Characterisation of human 5-hydroxytryptamine sub(2A) and 5-hydroxytryptamine sub(2C) receptors expressed in the human neuroblastoma cell line SH-SY5Y: Comparative stimulation by hallucinogenic drugs

Stable transfection of the human neuroblastoma cell line SH-SY5Y with the human 5-hydroxytryptamine sub(2A) (5-HT sub(2A)) or 5-HT sub(2C) 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-HT sub(2C) receptor (pEC sub(50) = 7.80 plus or minus 0.06) compared with the 5-HT sub(2A) receptor (pEC sub(50) = 7.30 plus or minus 0.08). Activation of the 5-HT sub(2A) receptor caused a transient fourfold increase in intracellular Ca super(2+) concentration. Whole-cell recordings of cells clamped at -50 mV demonstrated a small inward current (2 pA) in response to 10 mu M 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-HT sub(2A) 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-HT sub(2C) receptor. It is unlikely therefore that hallucinosis is mediated primarily by activity at the 5-HT sub(2C) receptor, whereas activity at the 5-HT sub(2A) receptor may represent an important but not unique mechanism associated with hallucinogenic drug action.