Modification of serotonin neuron properties in mice lacking 5-HT1A receptors.
Using null mutant mice for the 5-HT1A receptor (5-HT1A-/-), extracellular electrophysiological recordings were first conducted to evaluate the impact of its genetic deletion on the firing rate of dorsal raphe 5-hydroxytryptamine (5-HT) neurons. Experiments were also done using brain slices to assess whether any compensation phenomenon had taken place in key receptors known to control 5-HT and norepinephrine release. The mean firing rate of 5-HT neurons was nearly doubled in 5-HT1A-/- mice, although 65% of the neurons were firing in their normal range. In preloaded brain slices, the 5-HT1D/B receptor agonist sumatriptan equally inhibited the electrically evoked release of [3H]5-HT in mesencephalic slices (containing the dorsal and median raphe) from wildtype and 5-HT1A-/- mice. The 5-HT1B receptor agonist CP 93129 (1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrol (3, 2-b) pyridin-5-one) and the alpha2-adrenoceptor agonist UK14,304 (5-bromo-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine) produced the same inhibitory effect in both groups of mice in hippocampus and frontal cortex slices. No difference was observed on the UK14,304-mediated inhibition of [3H]norepinephrine from preloaded slices of the two latter structures between the two groups of mice. In conclusion, the loss of control of the 5-HT1A autoreceptor in 5-HT1A-/- mice lead to a significant enhancement of 5-HT neuronal firing, but it did not alter 5-HT or norepinephrine release in any of the brain structures examined. In addition, it was not associated with changes in the function of 5-HT1D and 5-HT1B autoreceptors and of alpha2-adrenergic heteroreceptors on 5-HT neurons, nor of that of alpha2-adrenoceptors on norepinephrine terminals.
Richer
Maxime
M
Neurobiological Psychiatry Unit, McGill University, 1033 Avenue des Pins Ouest, H3A 1A1, Montréal, Québec, Canada.
Hen
René
R
Blier
Pierre
P
D000818:Animals; D017660:Autoreceptors / Q000378:metabolism; D000068438:Brimonidine Tartrate; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology; D014316:Tritium
D017660:Autoreceptors; D011725:Pyridines; D011758:Pyrroles; D011810:Quinoxalines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D018341:Receptors, Adrenergic, alpha-2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D014316:Tritium; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; D012701:Serotonin; D000068438:Brimonidine Tartrate; D018170:Sumatriptan; D009638:Norepinephrine