1. Introduction
2. The 5-HT1A Receptor
3. What is the 5-HT1A receptor?
4. The importance of the heteroreceptor
5. What is the effect of binding at the heteroreceptor versus the autoreceptor?
6. SSRIs desensitise the heteroreceptor
7. Isotretinoin Increases Autoreceptor Expression
8. the prefrontal cortex: Fixing the 5-HT1A Receptor
9. How to therapeutically target the 5-HT1A receptor
10. ‘fixing’ the 5-HT1A receptor
11. Article Summary
12. References

Introduction

Accutane, also known by its generic name Isotretinoin, is a widely used retinoid, primarily prescribed for the treatment of severe acne. Over the years its effectiveness in treating stubborn, severe acne has been well-documented, however its profound neurological effects are now equally well-documented. The first recorded case attesting these psychological changes rather bizarrely comes from an artic explorer, Elisha Kane, are ingesting the retinoid-rich liver of a polar bear. To his fellow explorers he became irritable and confrontational.

It’s perhaps not surprising that a meta-analysis of over three thousand Accutane patients identified changes in mood and personality as among the most common side effect of the treatment. [1] For some individuals, the changes resulting from this medication are relatively mild, manifesting as symptoms like fatigue and irritability. However, for others, the effects can be potentially devastating. The acne medication has been associated with severe conditions, including major depression and psychosis. [2]

Despite ongoing research, the scientific community has yet to fully understand how a basic derivative of Vitamin A can induce such profound neurological effects. Nonetheless, several studies have provided crucial insights into this phenomenon. One such study came in 2005 from Bremner at al. in which functional brain imaging was performed on patients being treated with the acne drug. Over the course of the four-month treatment the researchers discovered a 21% decrease in activity of a highly significant region of the brain called the orbitofrontal cortex.

Effects on Regional Brain Metabolism in a Representative Patient Receiving Isotretinoin Treatment for Acne (J. Douglas Bremner et al. Functional Brain Imaging Alterations in Acne Patients Treated With Isotretinoin, American Journal of Psychiatry https://doi.org/10.1176/appi.ajp.162.5.983) [Fig 1.]

This small but pivotal part of the brain deals with higher cognitive functioning and mediates feeling of reward (a ‘hedonic hotspot’). [3] This discovery also gives a basis to the countless anecdotal reports of Accutane patients complaining of cognitive changes, and a general sense of apathy that can even persist for a long time following the treatment, symptoms encompassed by the informal diagnosis of Post Accutane Syndrome.

The 5-HT1A Receptor

This article will primarily focus on explaining the neurological effects associated with Accutane treatment, specifically relating to the 5-HT1A serotonin receptor. The science surrounding this topic is extensive and complex, but I will strive to present it in a clear and concise manner.

Understanding the behaviour of this particular serotonin receptor is crucial to comprehending the neurological impacts of Post Accutane Syndrome. While scientific literature generally categorizes these neurological effects as depression, anecdotal accounts often describe the depression as anhedonic.

This is characterized by a noticeable decrease in the sense of reward, coupled with a loss of motivation, as though the ability to feel excitement has been diminished. Although there is significant individual variation in experiencing these mental states, this general description aligns closely with the evidence of Isotretinoin’s effects on the 5-HT1A receptor, which will be elaborated upon later in the article.

The 5-HT1A receptor is also essential in understanding the deviations in sexual behaviour and cognitive functioning. Acknowledging the complexity of the science, I have included a key point summary to make the information accessible to those without a background in biology or medicine.

What is the 5-HT1A receptor?

The 5-HT1A receptor is a serotonin receptor, which means its bound by the neurotransmitter serotonin to exert its effects. Serotonin has long had connotations to ‘happiness’, stemming from early scientific evidence that the depletion of serotonin results in depressive symptoms. The vast majority of antidepressant medications work on this neurotransmitter, called SSRIs (Selective Serotonin Reuptake Inhibitors).

SSRIs boost the effect of serotonin by preventing it from being reabsorbed too quickly by the serotonin transporter. However, since SSRIs were first introduced medical paradigms have shifted in favour of theories of depression centred on ‘neurogenesis’ (the growth of new neurons), an effect stimulated by serotonergic medications primarily through the 5-HT1A receptor.

The 5-HT1A receptors are inhibitory receptors since they are G-protein-coupled receptors, when bound they result in reduced AMPA evoked currents. AMPA receptors are responsible for fast synaptic transmission, and so in this way, binding the 5-HT1A receptor suppresses neuronal activity.

The receptor is subdivided into two types with different distributions within the brain: autoreceptors and heteroreceptors. The autoreceptors are localised within the brain stem in a structure call the Raphe Nuclei, and it’s from this structure in the middle of the brain that all other serotonergic neurons project outward.

As the name might suggest, the (presynaptic) autoreceptor serves to self-regulate serotonin transmission out into the rest of the brain through a negative feedback mechanism. When serotonin over-accumulates within the Raphe Nuclei it binds to these receptors to then limit further serotonin release (since 5-HT1A receptors are inhibitory). As autoreceptors have a self-limiting effect on serotonin transmission, an overexpression limits serotonin release to other areas of the brain and is also notably identified in autopsies from patients with depression. [4]

The importance of the heteroreceptor

The post-synaptic heteroreceptor sites are distributed in the limbic and cortical regions. The limbic system is responsible for regulating emotion, learning and sexual behaviour. Like the autoreceptor, binding at the 5-HT1A heteroreceptor triggers hyperpolarisation of that neuron, thus reducing the firing rate.

Based on the description provided so far, one might conclude that serotonin binding to heteroreceptors would produce the same reduction in neuronal activity in these limbic and cortical structures. The reality is far more complicated, as the heteroreceptors are present on two different types of neurons with opposing effects: interneurons and pyramidal neurons.

The interneurons are GABAergic, which means they release the inhibitory neurotransmitter GABA. [5] Conversely, the pyramidal neurons release the excitatory neurotransmitter glutamate, and are particularly abundant in the cerebral cortex. These pyramidal neurons play a key role in memory, learning and attention, and are opposed by the GABAergic interneurons that feed into them.

Understanding how binding at the 5-HT1A heteroreceptor impacts mood will therefore depend on the relative distribution of these rival neurons. Consider a hypothetical agonist that preferentially binds to the heteroreceptor at the interneurons; this would suppress the transmission of the inhibitory GABA and subsequently boost cortical activity. To summarise:

Autoreceptors:

• These pre-synaptic receptors are distributed in the brain stem and negatively regulate 5-HT release to cortical and limbic structures.

Heteroreceptor:

• Interneurons are GABAergic, binding at the 5-HT1A receptor on these neurons lowers the release of GABA to have an activating effect.
• Pyramidal neurons are primarily glutamatergic and are distributed in the frontal cortex. Binding to the heteroreceptor sites on these glutamatergic and dopaminergic neurons would have a suppressive effect.

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

What is the effect of binding at the heteroreceptor versus the autoreceptor?

Given the complexity of the 5-HT1A receptor, medications acting upon it can sometimes behave in counterintuitive ways. Buspirone is the most common medication classed as 5-HT1A agonist (an agonist being a molecule that mimics serotonin in this instance). Buspirone is often prescribed as an anti-anxiety medication.

This seems logical as anxiety is associated with overactivity in cortical layers, and so by binding to the heteroreceptors within the prefrontal cortex would supposedly repress this activity.  As it turns out, Buspirone actually boosts activity in the prefrontal cortex and enhances dopamine and glutamate release. [6] Curiously, this actually gives it some additional applications as a cognitive enhancer.

The reason for this potentially confusing effect is because the action of Buspirone on the GABAergic interneurons predominates, and the subsequent reduction in firing rate of these inhibitory neurons enhances cortical glutamate activity. Instead, the anti-anxiety effects of Buspirone are likely due to quietening activity in limbic structures such as the Amygdala, and not the prefrontal cortex.

Since heteroreceptors are present on both the interneurons and pyramidal neurons, and that the suppressive effect of 5-HT1A binding on the interneurons predominates within the prefrontal cortex, a selective heteroreceptor agonist can be considered as stimulating and conducive to dopamine and glutamate release.

SSRIs desensitise the heteroreceptor

SSRI’s (Selective Serotonin Reuptake Inhibitors) are the first line of approach in treating major depressive disorder and are primarily understood to act through the 5-HT1A receptor. When serotonin accumulates within the autoreceptor site, it triggers negative feedback to block further release of serotonin.

This presents another perplexing quirk of the 5-HT1A receptor, as a build-up of serotonin at the autoreceptor would in theory then limit serotonin release to the rest of the brain through its negative feedback. Instead, these autoreceptors undergo desensitisation over chronic exposure to SSRIs, and eventually their inhibitory effect is blocked which allows for even greater serotonin transmission.

Since SSRIs essentially rely on disabling the autoreceptor, it’s been found that pre-treatment with a 5-HT1A antagonist (such as Pindolol) accelerates the antidepressant effect of SSRIs.[7]

The very different behavioural effects of binding at the heteroreceptor versus the autoreceptor were demonstrated most clearly by demonstrated by Garcia-Garcia et al. in their 2017 study. They took different groups of mice and knock-out (removed) either heteroreceptors or autoreceptors.

They discovered that the mice lacking heteroreceptors displayed depressive symptoms that were characteristic of anhedonia rather than anxiety. Conversely the mice that had their autoreceptors ablated experience heightened anxiety but still showed a drive for reward. [8] This study perhaps gives an indication as to how the 5-HT1A receptor influences sexual behaviour, with the binding at the heteroreceptor being particularly relevant. Substantiating this notion is the fact that the medication Flibanserin, which is used to treat hypo-active sexual disorder, binds most potentially to the heteroreceptor sites. [9]

Isotretinoin Increases Autoreceptor Expression

Now that I have given a general mechanistic overview of the 5-HT1A receptor, I can now go into the evidence for how its impacted by Isotretinoin treatment. Reilly et al. exposed cell lines from the raphe nuclei to Isotretinoin an observed a massive increase in the 5-HT1A autoreceptor protein levels. After just 48 hours of exposure there was up to a 70% increase of the autoreceptor protein. [10] The authors of the study posit that this is significant factor in the appearance of depressive behaviour exhibited by people treated with the acne drug.

In accordance with the behaviour of the autoreceptor previously outlined, an increase in the autoreceptor levels would cause an inhibition of serotonin release to the rest of the brain, and perhaps most significantly to the 5-HT1A heteroreceptor sites. An under activation of the heteroreceptor could induce some of the same anhedonic symptoms observed in the Garcia-Garcia study. However, it might be equally valid to suggest that since the loss of autoreceptor induces anxiety, and the increase in protein levels induced by Accutane might have some degree on an anxiolytic effect. [11]

We can get another indication of Isotretinoin effect in relation to the autoreceptor with respect to the brain imaging study performed by Bremner et al. He identified that after four months of treatment with Accutane, patients experience a massive decrease in metabolism of the orbitofrontal cortex. [12] The reduction in activity was an enormous 21%, and certainly a very significant factor in the rise of depressive symptoms reported by these patients. Given that binding to the heteroreceptor in these cortical structures stimulates activity, an increase in the level of the autoreceptor could explain these startling results.

the prefrontal cortex: Fixing the 5-HT1A Receptor

The loss of the heteroreceptor and the ensuing anhedonic symptoms poignantly mirrors an effect of chronic SSRI treatment. As described previously, treatment with SSRI’s eventually causes a desensitisation of the autoreceptor, which would hypothetically enhance binding at the heteroreceptor. Whilst this is true for at least some period of time, it doesn’t explain the efficacy of SSRI’s in treating anxiety conditions, since autoreceptor knock-out mice display more anxiety.