YM992 [(S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride] is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and a potent 5-HT 2A antagonist. The aim of the present study was to assess, using in vivo extracellular unitary recordings, the effect of acute and sustained administration of YM992 (40 mg kg Ϫ1 day Ϫ1 s.c., using osmotic minipumps) on the spontaneous firing activity of locus coeruleus (LC) norepinephrine (NE) neurons. Acute intravenous injection of YM992 (4 mg kg Ϫ1 ) significantly decreased NE neuron firing activity by 29% and blocked the inhibitory effect of a subsequent injection of the 5-HT 2 agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride]. A 2-day treatment with YM992 decreased the firing rate of NE neurons by 66%, whereas a partial recovery was observed after a 7-day treatment and a complete one after a 21-day treatment. Following the injection of the ␣ 2 -adrenoceptor antagonist idazoxan (1 mg kg -1 i.v.), NE neuron firing was equalized in controls and 2-day YM992-treated rats. This put into evidence an increased degree of activation of ␣ 2 -adrenergic autoreceptors in the treated rats. The suppressant effect of the ␣ 2 -adrenoceptor agonist clonidine was significantly decreased in longterm YM992-treated rats. The recovery of LC firing activity after long-term YM992 administration could thus be explained by a decreased sensitivity of ␣ 2 -adrenergic autoreceptors. Sustained SSRI administration leads to a gradual reduction of the firing activity of NE neurons during long-term administration, whereas YM992 produced opposite effects. The exact basis for the increased synaptic availability of NE by YM992 remains to be elucidated. This NE activity, resulting from 5-HT reuptake inhibition plus 5-HT 2A receptor antagonism, might confer additional benefits in affective and anxiety disorders.The norepinephrine (NE) and the serotonin (5-hydroxytryptamine; 5-HT) systems have both been implicated in anxiety and affective disorders. Although the etiopathology of these two disorders remains enigmatic, greater knowledge exists pertaining to the interactions/alterations of these monoaminergic systems during antidepressant drug treatment. It is well established that locus coeruleus (LC) NE neurons modulate the 5-HT system, and evidence is accumulating for a major influence of 5-HT on the NE system (see Haddjeri et al., 1997;Kaehler et al., 1999). The LC receives dense 5-HT projections coming from dorsal raphe and pericoerulear 5-HT neurons (Aston-Jones et al., 1991;Kaehler et al., 1999), which exert an inhibitory role (Léger and Descarries, 1978;Segal, 1979). This is supported by the observation that lesioning 5-HT neurons with a 5-HT neurotoxin produced a marked elevation of firing rate of NE neurons (Haddjeri et al., 1997). Long-term, but not acute or short-term (2-day) administration of SSRIs decreases the spontaneous firing activity of LC NE neurons in the rat (Béïque et al.,1998;Szabo et al., 2000;Szabo and Blier, 2001a;Grant a...