Effects of Serotonin (5-Hydroxytryptamine, 5-HT) Reuptake Inhibition Plus 5-HT_2A Receptor Antagonism on the Firing Activity of Norepinephrine Neurons

Abstract

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...

Effect of Vagus Nerve Stimulation on Serotonergic and Noradrenergic Transmission

“…These results are in keeping with those obtained with antidepressants acting selectively on the noradrenergic system (Invernizzi and Garrattini, 2004). However, they differ from those obtained with compounds acting on both serotonergic and noradrenergic neurotransmissions (Szabo and Blier, 2002). Because VNS is acting by modifying both neurotransmissions, one might expect to find a desensitization of ␣ 2 -autoreceptors.…”

“…NE neurons have inhibitory ␣ 2 -adrenergic autoreceptors on the soma and terminals that decrease the NE firing rate or NE terminal release, respectively, in the presence of excess endogenous NE or ␣ 2 -agonists such as clonidine. After longterm treatment with the dual SSRI and 5-HT 2A antagonist YM992, NE neurons showed an increase in firing rate induced by a decrease in sensitivity of the ␣ 2 -adrenergic autoreceptor (Szabo and Blier, 2002). Interestingly, lesioning the LC in animal studies blocks the antiepileptic action of VNS, suggesting that the LC is involved in its effective circuitry (Krahl et al, 1998).…”

Effects of the Selective Norepinephrine Reuptake Inhibitor Reboxetine on Norepinephrine and Serotonin Transmission in the Rat Hippocampus

“…This, however, does not preclude that antidepressant agents specific for one monoaminergic transporter, or receptor subtype, may exert their therapeutic action through interactions between the 5-HT and NE systems. For example, SSRIs induce a gradual decrease in the spontaneous firing activity of NE neurons after long-term administration (Szabo et al 1999, via a complex neuronal circuitry (Szabo and Blier 2000a), which may contribute to their beneficial and/or side effects depending on the symptomatic profile of the patients (Blier 2000). On the other hand, the selective NE reuptake inhibitor desipramine increases the synaptic availability of NE but also alters 5-HT parameters after long-term administration, such as enhancing extracellular 5-HT concentrations and the responsiveness of 5-HT receptors in postsynaptic structures (de Montigny and Aghajanian 1978;Wang and Aghajanian 1980;Menkes and Aghajanian 1981;Yoshioka et al 1995).…”

Augmentation of SSRI Effects on Serotonin by 5-HT2C Antagonists: Mechanistic Studies

“…Over the last few decades, several such augmentation strategies have been developed. These add-on strategies range from antagonism of serotonergic autoreceptors like 5-HT 1A and 5-HT 1B (Hjorth et al, 2000;Blier et al, 1998;Artigas et al, 1994Artigas et al, , 1996Bosker et al, 2001;Celada et al, 2001;Cremers et al, 2000a, b), but also comprise heteroceptors such as adrenoceptors (Bengtsson et al, 1998;Szabo and Blier, 2001;Besson et al, 2000;Hopwood and Stamford, 2001;Bortolozzi and Artigas, 2003;Pudovkina et al, 2003;Rouquier et al, 1994;Amargos-Bosch et al, 2003;Weikop et al, 2004;Gobert et al, 1997;Gobert and Millan, 1999;De Boer et al, 1996), 5-HT 2A receptors (Szabo and Blier, 2002), GABA B receptors (Abellan et al, 2000;Slattery et al, 2005;Mombereau et al, 2004;Nakagawa et al, 1996), and substance P receptors (Guiard et al, 2004), to mention but a few.…”