Modulation of the firing activity of noradrenergic neurones in the rat locus coeruleus by the 5‐hydroxtryptamine system

The aim of the present study was to investigate the putative modulation of locus coeruleus (LC) noradrenergic (NA) neurones by the 5‐hydroxytryptaminergic (5‐HT) system by use of in vivo extracellular unitary recordings and microiontophoresis in anaesthetized rats. To this end, the potent and selective 5‐HT 1A receptor antagonist WAY 100635 ( N ‐{2‐[4(2‐methoxyphenyl)‐1‐piperazinyl]ethyl}‐ N ‐(2‐pyridinyl)cyclohexanecarboxamide trihydroxychloride) was used. In the dorsal hippocampus, both local (by microiontophoresis, 20 nA) and systemic (100 μg kg −1 , i.v.) administration of WAY 100635 antagonized the suppressant effect of microiontophorectically‐applied 5‐HT on the firing activity of CA 3 pyramidal neurones, indicating its antagonistic effect on postsynaptic 5‐HT 1A receptors. WAY 100635 and 5‐HT failed to modify the spontaneous firing activity of LC NA neurones when applied by microiontophoresis. However, the intravenous injection of WAY 100635 (100 μg kg −1 ) readily suppressed the spontaneous firing activity of LC NA neurones. The lesion of 5‐HT neurones with the neurotoxin 5,7‐dihydroxytryptamine increased the spontaneous firing activity of LC NA neurones and abolished the suppressant effect of WAY 100635 on the firing activity of LC NA neurones. In order to determine the nature of the 5‐HT receptor subtypes mediating the suppressant effect of WAY 100635 on NA neurone firing activity, several 5‐HT receptor antagonists were used. The selective 5‐HT 3 receptor antagonist BRL 46470A (10 and 100 μg kg −1 , i.v.), the 5‐HT 1D receptor antagonist GR 127935 (100 μg kg −1 , i.v.) and the 5‐HT 1A/1B receptor antagonist (−)‐pindolol (15 mg kg −1 , i.p.) did not prevent the suppressant effect of WAY 100635 on the firing activity of LC NA neurones. However, the suppressant effect of WAY 100635 was prevented by the non‐selective 5‐HT receptor antagonists spiperone (1 mg kg −1 , i.v.) and metergoline (1 mg kg −1 , i.v.), by the 5‐HT 2 receptor antagonist ritanserin (500 μg kg −1 , i.v.). It was also prevented by the 5‐HT 1A receptor/α 1D ‐adrenoceptor antagonist BMY 7378 (1 mg kg −1 , i.v.) and by the α 1 ‐adrenoceptor antagonist prazosin (100 μg kg −1 , i.v.). These data support the notion that the 5‐HT system tonically modulates NA neurotransmission since the lesion of 5‐HT neurones enhanced the LC NA neurones firing activity and the suppressant effect of WAY 100635 on the firing activity of NA neurones was abolished by this lesion. However, the location of the 5‐HT 1A receptors involved in this complex circuitry remains to be elucidated. It is concluded that the suppressant effect of WAY 100635 on the firing activity of LC NA neurones is due to an enhancement of the function of 5‐HT neurones via a presynaptic 5‐HT 1A receptor. In contrast, the postsynaptic 5‐HT receptor mediating this effect of WAY 100635 on NA neurones appears to be of the 5‐HT 2A subtype.British Journal of Pharmacology (1997) 120 , 865–875; doi: 10.1038/sj.bjp.0700968