A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system.
A nonclassical 5-hydroxytryptamine (5-HT) receptor mediates the stimulation of adenylate cyclase activity in mouse embryo colliculi neurons in primary culture. The pharmacological profile characterized with agonists and antagonists suggests that this 5-HT receptor does not appear to correspond to a known 5-HT receptor. On this 5-HT receptor, 5-HT (EC50 = 109 +/- 17 nM) and 5-methoxytryptamine (5-MeOT) were equipotent agonists. The other tryptamine derivatives, 5-carboxamidotryptamine (5-CT) and 5-methoxy-N,N-dimethyltryptamine (5-MeOT-N,N-DMT), were full potent agonists, whereas tryptamine, bufotenine, and 2-CH3-5-HT were weak partial agonists. Two selective 5-HT1A agonists: 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and ipsapirone, could not stimulate adenylate cyclase. RU 24969, a tetrahydropyridoindole derivative that is a potent 5-HT1A and 5-HT1B agonist was also inactive, whereas RU 28253, another member of this series, could stimulate cAMP production. The action of antagonists acting on 5-HT1 or 5-HT2 receptors, such as methiothepin (5-HT1 and 5-HT2), metergoline (5-HT1 and 5-HT2), spiperone (5-HT1A and 5-HT2), (-)-pindolol (5-HT1B), mesulergine (5-HT1C), and ketanserin (5-HT2), were almost inactive in reversing the 5-HT stimulating effect. The selective 5-HT3 antagonist ICS 205 930 was a full competitive antagonist at this receptor. Nevertheless, MDL 72222, which is also a 5-HT3 antagonist, was very weak in antagonizing the 5-HT stimulatory effect. A receptor with similar characteristics has also been found in guinea pig hippocampal membranes. In these membranes, the second receptor of low affinity for 5-HT, termed RL, which is positively coupled to adenylate cyclase, was also antagonized by ICS 205 930. The relatively low affinity of this hippocampal receptor for 5-CT, its stimulation by RU 28253 but not by RU 24969, and its previously reported pharmacological characteristics support the contention that this 5-HT receptor and the 5-HT receptor of mouse embryo colliculi neurons in primary culture (both positively coupled to cAMP formation) present great homologies. Inasmuch as none of the classical specific 5-HT1 and 5-HT2 agonists or antagonists interact with these 5-HT receptors, it is unlikely that they belong to 5-HT1 or 5-HT2 receptor categories.(ABSTRACT TRUNCATED AT 400 WORDS)
Dumuis
A
A
Centre CNRS-INSERM de Pharmacologie Endocrinologie, Montpellier, France.
Bouhelal
R
R
Sebben
M
M
Cory
R
R
Bockaert
J
J
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D006168:Guinea Pigs; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013477:Superior Colliculi / Q000378:metabolism; D000077526:Tropisetron; D014363:Tryptamines / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014363:Tryptamines; D012701:Serotonin; D000077526:Tropisetron; D000242:Cyclic AMP; D000262:Adenylyl Cyclases