Multiple Functional Enhancements of Dopamine Signaling by LSD – A Summary

by Eric M. Fortier, B.A.

This article is a brief summary of the following study: Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes.[1]

Serotonin (5-HT) is known to counteract Dopamine 2 (D2) signaling via the 5-HT2A protomer (single receptor of a complex). This study was an attempt to elucidate the relation between the psychedelic actions of two high-affinity 5-HT2A agonists (LSD and DOI) and the D2LR + 5-HT2AR heteromeric receptor complex. Researchers hypothesized that LSD and DOI would produce a different kind of interaction at the receptor complex than that of endogenous serotonin.

Briefly, experimenters tested this hypothesis by manipulating D2 signaling in experimental HEK293 cells (in which they co-transfected both receptors) and the nucleus accumbens of rats, with the help of serotonin 2A agonists (LSD, DOI, and TCB2), and antagonist (ketanserin); a dopamine agonist (quinpirole), antagonist (3H-Raclopride) and inverse agonist (Haloperidol).

Immunofluorescence and proximity ligation assays (PLA) detected an increased presence of the heteromeric complex on the cell surfaces of both the nucleus accumbens of rats and in co-transfected HEK293 cells after treatment with LSD or DOI. 3H-Raclopride displacement tests revealed an enhancement of D2 receptor affinity for high-affinity dopamine ligands, with LSD’s or DOI’s co-presence in the 5-HT2A protomer of the complex. CRE-luciferase reporter gene experiments with quinpirole revealed an enhancement of D2 protomer coupling to the Gi protein, with co-presence of LSD or DOI in the 5-HT2A receptor.

Higher affinity D2 binding, increased G-protein coupling to the receptor complex, and elevated expression of D2 receptors in the cell, all provide evidence for functionally specific enhancements of dopaminergic signaling in the primary motivation center of the brain.

Their results support the hypothesis that LSD and DOI produce in fact the opposite effects in D2L-5-HT2A receptor complexes than those of serotonin, and suggest that the psychoactivity of LSD and DOI may be partially attributed to the their enhancement of dopaminergic receptor function in the nucleus accumbens and dorsal striatum via the 5-HT2A protomer.

The authors state no explicit limitations, but these experiments did not examine the rats’ behavioral responses to the drugs. Behavioral observation, and perhaps human trials with psychological assessment, may be required to further understand the biological relevance of the D2L-5-HT2A heteromeric complex (and the lasting effects of potent 5-HT2A agonists on D2 receptors) in the psychoactivity of LSD.

Footnote: an increased expression of serotonin 2A receptors has been found to increase behavioral response to potent dopamine agonists,[2] and the D2 receptor appears to be key to the therapeutic effects of amphetamine on ADHD.[3] More evidence suggests serotonin receptors modulate dopamine signalling,[4] which may be involved in their therapeutic efficacy, particularly in cases regarding addiction, motivation and priority setting. The modification of dopamine signalling by psychedelics, as well as the increasingly internally generated perceptual and thought content, and the shift of exteroception to interoception,[5] offer potential explanations for why so many anecdotal reports include alleviation of ADHD symptoms.

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[1] Borroto-Escuela, D. O., Romero-Fernandez, W., Narvaez, M., Oflijan, J., Agnati, L. F., & Fuxe, K. (2014). Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes. Biochemical and Biophysical Research Communications, 443(1), 278-284. doi:10.1016/j.bbrc.2013.11.104

[2] Herin, D. V., Bubar, M. J., Seitz, P. K., Thomas, M. L., Hillman, G. R., Tarasenko, Y. I., . . . Cunningham, K. A. (2013). Elevated Expression of Serotonin 5-HT2A Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine. Frontiers in Psychiatry, 4. doi:10.3389/fpsyt.2013.00002

[3] Fan, X., Xu, M., & Hess, E. J. (2010). D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD. Neurobiology of Disease, 37(1), 228-236. doi:10.1016/j.nbd.2009.10.009 

[4] Chenu, F., Shim, S., Mansari, M. E., & Blier, P. (2013). Role of melatonin, serotonin 2B, and serotonin 2C receptors in modulating the firing activity of rat dopamine neurons. Journal of Psychopharmacology, 28(2), 162-167. doi:10.1177/0269881113510071

[5] Kometer, M., Cahn, B. R., Andel, D., Carter, O. L., & Vollenweider, F. X. (2011). The 5-HT2A/1A Agonist Psilocybin Disrupts Modal Object Completion Associated with Visual Hallucinations. Biological Psychiatry, 69(5), 399-406. doi:10.1016/j.biopsych.2010.10.002