Characterisation of Human 5‐Hydroxytryptamine_2A and 5‐Hydroxytryptamine_2C Receptors Expressed in the Human Neuroblastoma Cell Line SH‐SY5Y: Comparative Stimulation by Hallucinogenic Drugs

Abstract

Stable transfection of the human neuroblastoma cell line SH‐SY5Y with the human 5‐hydroxytryptamine2A (5‐HT2A) or 5‐HT2C receptor cDNA produced cell lines demonstrating ligand affinities that correlated closely with those for the corresponding endogenous receptors in human frontal cortex and choroid plexus, respectively. Stimulation of the recombinant receptors by 5‐HT induced phosphoinositide hydrolysis with higher potency but lower efficacy at the 5‐HT2C receptor (pEC50 = 7.80 ± 0.06) compared with the 5‐HT2A receptor (pEC50 = 7.30 ± 0.08). Activation of the 5‐HT2A receptor caused a transient fourfold increase in intracellular Ca2+ concentration. Whole‐cell recordings of cells clamped at −50 mV demonstrated a small inward current (2 pA) in response to 10 µM 5‐HT for both receptors. There were no differences in potency or efficacy of phosphoinositide hydrolysis among four hallucinogenic [d‐lysergic acid diethylamide (LSD), 1‐(4‐iodo‐2,5‐dimethoxyphenyl)‐2‐aminopropane (DOI), 5‐methoxy‐N,N‐dimethyltryptamine, and mescaline] and three nonhallucinogenic drugs (m‐chlorophenylpiperazine, quipazine, and ergotamine). Comparison of equipotent doses producing 20% of the maximal response induced by 5‐HT revealed selective activation of the 5‐HT2A receptor by LSD and to a lesser degree by DOI, mescaline, and ergotamine. Quipazine and 5‐methoxy‐N,N‐dimethyltryptamine were relatively nonselective, whereas m‐chlorophenylpiperazine selectively activated the 5‐HT2C receptor. It is unlikely therefore that hallucinosis is mediated primarily by activity at the 5‐HT2C receptor, whereas activity at the 5‐HT2A receptor may represent an important but not unique mechanism associated with hallucinogenic drug action.

RNA Editing of the Human Serotonin 5-HT2C Receptor Alterations in Suicide and Implications for Serotonergic Pharmacotherapy

“…( ϩ ) LSD, a hallucinogenic ergot derivative, has been shown to have agonist properties in a neuroblastoma cell line expressing human 5-HT 2C-INI receptors (Newton et al 1996). In the present studies, LSD produced a robust phosphoinositide hydrolysis response in fibroblasts stably expressing the h5-HT 2C-INI R ( Figure 1); however, the hallucinogen failed to elicit a reproducible response in fibroblasts expressing the h5-HT 2C-VGV R (Figure 1).…”

The mRNA Expression of Serotonin 2C Subtype Receptors Uncoupled With Inositol Hydrolysis in NG108-15 Cells

“…The physiological functions of 5-HT2CR are involved in feeding behavior and epilepsy, as shown by results obtained with knockout mice (4). Pharmacological studies have shown that 5-HT2CR appears to be the binding site for antipsychotic drugs (5), hallucinogens (6) and antidepressants (7,8). We also reported that repeated treatment with antidepressants stimulates the expression of 5-HT2CR mRNA in the rat brain (9,10).…”

Pharmacogenetics of antidepressant response

“…[247][248][249][250] It has consistently been reported that drugs with 5-HTR2A agonist properties may have acute euphoriant effects. 251 Moreover, paroxetine and nefazodone may exert their antidepressant effects through regulation of 5-HT 2A receptors, 249,[252][253][254] although controversial findings can also be found. 255 Finally, 5-HT 2A receptors have been reported to mediate some of the antidepressant effects seen in experimental animal models of depression.…”