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.