Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways

Abstract

The neuropsychological effects of naturally occurring psychoactive chemicals have been recognized for millennia. Hallucinogens, which include naturally occurring chemicals such as mescaline and psilocybin, as well as synthetic compounds, such as lysergic acid diethylamide (LSD), induce profound alterations of human consciousness, emotion, and cognition. The discovery of the hallucinogenic effects of LSD and the observations that LSD and the endogenous ligand serotonin share chemical and pharmacological profiles led to the suggestion that biogenic amines like serotonin were involved in the psychosis of mental disorders such as schizophrenia. Although they bind other G protein-coupled receptor (GPCR) subtypes, studies indicate that several effects of hallucinogens involve agonist activity at the serotonin 5-HT_2A receptor. In this chapter, we review recent advances in understanding hallucinogen drug action through characterization of structure, neuroanatomical location, and function of the 5-HT_2A receptor.

Keywords: 5-HT2A receptor; Antipsychotics; G protein-coupled receptor (GPCR); Hallucinogen; Lysergic acid diethylamide (LSD); Mescaline; Psilocin; Psilocybin; Psychedelics; Psychosis; Schizophrenia; Serotonin.

Fig. 1

Consecutive histological sections of human striatum showing the distribution of binding sites labeled by [¹²⁵I]DOI (a) and [³H]MDL100,907 (b). Arrow heads indicate some of the striosomes visualized with these radioligands. Cd, caudate; Put, putamen; CL, claustrum

Fig. 2

a Chemical structures of hallucinogen (LSD and mescaline) and non-hallucinogen (lisuride and ergotamine) 5-HT_2A receptor agonists. b [³H]Ketanserin competition curves by LSD, mescaline, lisuride and ergotamine in mouse somatosensory cortex plasma membrane preparations (see Gonzalez-Maeso et al. 2007). Note that the affinity of the ligand does not correlate with its psychoactive potential

Fig. 3

The ternary complex model. According to this model, the receptor in its inactive state (R) undergoes a conformational transition, which leads to the formation of an active state (R*). This active state in turn interacts with heterotrimeric G proteins (G). Note that according to this model, the relative degree of activation of each effector pathway by the tested agonists must be the same

Fig. 4

Model of biased agonism. Selective agonists stabilize a subset of receptor conformations that selectively activates some but not all signaling pathways. Recent findings suggest that biased agonism is involved in the psychoactive differences between hallucinogen and closely related non-hallucinogen 5-HT_2A receptor agonists

Fig. 5

Immunogold labeling for 5-HT_2A and mGlu2 receptors in mouse cortical neurons. Note that the 10-nm gold particles (filled arrows) and the 6-nm gold particles (open arrows) are located in very close proximity at the synaptic junction (see Moreno et al. 2012). Inset, high magnification view of region delineated in boxed area. Scale bars, 100 nm. (den, dendrite; at, axon terminal)

Fig. 6

a Head-twitch behavior induced by DOI and LSD is absent in mGlu2 knockout mice (see Moreno et al. 2011). b, c Expression of 5-HT_2A and mGlu2 as a GPCR heteromer is necessary for head-twitch psychosis-like behavior induced by hallucinogenic 5-HT_2A agonists in mice (see Moreno et al. 2012). Representative image of HSV-mediated transgene expression in mouse frontal cortex. Scale bar, 200 μm (b). Virally mediated over-expression of wild-type mGlu2, but not the mGlu2/mGlu3 chimeric construct mGlu2∆TM4 N that does not form the 5-HT_2A-mGlu2 heteromeric receptor complex, rescues the head-twitch behavior induced by the hallucinogenic 5-HT_2A receptor agonist DOI (c)

Fig. 7

Model of the mechanism underlying hallucinogen-induced head-twitch behavioral response