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5-hydroxytryptamine depolarizes neonatal rat motorneurones through a receptor unrelated to an identified binding site
Ist Teil von
Neuropharmacology, 1989-06, Vol.28 (6), p.625-634
Ort / Verlag
Oxford: Elsevier Ltd
Erscheinungsjahr
1989
Quelle
Elsevier Journal Backfiles on ScienceDirect (DFG Nationallizenzen)
Beschreibungen/Notizen
Superfusion of hemisected lumbar spinal cord of the neonatal rat with solutions containing 10
−6 to 10
−3 M 5-hydroxytryptamine (5-HT) elicited depolarizations of graded amplitude which were recorded from motorneurones through a ventral root. Maximum responses (amplitude 1.0 ± 0.1 mV, mean ± SEM,
n = 30) were evoked by 10
−4 M 5-HT. Repeated concentration-response curves could be determined from the same preparation.
There was no involvement of 5-HT
2 receptors in the depolarizing response to 5-HT, since neither ritanserin nor ICI 169, 369 showed any antagonist action.
Amongst agents with activity at 5-HT
1A sites, the selective 5-HT
1A receptor agonist, 8-hydroxy-2-(di-
N-propylamino) tetralin (8-OH-DPAT), neither mimicked the action of 5-HT nor antagonised it, while spiperone (10
−8-10
−7 M) antagonised responses to 5-HT in a concentration-related manner. Responses to 10
−4 M noradrenaline, used as a control depolarizing agent, were unaffected by spiperone. The onset of blockade by spiperone was slow, 1 hr being required for equilibration of the tissue with antagonist. The blockade was surmountable by larger concentrations of 5-HT. Concentration-response curves to 5-HT were shifted to the right in an approximately parallel manner by spiperone. The dose ratios measured from these curves at the EC
50 level, yielded an apparent p
A
2 of 8.24 ±0.14 (mean ± SEM,
n = 15), although the Schild plot of the data had a slope less than unity.
The lack of activity of the selective 5-HT
1B receptor agonist, RU 24969, and the 5-HT
1B receptor antagonists, (±)
cyanopindolol and quipazine, indicated that 5-HT
1B receptors were not involved in the 5-HT response of motorneurones to 5-HT.
Mesulergine, metergoline and cyproheptadine also antagonised responses of motorneurones to 5-HT, producing a surmountable blockade. Mesulergine (10
−8, 3 × 10
−8 and 10
−7 M) caused a progressive rightward shift of the concentration-response curves, but 10
−7 M depressed the maximum response to 5-HT. Responses to noradrenaline were not affected by these concentrations of mesulergine. The apparent pA
2 for blockade of 5-HT responses by mesulergine, calculated from experiments in which there was a parallel displacement of the concentration-response curves, was 8.75 ± 0.11 (mean ± SEM,
n = 10). Metergoline (10
−7 M) produced a modest degree of antagonism, the apparent
pA
2 being 7.2 ± 0.2(mean ± SEM,
n = 6). Cyproheptadine (10
−9 and 10
−8 M) induced rightward, parallel shifts of the concentration-response curves to 5-HT and the apparent
pA
2 was 8.88 ± 0.24 (mean ± SEM,
n = 10). Responses to noradrenaline were unaffected by these concentrations of cyproheptadine.
The pharmacological profile of the 5-HT receptor of the motorneurone from this and previous results (Connell and Wallis, 1988) is, thus: (a) 5-HT, α-Me-5-HT, 5-carboxamidotryptamine (5-CT) and 5-methoxytryptamine (5-MeOT) were full agonists, the order of agonist potency being 5-HT > α-Me-5-HT > 5-CT > 5-MeOT ⪢ tryptamine. The compounds 8-OH-DPAT, RU 24969 and 2-Me-5-HT were inactive as agonists, (b) Methysergide, spiperone, mesulergine, cyproheptadine and metergoline were antagonists active at nM concentrations. Ketanserin was a weak antagonist, while ritanserin, methiothepin, (±)
cyanopindolol, MDL 72222, ICS 205-930, quipazine, ICI 169, 369, yohimbine, 8-OH-DPAT and RU 24969 were without antagonist activity.
This profile cannot be equated with the CNS 5-HT
1A, 5-HT
1B, 5-HT
1C, 5-HT
1D or 5-HT
2 binding sites, nor with 5-HT
3 receptors. It is also distinguishable from a number of other functional 5-HT, -like receptors which do not conform to an identified 5-HT binding site.