A 5-HT7 Heteroreceptor-Mediated Inhibition of [3H]Serotonin Release in Raphe Nuclei Slices of the Rat: Evidence for a Serotonergic–Glutamatergic Interaction
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- Harsing, L.G., Prauda, I., Barkoczy, J. et al. Neurochem Res (2004) 29: 1487. doi:10.1023/B:NERE.0000029560.14262.39
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Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain, loaded with [3H]serotonin ([3H]5-HT), superfused, and the electrically induced efflux of radioactivity was determined. The nonselective 5-HT receptor agonist 5-carboxamido-tryptamine (5-CT; 0.001 to 1 μM) inhibited the electrically stimulated [3H]5-HT overflow from raphe nuclei slices (IC50 of 3.34 ± 0.37 nM). This effect of 5-CT on [3H]5-HT overflow was antagonized by the 5-HT7 receptor antagonist SB-258719 (10 μM) and the 5-HT1B/1D antagonist SB-216641 (1 μM), the IC50 values for 5-CT in the presence of SB-258719 and SB-216641 were 94.23 ± 4.84 and 47.81 ± 4.66 nM. The apparent pA2 values for SB-258719 and SB-216641 against 5-CT were 6.43 and 7.12, respectively. The inhibitory effect of 5-CT on [3H]5-HT overflow was weakly antagonized by 10 μM of WAY-100635, a 5-HT1A receptor antagonist (IC50 6.65 ± 0.56 nM, apparent pA2 4.99). The antagonist effect of SB-258719 (10 μM) on 5-CT–evoked [3H]5-HT overflow inhibition was also determined in the presence of 1 μM SB-216641 or 1 μM SB-216641 and 10 μM WAY-100635, and additive interactions were found between the antagonists of 5-HT7 and 5-HT1 receptor subtypes. Addition of the Na+ channel blocker tetrodotoxin (1 μM) in the presence of SB-216641 (1 μM) and WAY-100635 (10 μM) attenuated the inhibitory effect of 5-CT on KCl-induced [3H]5-HT overflow. These findings indicate that 5-CT inhibits [3H]5-HT overflow from raphe nuclei slices of the rat by stimulation of 5-HT7 and 5-HT1B/1D receptors, whereas the role of 5-HT1A receptors in this inhibition is less pronounced. They also suggest that 5-HT7 receptors are probably not located on serotonergic neurons and thus may serve as heteroreceptors in regulation of 5-HT release in the raphe nuclei. 5-CT (0.1 μM) also inhibited [3H]glutamate release, and SB-258719 (10 μM) suspended this effect. We therefore speculated that the axon terminals of the glutamatergic cortico-raphe neurons may possess 5-HT7 receptors that inhibit glutamate release, which consequently leads to decreased activity of serotonergic neurons. The postulated glutamatergic–serotonergic interaction in the raphe nuclei was further evidenced by the finding that N-methyl-d-aspartate and AMPA enhanced [3H]5-HT release.