How SSRIs Affect Hypothalamus and Hormones

Introduction

In previous articles, I’ve emphasized the importance of the 5-HT1A receptor in understanding the enduring effects of SSRI treatment (read more). This specific serotonin receptor is crucial not only for the intended action of SSRIs but also for the broad range of unintended effects they may produce. The 5-HT1A receptor is expressed in neurons projecting into areas like the prefrontal cortex, hippocampus, and hypothalamus. In this article, I’ll focus on its projections into the hypothalamus, as they play a vital role in understanding the potential long-term changes in hormonal balance associated with SSRI treatment.

The hypothalamus is a small but highly important structure in the middle of the brain, sitting just above the brain stem. It integrates signals from the nervous system to produce changes in hormone release via the pituitary gland. This makes it central to regulating sexual response, hunger, sleep, body temperature and more. It’s therefore of particular concern that chronic exposure to SSRIs can lead to alterations in the functioning of the hypothalamus by impacting the 5-HT1A receptor.

How do SSRIs Impact the 5-HT1A Receptor

The 5-HT1A receptor is a serotonin receptor, which means it is bound by the neurotransmitter serotonin to exert its effects. The 5-HT1A receptors are inhibitory, as evidenced by a reduction in AMPA-evoked currents when bound by serotonin (AMPA receptors are bound by the excitatory neurotransmitter glutamate). Binding the 5-HT1A receptor suppresses neuronal activity through various mechanisms, including potassium channel activation and calcium channel inhibition. By causing a neuron to become hyperpolarised, it cannot reach its action potential and, therefore, fails to initiate transmission. [1][2]

As a G-protein-coupled receptor (GPCR), the 5-HT1A receptor undergoes internalisation after prolonged activation. In this process, the receptor is removed from the cell surface and brought into the cell, desensitising it to further activation. This internalisation is essential for understanding the effects of selective serotonin reuptake inhibitors (SSRIs).

The 5-HT1A receptor exists in two forms with distinct brain distributions: presynaptic autoreceptors and postsynaptic heteroreceptors. The autoreceptors are located in the brainstem, specifically in the Raphe Nuclei, a central region from which serotonergic neurons project throughout the brain. The 5-HT1A autoreceptors in the Raphe Nuclei are primary targets in SSRI treatment, as they regulate serotonin release into the brain via a negative feedback mechanism.

“Creative Commons, Sagittal Graphic, Servier / Modified from original image with added graphics to indicate 5-HT1A Circuitry”

The therapeutic aim of SSRI treatment is to desensitize these 5-HT1A autoreceptors, diminishing their negative feedback effect. This desensitisation allows more serotonin to be released to target heteroreceptors in the prefrontal cortex and limbic system, where serotonin binding is associated with beneficial changes in cognition and mood. [3][4]

However, more recent research has revealed that SSRI treatment is fundamentally undermined by that fact that eventually the heteroreceptor also undegoes this same process of desensitisation and internalisation. As explained over previous articles, this results in a number unintended consequences, such as reduced brain metabolism in the prefrontal cortex. [5]

Blunted hormonal response: Oxytocin & ACTH

The 5-HT1A heteroreceptor is present on hypothalamic neurons. When serotonin to these receptor it triggers a cascade of signals to influence the release of hormones. The hypothalamus is like the master switch which can alter the secretion of hormones from the pituitary gland directly via nerve signals. Furthermore, the hypothalamus can encourage the release of hormones from other glands throughout the body by stimulating the release of “releasing hormones“, such as Thyrotropin-releasing hormone which causes the pituitary to release thyroid-stimulating hormone.

OpenStax College, CC BY 3.0 https://creativecommons.org/licenses/by/3.0, via Wikimedia Commons

The 5-HT1A receptor is particularly relevant in regulating several hormones including Cortisol, Oxyctocin, and Growth Hormone. When serotonin binds to the 5-HT1A receptor it triggers the release of corticotropin-releasing hormone (CRH) from the hypothalamus. This in turn causes the pituitary gland to release Adrenocorticotropic hormone (ACTH). [10] This hormone plays vital role in hypothalamic-pituitary-adrenal axis. ACTH travels through the blood to reach the adrenal gland where it stimulates the release of Cortisol and androgens. [11] Deficiency of ACTH can cause adrenal insufficiency, which causes chronic fatigue, weakness, weight loss and low blood pressure.

As previously explained, sustained use of SSRIs can cause a desensitisation of 5-HT1A receptors, including in the hypothalamus. This can lead to alterations in hormonal balance that can persist longer after the drug has been withdrawn. In one animal study, rats were treated with the SSRI fluoxetine for 14 days. The rats were then treated with the 5-HT1A agonist, 8-OH-DPAT, to stimulate oxytocin and ACTH. Just 2 days after the end of treatment, the SSRI group showed 74% lower levels of Oxytocin and 68% lower levels of ACTH compared to control. This change reflects a profound desensitisation of the 5-HT1A heteroreceptors caused by Fluoxetine.

The ACTH response to the 5-HT1A agonist gradually improved such that after 14 days, it was the same as controls. Although, ACTH is considered a less sensitive indicator of 5-HT1A desensitisation. In contrast, the Oxytocin response remained significantly reduced, by 26% against controls, even 60 days after Fluoxetine treatment had ended. [6]

The researchers also confirmed that the Fluoxetine and metabolites had been completely cleared from the plasma and brain tissue. Intriguingly, there was also not an identifiable reduction in protein levels in the hypothalamus. This suggests that the changes in hormonal response were due to changes in 5-HT1A interactions, rather than their absolute protein level. Studies in humans have also found Chronic SSRI treatment to also reduce responsiveness of the HPA-axis. [15] 16 weeks of Citalopram caused a reduction of ACTH release using a dexamethasone-suppressed CRH test. [14]

Oxytocin is sometimes called the ‘love hormone’ owing to its role in human bonding and sexual activity. The levels of oxytocin reach their peak during sexual intimacy, and thereby help to encourage bonding and emotional connection. Administering Oxytocin to the hypothalamus has even been found to facilitate sexual behaviour. [12] It’s therefore possible that the desensitisation of the 5-HT1A receptors on these key hypothalamic neurons could play a significant role in explaining the suppressive effect of chronic SSRI treatment on sexual behaviour.

SSRIs have been used to treat premature ejaculation, which may be in part mediated by inhibiting oxytocin release. [7] [13] Oxytocin doesn’t only determine the psychological response of sexual activity but also but also directly influences erectile response, through activation of nitric oxide synthase. [8]

Article Summary

5-HT1A receptor changes: SSRI treatment in animals leads to desensitisation of the 5-HT1A serotonin receptor, which persists long after treatment ends. This receptor plays a critical role in regulating hormonal responses, influencing hunger, sexual behaviour, emotional attachment, and sleep.
Hypothalamic impact: Fluoxetine treatment in rats caused long-term desensitization of 5-HT1A receptors in the hypothalamus, reducing oxytocin and ACTH release even 60 days after treatment, which could explain some of the behavioural and hormonal effects of SSRIs, including impacts on sexual function.
Oxytocin suppression: SSRI-induced blunting of oxytocin release may contribute to sexual dysfunctions, including reduced sexual motivation and erectile issues, which are observed in some patients under chronic SSRI treatment.
Mechanisms of desensitization: These changes are not due to reduced protein levels but to altered receptor interactions, emphasizing the lasting physiological impact of SSRIs on serotonin signalling.