The Role of Serotonin (5-HT) in Impulsivity/Aggression, Anxiety/Stress and Cognition
Prof. David Nutt
Edmond J. Safra Professor of Neuropsychopharmacology
Imperial College London
- SSRIs reduce stress and anxiety probably through increased post-synaptic 5-HT1A receptor stimulation.
- There is less good evidence that 5-HT can reduce impulsivity and aggression.
- 5-HT has complex effects on cognition:
- It can produce cognitive bias in the amygdala against stressful images and probably thoughts
- It can promote hippocampal neurogenesis that is required for memory encoding
So next, now, we move on to the role of 5-HT in impulsivity, aggression, anxiety and stress and cognition.
We can study the serotonin system using a number of different tools. One of these is rapidly acting potent 5-HT releasers such as MDMA (methylenedioxymethamphetamine). We can also study the 2A receptor using psychedelic drugs such as psilocybin and lysergic acid diethylamide or LSD. And these are agonists at the 2A receptor. And these substances can be particularly informative about the role of serotonin transmission in the brain.
You can see from the images here very high resolution images of the distribution of the 5-HT1A and the 5-HT2A receptors in the brain ??. There is a much higher density of the 2A receptor in cortical regions compared with the 1A receptor. The 1A receptor has a particularly high expression in areas like the hippocampus that’s part of the limbic system.
So I’m going to focus now on the 2A receptor which you see from the images has very high density in the cortex but only in areas of the cortex which are involved in high level cortical processing And these areas are the prefrontal cortical regions, the cingulate cortex and the posterior cingulate cortex. And those are parts of the temporal and parietal lobes. In fact, the 5-HT2A receptor is the predominant, most abundant 5-HT receptor in the cortex. It has a very special distribution because it is highly expressed on layer V pyramidal cells in the cortex. And these are particularly important pyramidal cells because they regulate information transmission across the brain.
The 5-HT1A receptor is very different. It’s highly expressed on serotonergic neurons where it’s an autoreceptor and regulates the firing of those neurons. So you see high density of these receptors in the dorsal and median raphe nuclei. This gives homeostatic control over the 5-HT neuron firing rates and so regulates the 5-HT efflux in the forebrain. But the majority of 5-HT1A receptors are expressed postsynaptically in many brain regions but particularly the limbic system in the hippocampus and parts of the cortex, not the cingulate cortex.
The 5-HT has many roles in the brain but one of the most reliable behavioral effects of 5-HT is to regulate impulsivity and aggression. We know that if we reduce 5-HT in the brain by depleting the brain of the precursor tryptophan, so 5-HT level is full, we get increased impulsive and aggressive behaviors. In contrast, if we give substances which enhance them, such as MDMA, we reduce aggression and impulsivity. And this led to these compounds being called “serenics” in the sense that they make the person more serene because they turn you into someone who’s essentially more in tune, less irritable, less upset by other people. And this, we believe, is because MDMA is a potent 5-HT releaser.
Another pointer to the role of serotonin in aggression and impulsivity, our postmortem studies and live person studies looking at the concentrations of the serotonin metabolite 5-HIAA, 5-hydroxyindoleacetic acid, low levels of 5-HIAA, we believe, are due to low levels of 5-HT turnover in the brain. And people with low 5-HIAA are more impulsive. They’re also more aggressive and are more likely to commit suicide. Also in normal living human beings, if we use tryptophan depletion which we can induce simply through a diet that produces transient depletion of central 5-HT, this procedure enhances impulsivity and aggression.
There are good grounds for believing that the anti-aggression and anti-impulsivity effects of serotonin are mediated by postsynaptic 5-HT1A receptor signaling. And so I think we can safely infer that these postsynaptic receptors have a role in reducing aggressive and impulsive behaviors if they are stimulated by agonists or if serotonin in the synapse is enhanced to stimulate them. There are some clinical pointers towards the role of direct 5-HT1A acting drugs in reducing aggression. For example, the partial agonist buspirone has been used to reduce anger in psychiatric patients ??. One such compound, eltoprazine, was developed specifically to reduce aggression in people with learning disabilities and it proved effective.
Like impulsivity and aggression, anxiety can be negatively modulated. We can downregulate anxiety by stimulating the 5-HT1A receptor. So for instance, with the releasing drug MDMA, but more obviously in clinical practice with SSRI treatment over several weeks, we can increase serotonin, stimulate those postsynaptic 1A receptors in the stress-sensitive limbic regions and reduce anxiety. And it’s important to note that the 5-HT1A receptor here is an inhibitory receptor. It dampens down overactivity of the limbic system and therefore reduces anxiety. This explanation also helps us understand why drugs such as buspirone which are direct agonists at the 5-HT postsynaptic receptor can also have anxiolytic effects.
5-HT2A receptor signaling can have the opposite effect. It can have an anxiogenic component particularly in the early phase of the use with drugs such as psychedelics. We also believe that there may be trait factors, biological factors such as receptor polymorphisms of these receptors which can underlie changes in personality or variations in personality relating to anxiety and also to suggestibility.
Moving on now to learning and cognition: So we now believe that stimulation of postsynaptic 5-HT1A receptors is generally considered to be a desirable property of anxiolytic and antidepressant medications and we believe that the postsynaptic 5-HT1A receptor is the principal therapeutic site of the action of SSRIs. And as well as inhibiting overactivity of the brain, this receptor also has a role in neurogenesis because serotonin in the hippocampus can lead to the release of BDNF, brain-derived neurotrophic factor, and improved neurogenesis. And that can lead to improvement in learning and cognition.
In contrast, cognitive flexibility is thought to be modulated by the 5-HT2A receptor. And there is evidence that stimulation of the 5-HT2A receptor with agonists such as LSD and psilocybin enhance cognitive flexibility and can improve creative thinking. In contrast, if we deplete serotonin and block the 5-HT2A receptor, we can get an impairment of cognitive flexibility and we believe that this is due to the impairment or decreased activity at baseline of the 5-HT1A receptor.
So let me go over again the key points in relation to anxiety, stress and cognition. So 5-HT has an important role in stress and anxiety. And SSRIs profoundly reduce these probably through increased postsynaptic 5-HT receptor stimulation caused by increased levels of serotonin in the synapse. There is evidence but it’s less strong that 5-HT can reduce impulsivity and aggression and again this seems likely to be mediated through a postsynaptic 5HT1A receptor being stimulated. 5-HT has quite complex effects on cognition. It can produce cognitive bias in the amygdala protecting against stressful images and also probably protecting against negative thinking but it can also promote hippocampal neurogenesis and that can enhance memory encoding.
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Also, you can access to the original version in Spanish: “El rol de la serotonina (5-HT) en impulsividad / agresión, ansiedad / estrés y cognición”
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