). For susceptible women, the brain may struggle to adapt to the sudden loss of this enhanced GABAergic signaling. This withdrawal can lead to a state of neural hyperexcitability, contributing to symptoms of depression, anxiety, and insomnia. Studies have found that women with more severe PPD symptoms sometimes have lower postpartum allopregnanolone levels.
The influence of allopregnanolone extends beyond the postpartum period. Its cyclical fluctuations are also implicated in Premenstrual Dysphoric Disorder (PMDD), a severe form of premenstrual syndrome. In individuals with PMDD, an abnormal brain response to its changing levels during the luteal phase is thought to provoke negative mood symptoms. This suggests a vulnerability in the GABA system’s ability to handle hormonal shifts.
Dysregulation in the allopregnanolone-GABA system is also investigated in Major Depressive Disorder (MDD) and anxiety disorders. Research has shown that individuals with MDD may have lower levels of allopregnanolone in their cerebrospinal fluid. Its ability to reduce neuronal excitability suggests a potential role in managing conditions like epilepsy and protecting the brain from damage following a traumatic brain injury.
Therapeutic Applications
The understanding of allopregnanolone’s role in PPD led to the development of targeted therapies. The first of these was brexanolone (Zulresso), a synthetic, intravenous formulation of allopregnanolone approved for moderate to severe PPD. It is administered as a continuous 60-hour IV infusion in a monitored healthcare setting to rapidly restore neurosteroid levels. Clinical trials have shown this approach can lead to a rapid reduction in depressive symptoms.
The logistical challenge of an IV infusion prompted the development of zuranolone (Zurzuvae), an oral medication. This synthetic analog of allopregnanolone is also approved for PPD. Zuranolone is a once-daily pill taken for a 14-day course, making treatment more accessible for new mothers. Zuranolone is also being investigated for its effectiveness in treating MDD.
These neurosteroid-based treatments are associated with certain side effects. The most common adverse events for both brexanolone and zuranolone are related to their mechanism of action and include sedation, somnolence, and dizziness. Due to the risk of excessive sedation and potential loss of consciousness, brexanolone administration requires careful patient monitoring through a restricted program.