Responses to 5-hydroxytryptamine evoked in the hemisected spinal cord of the neonate rat.
1. Superfusion of isolated hemisected spinal cord from neonate rats with 5-hydroxytryptamine (5-HT) (10(-6) to 10(-3) M) evoked concentration-related depolarizations. The maximal depolarization elicited by a concentration of 10(-4) M was 1.0 +/- 0.1 mV (mean +/- s.e.mean, n = 30). Noradrenaline in a similar range of concentrations also elicited depolarizations. 2. The depolarizations probably originate in motoneurones as a result of direct interaction of the amines with these cells, since responses were unaltered by tetrodotoxin (10(-7) M) or Ca2+-free/Mg2+-rich medium. 3. 5-Carboxamidotryptamine (5-CT), S(+)-alpha-methyl-5-hydroxytryptamine (alpha-Me5-HT) and 5-methoxytryptamine (5-MeOT) evoked similar depolarizations to 5-HT. Tryptamine evoked depolarizations of smaller maximal amplitude. 5-Hydroxytryptophan, 2-methyl-5-hydroxytryptamine, 8-hydroxy-2-(di-N-propylamino) tetralin hydrobromide (8-OH-DPAT) and 5-methoxy-3-[1,2,3,6-tetrahydro-4-pyridinyl]-1-H-indole succinate (RU 24969) had no depolarizing action. 4. Concentration-response (CR) curves were determined for 5-HT, 5-CT, alpha-Me5-HT, 5-MeOT and tryptamine. The ED50 value for 5-HT was 20.5 +/- 1.2 microM. The equipotent molar ratios (EPMRs) for 5-CT and alpha-Me5-HT were close to unity, while 5-MeOT was approximately 3 times and tryptamine 13 to 14 times less potent than 5-HT. 5. The relative agonist potency of 5-HT with respect to other tryptamine analogues capable of depolarizing motoneurones was increased when 5-HT uptake was blocked by citalopram (10(-7) M). In the presence of citalopram, 5-HT was 2.7 times more potent than alpha-Me5-HT and 16.9 times more potent than 5-CT. The apparent order of potency was 5-HT greater than alpha-Me5-HT greater than 5-CT (greater than 5-MeOT much greater than tryptamine). 6. The monoamine oxidase inhibitor, pargyline (5 x 10(-4) M), had no effect on depolarizations to 5-HT, 5-CT or alpha-Me5-HT. 7. Methiothepin, 1 alpha H, 3 alpha, 5H-tropan-3-yl-3,5-dichlorobenzoate methanesulphonate (MDL 72222) and [3 alpha-tropanyl]-1H-indole-3-carboxylic acid ester hydrochloride (ICS 205-930) had no effect on 5-HT depolarizations elicited in motoneurones. Ketanserin (0.75 x 10(-7) M to 10(-6) M) showed modest antagonistic action and depressed maximal response amplitude; the pIC50 was 6.5. 8. Methysergide (10-8 to 10- 7M) was a potent antagonist of responses to 5-HT. CR curves were displaced to the right and flattened in the presence of the antagonist. The pIC5o assessed from the effect on depolarizations evoked by 5-HT 1O-4M was 7.5. 9. It is concluded that 5-HT acts directly to depolarize mammalian spinal motoneurones through receptors that are also activated by 5-CT, alpha-MeS-HT and 5-MeOT and are blocked by methysergide. The receptor profile, although not 5-HT3-like, does not clearly coincide with that for either 5-HT1-like or 5-HT2 receptors.
Connell
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Department of Physiology, University College, Cardiff.
Wallis
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D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D015283:Citalopram / Q000494:pharmacology; D004566:Electrodes; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects*
D009467:Neuromuscular Depolarizing Agents; D012702:Serotonin Antagonists; D015283:Citalopram; D012701:Serotonin; D007650:Ketanserin; D010293:Pargyline; D009638:Norepinephrine; D008784:Methysergide