Tommy O’Regan tells the story of how, for the first time in medical history, a drug has been found to have completely opposing effects on the memories of mice depending on their sex.
A team of researchers investigating the molecular mechanisms underlying fear memories at the Universitat Autònoma de Barcelona (INc-UAB) has discovered something striking about the drug Osanetant. In a Nature Communications article, they revealed that the discontinued drug formerly researched to treat schizophrenia has opposing effects on male and female mice’s ability to recall traumatic events.
Trials have shown that, after being administered the drug, male mice experienced a reduced ability to remember and predict traumatic events, while female mice displayed an increased tendency to recall such events when the drug was administered during the proestrus stage of her hormonal cycle, just before ovulation.
So what are fear memories and why are they important? As an organism goes about its day, the brain stores information obtained from sense organs that can be retrieved as memories when necessary. Be it the familiar sight or scent of a bountiful fig tree, or the unsettling hissing and writhing displayed in a rattlesnake encounter, memories increase longevity throughout the animal kingdom. Fear memories are particularly potent when it comes to associating certain cues with potential danger and inciting fear responses in the organism, such as an increased heart rate to bolster their aversive skillset.
As our ancestors’ fears of starvation and predation are gradually replaced by modern-world afflictions like social rejection and isolation, the way we handle our fear memories remains deeply-rooted. Research suggests that the very fear memory process that once extended our ancestors’ lifetimes is causing psychological harm in the form of phobias and PTSD today. Andero’s team seeks to alleviate these disorders through research into blocking the mechanisms underlying fear memory.
“Research suggests that the very fear memory process that once extended our ancestors’ lifetimes is causing psychological harm in the form of phobias and PTSD today.”
Memory formation is widely categorised into two stages: short term memory (lasting minutes to hours) and long term memory (lasting days to years), and it is the consolidation of long term memories that involves the processes of gene regulation and protein synthesis. These processes are where Osanetant has its sexist functionality.
The brain is composed of neural pathways, and the Tachykinin 2 (Tac2) pathway is necessary for controlling fear memories. In the process of retrieving long-term fear memories, a sequence of complex pharmacological reactions occur including the synthesis of a neuropeptide NkB, and the binding of this NkB to a receptor called Nk3R. Osanetant is an Nk3R antagonist, meaning its shape allows it to get in the way of NkB and Nk3R from binding, which inhibits the fear memory retrieval process. It was subsequently hypothesised that this effect would be repeated in female mice, with suitable alterations in dose size. When Dr. Andero’s team discovered that female mice actually displayed an increased frequency of fear responses with fear memory retention being dependent on what stage of the hormonal cycle the female mouse was in, it was a fascinating and unprecedented discovery.
The reason for this sexual disparity is currently explained to be due to the sex hormone levels in the brain and their specific receptors in the central amygdala (testosterone in males and oestradiol in females). It was discovered that the hormonal cycle had a significant effect on results in female mice, with this incredible opposite effect only occurring in mice in the proestrus stage when oestradiol levels are at their highest. Simply put, the difference in sex hormone levels in the central amygdala in males and females affects the activation of a molecular mechanism with the catchy name of Akt/GSK3β/β-Catenin. This mechanism is also heavily involved in fear memory modulation. In females, the amount of oestradiol present in the brain can be high enough such that when osanetant activates the Akt/GSK3β/β-Catenin mechanism, the activation is increased. In males, the lack of oestradiol present means the activation of this mechanism is reduced. As a result, a male and female brain can intake exactly the same compound and, amazingly, experience opposite outcomes.
“A discovery like this sheds important light on the issue of sexual misrepresentation in clinical trials.”
A discovery like this sheds important light on the issue of sexual misrepresentation in clinical trials. Historically there has been a stark lack of clinical trials conducted on females compared to males. In recent years, researchers published 5.5 studies on males for every 1 on females. This disparity is even more alarming when you consider the evidence that women are more likely to have fear-related disorders such as phobias or PTSD. The team at INc-UAB initially reported their successes in understanding the Tac2 circuit in a previous paper having only studied male subjects, while predicting similar results in females. Had these researchers not subsequently tested the drug on female subjects of all hormone cycle stages, it isn’t hard to imagine the medical catastrophe that would have ensued. The hormonal mechanisms in mice and humans are strikingly similar, and Osanetant is safe for use in humans, so approval could have been granted quickly. The extremely damaging effect that Osanetant has on proestrus female patients would have gone under the radar, leading to exacerbation of pre-existing PTSD and phobia disorders.
Not only is this even more evidence to add to the plethora of reasons why the male and female body should be examined equally and independently in all clinical trials, it is food for thought when pondering the differences between the male and female brain. If Andero’s team could not predict that sex hormones had an effect on how the sexes process memories, one can only hypothesise what other neural pathways are guarded by hormonal gatekeepers that have not been stumbled upon in our long journey of fully understanding our minds.
Written by Tommy O’Regan who is a 4th year Biological & Medicinal Chemistry student, interested in pharmacology and drug discovery. You can find him on LinkedIn.
Edited by Ishbel Dyke.