5HT2A Serotonin Receptor System in Dreaming

5HT2A systems may regulate dream experiences.

Posted Feb 15, 2018

Back in 2004 I made the claim that the serotonin 2A receptor (5HT2AR) would be crucial for brain mechanisms of REM sleep and the peculiar phenomenology of dreams (McNamara, 2004).  Why is this claim important? If we can identify a pharmacologic mechanism that reliably alters dream phenomenology, we can potentially develop pharmacologic treatments for those disorders.

What is the evidence that 5HT2A signaling is particularly important for REM dream phenomenology? Well, there is a class of drugs that bind to the 5HT2A receptor pretty strongly. These are the so-called atypical anti-psychotics. Administration of these antipsychotic agents that antagonize the 5HT2A receptor improves cortical function, eliminates hallucinations and ameliorates schizophrenic symptomology. These clinical facts suggest that 5HT2A signaling mechanisms may actually produce the hallucinatory and bizarre cognitive states associated with psychosis. Given the fact that some dreams are like psychotic or hallucinatory states, it may be then that they too are produced by 5HT2A signaling.

REM sleep is associated with deactivation of one portion of the prefrontal cortex. That deactivation (in REM) may be mediated, in part by 5HT2A receptor signaling, though I know of no direct experimental evidence for this claim. There is some indirect evidence that 5HT2A receptor signaling systems are involved in regulation of REM. 5HT2A receptor sites have been found on cholinergic REM on-off neurons in the brainstem. Direct injection of agents (onto these REM on-off cells) that block or enhance 5HT2A signaling also change the number of REM episodes the animal undergoes.

The 5HT2A receptor, however, exerts its greatest pharmacologic effects on cortical functions. The receptor is found in great densities within the pyramidal projection neurons of the prefrontal cortex and the sensory association areas of the cortex.  

The most potent and common 5HT2A agonists are the so-called psychedelic drugs like psilocybin and LSD. Administration of these agents to human volunteers produce a variety of unusual perceptual phenomena as well as a hallucinatory dream-like states. The most important effect of these drugs is sometimes “ego dissolution”-- a profound alteration in the sense of self and bodily boundaries. Ego dissolution can be a positive or a terrifying experience. In positive ego dissolution the individual lets go of a limited sense of self and identified with an enriched sense of self. The intensity of the ego-dissolution experience predicts the magnitude of the perceptual and cognitive changes associated with the psychedelic experience.

Kraehenmann et al., (2017) have demonstrated that the cognitive bizarreness (i.e. presence of improbable, impossible or incongruent events during a given experience) common to both dreams and LSD experiences correlate with other aspects of the psychedelic experience such as ego-dissolution and depend upon 5-HT2A receptor activation.

A transient loss of agency or ego-dissolution occurs in some REM dreams. The dreamer’s volition, agency or intentional states seem blocked or impaired. The well-known motor paralysis associated with REM likely contributes to some of this sense of agentic impairment in dreams but just as important could be the cortical changes associated with REM.

Functional brain changes when undergoing REM is known to involve a down regulation of dorsolateral prefrontal, parietal and supplementary motor cortex, as well as an upregulation of limbic and sensory association cortex. The sense of a volitional self likely depends on the very regions that are down regulated in REM.

Functional brain changes under the influence of 5HT2A agonists have also been carefully studied with fMRI and other techniques. 5HT2A agonists like psilocybin and LSD consistently produce an ensemble of brain changes that involve a global down-regulation of dorsolateral prefrontal (and perhaps parietal) activity and an upregulation of sensory association areas and limbic emotional areas. This profile of functional brain changes is remarkably similar to what occurs in REM sleep. The higher executive control systems centered in the dorsolateral prefrontal cortex are relaxed or actively inhibited while the sensory processing and emotional processing centers go into overdrive (Carhart-Harris et al., 2016: Muthukumaraswamy et al., 2013). The influence of neural activity from lower-order sensory association and limbic regions upon higher-order regions is dramatically enhanced. Presumably under these functional brain conditions, the integrative processing centers within the orbitomedial prefrontal regions is inundated with very highly processed sensory information.

In summary the claim that 5HT2A plays a role in REM dreaming while largely circumstantial is likely to be, at least to some extent, correct. But why would Mother Nature arrange things in this way? Why create a signaling or regulatory system (centered on 5HT2A receptor signaling) that tends to relax or actively inhibit top-down control systems while simultaneously revving-up sensory and emotional analyses to the point that psychotic-like states ensue? Why present the results of these revved-up analyses in the form of dreams?

Lets add one more piece to the puzzle of the role of 5HT2A signaling systems in human brain and behavior. Scientists have long known that serotonin activity levels correlate with social status for dominant males in primate colonies. Up to a point the higher the activity levels the greater and more effective are aggressive displays in these primate males. 5-HT2A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. The greater the alteration in sense of self the less the individual worries about social exclusion. In addition, carrying carrying a G-allele version of the gene for 5HT2AR considerably enhances the positive social effects of aggression and having female friends on adolescent males. Apparently the greater activity in 5HT2A signaling systems (up to a point) in these adolescent males the greater is the social success of their aggressive displays.

While these culture-gene interaction effects might help to explain why the 5HT2A system exists at all, does it help us to explain why the system produces such dramatic changes in consciousness and the sense of self? Recall that 5HT2A agonists produce a de-activation of higher order control systems and a release from inhibition of lower sensory and emotional systems. That loss of executive control (ego-dissolution) associated with deactivation of prefrontal systems undoubtedly releases aggressive impulses nd these are reflected in dreams. REM dreams, particularly those with high number of bizarre elements in them, almost invariably express intense levels of aggression as well—especially in males. Apparently that aggression can be put to good use by adolescent males.

References

Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, Tyacke RJ, Leech R, Malizia AL, Murphy K, Hobden P, Evans J, Feilding A, Wise RG, Nutt DJ (2012) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A 109:2138–2143.

Carhart-Harris RL et al. (2016) Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc Natl Acad Sci U S A 113:4853–4858.

Kraehenmann, R. (2017). Dreams and psychedelics: neurophenomenological comparison and therapeutic implications. Curr. Neuropharmacol. 15, 1032–1042. doi: 10.2174/1573413713666170619092629

Kraehenmann, R., Pokorny, D., Vollenweider, L., Preller, K. H., Pokorny, T., Seifritz, E., et al. (2017). Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation. Psychopharmacology 234, 2031–2046. doi: 10.1007/s00213-017-4610-0

McNamara, P. (2004). An evolutionary psychology of sleep and dreams. Westport, CT: Praeger/Greenwood Press.

Muthukumaraswamy SD, Carhart-Harris RL, Moran RJ, Brookes MJ, Williams TM, Errtizoe D, Sessa B, Papadopoulos A, Bol- stridge M, Singh KD, Feilding A, Friston KJ, Nutt DJ (2013) Broadband cortical desynchronization underlies the human psychedelic state. J Neurosci 33:15171–15183.

Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181.