Differential pharmacology and function of two 5-HT1 receptors modulating transmitter release in rat cerebellum.
The release of endogenous glutamate (GLU) elicited by depolarization of rat cerebellum synaptosomes was inhibited potently (pEC30 = 9.77) by 5-hydroxytryptamine (5-HT). The 5-HT action was antagonized by methiothepin (pA2 = 10.37); ketanserin, methysergide, cinanserin and spiperone were ineffective. Exogenous 5-HT also inhibited the release of [3H]-5-HT from cerebellar synaptosomes (pEC30 = 8.73). Methiothepin, but not ketanserin, methysergide, cinanserin or spiperone counteracted the inhibition (pA2 = 9.28). The receptors involved (presynaptic 5-HT heteroreceptors and autoreceptors) were activated by the 5-HT1 agonist RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole) which showed comparable activity at the two receptor systems. (-)-Propranolol, used as a 5-HT1 antagonist, shifted to the right (pA2 = 8.05) the dose-response curve of 5-HT at the autoreceptors, but was ineffective at the receptors regulating GLU release. On the contrary, the 5-HT1A agonist 8-hydroxy-2-di-N-propylamino)tetralin activated the presynaptic heteroreceptors (pEC30 = 7.98), but was ineffective as a 5-HT autoreceptor agonist. The results allow the following major conclusions: 5-HT receptors are located on GLU terminals in rat cerebellum where they may modulate in an inhibitory way the release of GLU; 5-HT autoreceptors possibly involved in a negative feedback regulation of 5-HT release are present on cerebellar 5-HT nerve endings; 5-HT autoreceptors and heteroreceptors can be pharmacologically differentiated and appear to represent subtypes of the 5-HT1 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Raiteri
M
M
Maura
G
G
Bonanno
G
G
Pittaluga
A
A
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D002531:Cerebellum / Q000032:analysis* / Q000187:drug effects; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000032:analysis* / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D005971:Glutamates; D007211:Indoles; D018377:Neurotransmitter Agents; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole; D012701:Serotonin; D018698:Glutamic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D011433:Propranolol; D011188:Potassium