Serotonin (5-hydroxytryptamine, 5-HT) and norepinephine (NE) neurons have reciprocal connections. These may thus interfere with anticipated effects of selective pharmacological agents targeting these neurons. The main goal of the present study was to assess whether the somatodendritic 5-HT(1A) autoreceptor is tonically activated by endogenous 5-HT in anesthetised rats, using in vivo extracellular unitary recordings. In rats with their NE neurons lesioned using 6-hydroxydopamine (6-OHDA) and in controls administered the NE reuptake inhibitor desipramine to suppress NE neuronal firing, the alpha2-adrenoceptor agonist clonidine no longer inhibited 5-HT neuron firing, therefore indicating the important modulation of the firing activity of 5-HT neurons by NE neurons. In control rats, the administration of the potent and selective 5-HT(1A) receptor antagonist WAY 100,635 ((N-[2-[4(2-methoxyphenyl)-1-piperazinyl]ethy]-N-(2-pyridinyl)cyclohexanecarboxamide trihydroxychloride) (100 microg/kg, i.v.) did not modify the spontaneous firing activity of 5-HT neurons, but in NE-lesioned rats using either 6-OHDA or DSP-4, WAY 100,635 produced a mean firing increase of 80 and 69%, respectively. When desipramine and D-amphetamine were used in control rats to prevent alterations in the availability of NE in the dorsal raphe, again WAY 100,635 produced a significant disinhibition of the firing of 5-HT neurons (83 and 53%, respectively). These data support the notion that the NE system tonically activates the firing activity of 5-HT neurons. When the fluctuations of the function of NE neurons normally produced by WAY 100,635 were prevented, a tonic activation of 5-HT(1A) autoreceptors by endogenous 5-HT was unmasked.