REGULATION OF 5-HYDROXYTRYPTAMINE RELEASE FROM RAT MIDBRAIN RAPHE NUCLEI BY 5-HYDROXYTRYPTAMINE(1D) RECEPTORS - EFFECT OF TETRODOTOXIN, G-PROTEIN INACTIVATION AND LONG-TERM ANTIDEPRESSANT ADMINISTRATION
G. Pineyro et P. Blier, REGULATION OF 5-HYDROXYTRYPTAMINE RELEASE FROM RAT MIDBRAIN RAPHE NUCLEI BY 5-HYDROXYTRYPTAMINE(1D) RECEPTORS - EFFECT OF TETRODOTOXIN, G-PROTEIN INACTIVATION AND LONG-TERM ANTIDEPRESSANT ADMINISTRATION, The Journal of pharmacology and experimental therapeutics, 276(2), 1996, pp. 697-707
Our study was undertaken to characterize the functional properties of
5-hydroxytryptamine (5-HT)(1D) receptors in the rat midbrain raphe nuc
lei. In a first series of experiments, designed to assess whether 5-HT
1D receptors are coupled to G(i/o) proteins, the intracerebral injecti
on of pertussis toxin into the dorsal raphe as well as incubation of m
idbrain raphe slices with the alkylating agent N-ethyl-maleimide (NEM)
reduced the efficacy of the 5-HT1B/1D agonist sumatriptan to inhibit
the electrically evoked overflow of [H-3]5-HT from preloaded slices. F
urthermore, preincubation with NEM also reduced the efficacy with whic
h the 5-HT1B/1D antagonist GR 127935 enhanced evoked overflow of [H-3]
5-HT. These results indicate that, in rat midbrain raphe nuclei, 5-HT1
D receptors are linked to G(i/o) proteins. In an attempt to determine
whether 5-HT1D receptors are located on 5-HT neurons, the inhibitory e
ffect of sumatriptan and of the nonselective 5-HT agonist 5-carboxyami
dotryptamine on K+-evoked overflow of [H-3]5-HT was assessed in the pr
esence of the Na+ channel blocker tetrodotoxin. Neither the inhibitory
effect of sumatriptan nor that of 5-carboxyamidotryptamine were reduc
ed by the addition of tetrodotoxin to the superfusion medium, suggesti
ng that these 5-HT1D receptors are located on 5-HT neurons and may be
considered autoreceptors. In a third series of experiments, rats were
treated for 21 days either with the selective 5-HT reuptake inhibitor
paroxetine (10 mg/kg/day, s.c.) or the reversible type A monoamine oxi
dase inhibitor befloxatone (0.75 mg/kg/day, s.c.) and superfusion expe
riments were performed after a 48-hr washout period. 5-HT1D receptors,
similarly to 5-HT1A autoreceptors, desensitize after long-term treatm
ent with a selective 5-HT reuptake inhibitor or a reversible type A mo
noamine oxidase inhibitor because the efficacy of sumatriptan and of 8
-OH-DPAT to inhibit the electrically evoked overflow of [H-3]5-HT was
reduced after the administration of either drug.