Effects of ST1936, a selective serotonin-6 agonist, on electrical activity of putative mesencephalic dopaminergic neurons in the rat brain.
The serotonin-6 (5-HT6) receptor is the most recently discovered serotonin receptor, and it represents an increasingly promising target for improving cognition in both normal and disease states. Recently, a new selective 5-HT6 receptor agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine (ST1936), with nanomolar affinity for 5-HT6 receptors was described. We performed in-vivo electrophysiological studies to investigate the physiological role of 5-HT6 receptors in the control of the function of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Extracellular single-unit recordings were performed from putative dopamine-containing neurons in the SNc and VTA of anesthetised rats. In the SNc, acute systemic administration of ST1936 had no effects on basal firing activity of these dopamine neurons; however, in the VTA, ST1936 induced either dose-related increases (45% of cells) or decreases in basal activity of these dopaminergic neurons. Local application of ST1936 into the VTA caused excitation in all of the dopamine neurons, but had no effects on non-dopamine VTA neurons. Both effects of systemic and microiontophoretic ST1936 were completely reversed by the potent and selective 5-HT6 receptor antagonist 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2- benzothiophene-sulfonamide (SB271046). Systemic application of another 5-HT6 agonist, 2-(1-{6-chloroimidazo[2,1-b] [1,3]thiazole-5-sulfonyl}-1H-indol-3-yl)ethan-1-amine (WAY-181187), induced dose-dependent inhibition of these VTA dopaminergic neurons. ST1936 and WAY-181187 appear to have different effects on these VTA dopaminergic neurons, potentially due to different mechanisms of action or to the complexity of 5-HT6 receptor functions. Our data demonstrate the need for further investigations into the use of 5-HT6 receptor agonists to control cognitive disfunction, such as in schizophrenia and depression.
Sigma-Tau Industrie Farmaceutiche Riunite SpA, Pomezia, Roma, Italy.
Franco
F
Borsini
Sigma-Tau Industrie Farmaceutiche Riunite SpA, Pomezia, Roma, Italy.
Fabio
F
Bordi
Fondazione 'Mario Negri' Sud, Santa Maria Imbaro, Chieti, Italy.
Andreina
A
Poggi
Fondazione 'Mario Negri' Sud, Santa Maria Imbaro, Chieti, Italy vdimatteo@negrisud.it.
Vincenzo
V
Di Matteo
D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005021:Ethylamines / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D014363:Tryptamines / Q000008:administration & dosage / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
C558115:2-(5-chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine; D005021:Ethylamines; D007211:Indoles; C525454:N(1)-(6-chloroimidazo(2,1-b)(1,3)thiazole-5-sulfonyl)tryptamine; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D014363:Tryptamines; C097216:serotonin 6 receptor
ST1936; electrophysiology; serotonin-6 receptors; substantia nigra pars compacta; ventral tegmental area