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

Last updated: November 3, 2018

 

  • 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.

References

  1. Bradbury S, Bird J, Colussi-Mas J, et al. (2013) Acquisition of MDMA self-administration: pharmacokinetic factors and MDMA-induced serotonin release. Addict Biol.
  2. Carhart-Harris RL, Kaelen M, Bolstridge M, et al. (2016. c) The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychol Med: 1–12.
  3. Lanzenberger R.R et al reduced serotonin-1a receptor binding in social anxiety disorder. Biol Psychiatry 2007;61:1081–1089
  4. Gross-Isseroff R, Salama D, Israeli M, et al. (1990) Autoradiographic analysis of age-dependent changes in serotonin 5-HT2 receptors of the human brain postmortem. Brain Res 519: 223–227.
  5. Hall H, Farde L, Halldin C, et al. (2000) Autoradiographic localization of 5-HT(2A) receptors in the human brain using [(3)H]M100907 and [(11)C]M100907. Synapse 38: 421–431.
  6. Pazos A, Probst A, Palacios JM. (1987) Serotonin receptors in the human brain–III. Autoradiographic mapping of serotonin-1 receptors. Neuroscience 21: 97–122.
  7. Varnas K, Halldin C, Hall H. (2004) Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp 22: 246–260.
  8. Beliveau V, Ganz M, Feng L, et al. (2016) A high-resolution in vivo atlas of the human brain’s serotonin system. J Neurosci 37:120–128.
  9. Weber ET, Andrade R. (2010) Htr2a gene and 5-HT(2A) receptor expression in the cerebral cortex studied using genetically modified mice. Front Neurosci 4.
  10. The image is adapted from (Beliveau V, Ganz M, Feng L, et al. (2016) A high-resolution in vivo atlas of the human brain’s serotonin system. J Neurosci 37:120–128.) and published in Carhart-Harris RL, Nutt DJ Serotonin and brain function: a tale of two receptors Psychopharmacol. 2017 Sep; 31(9): 1091–1120.
  11. Lanfumey L, Hamon M. (2000) Central 5-HT(1A) receptors: regional distribution and functional characteristics. Nucl Med Biol 27: 429–435.
  12. Olivier B, Mos J. (1990) Serenics, serotonin and aggression. Prog Clin Biol Res 361:203–30
  13. Audero E, Mlinar B, Baccini G, et al. (2013) Suppression of serotonin neuron firing increases aggression in mice. J Neurosci 33: 8678–8688.
  14. Brown GL, Goodwin FK, Ballenger JC, et al. (1979) Aggression in humans correlates with cerebrospinal fluid amine metabolites. Psychiatry Res 1: 131–139.
  15. Duke AA, Begue L, Bell R, et al. (2013) Revisiting the serotonin-aggression relation in humans: a meta-analysis. Psychol Bull 139: 1148–1172
  16. Fairbanks LA, Melega WP, Jorgensen MJ, et al. (2001) Social impulsivity inversely associated with CSF 5-HIAA and fluoxetine exposure in vervet monkeys. Neuropsychopharmacology 24: 370–378
  17. Brown GL, Linnoila MI. (1990) CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence. J Clin Psychiatry 51 Suppl: 31–41; discussion 42-33.
  18. Asberg M, Traskman L, Thoren P. (1976) 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Arch Gen Psychiatry 33: 1193–1197.
  19. Dougherty DM, Moeller FG, Bjork JM, et al. (1999) Plasma L-tryptophan depletion and aggression. Adv Exp Med Biol 467: 57–65.
  20. Sanchez C, Hyttel J. (1994) Isolation-induced aggression in mice: effects of 5-hydroxytryptamine uptake inhibitors and involvement of postsynaptic 5-HT1A receptors. Eur J Pharmacol 264: 241–247.
  21. Schreiber R, De Vry J. (1993) 5-HT1A receptor ligands in animal models of anxiety, impulsivity and depression: multiple mechanisms of action? Prog Neuropsychopharmacol Biol Psychiatry 17: 87–104.
  22. de Boer SF, Koolhaas JM. (2005) 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis. Eur J Pharmacol 526: 125–139.
  23. Heisler LK, Chu HM, Brennan TJ, et al. (1998) Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci U S A 95: 15049–15054.
  24. Parks CL, Robinson PS, Sibille E, et al. (1998) Increased anxiety of mice lacking the serotonin1A receptor. Proc Natl Acad Sci U S A 95: 10734–10739.
  25. Bressa GM, Marini S, Gregori S. (1987) Serotonin S2 receptors blockage and generalized anxiety disorders. A double-blind study on ritanserin and lorazepam. Int J Clin Pharmacol Res 7: 111–119.
  26. Carhart-Harris RL, Erritzoe D, Williams T, et al. (2012. a) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A 109: 2138–2143.
  27. Carhart-Harris RL, Kaelen M, Whalley MG, et al. (2015. a) LSD enhances suggestibility in healthy volunteers. Psychopharmacology (Berl) 232: 785–794.
  28. Artigas F. (2015) Developments in the field of antidepressants, where do we go now? Eur Neuropsychopharmacol 25: 657–670.
  29. Artigas F. (2013. a) Future directions for serotonin and antidepressants. ACS Chem Neurosci 4: 5–8.
  30. Artigas F. (2015) Developments in the field of antidepressants, where do we go now? Eur Neuropsychopharmacol 25: 657–670
  31. Boulougouris V, Glennon JC, Robbins TW. (2008) Dissociable effects of selective 5-HT2A and 5-HT2C receptor antagonists on serial spatial reversal learning in rats. Neuropsychopharmacology 33: 2007–2019.
  32. Frecska E, More CE, Vargha A, et al. (2012) Enhancement of creative expression and entoptic phenomena as after-effects of repeated ayahuasca ceremonies. J Psychoactive Drugs 44: 191–199.
  33. Harman WW, McKim RH, Mogar RE, et al. (1966) Psychedelic agents in creative problem-solving: a pilot study. Psychol Rep 19: 211–227.

Also, you can access to the original version in Spanish:  “El rol de la serotonina (5-HT) en impulsividad / agresión, ansiedad / estrés y cognición”

Published in: ,

Earn CME/SA credits

  • Up to 36 CME credits/year
  • Up to 16 SA credits/year
  • Download more than 70 videos
  • Exclusive updates

Free Course: “SSRIs: The Essentials”

Learn the essentials of SSRIs with our free online course.

One module per week:

  • The Mechanism of Action of SSRIs
  • Fluoxetine
  • Fluvoxamine
  • Paroxetine
  • Sertraline
  • Citalopram and Escitalopram
SSRIs

2018 Psychopharmacology Online Update

Earn Up to 36 CME Credits / Year

  • Access exclusive updates: new videos every month
  • Download our entire library: more than 70 videos
  • Earn up to 36 CME credits /year
learn-psychopharmacology