Key role of 5-HT1A receptors in the modulation of the neuronal network underlying the respiratory rhythm generation in lampreys

In mammals, 5-HTexcitatory respiratory effects imply 5-HT1A receptor-mediated disinhibition of pre-Botzinger complex neurons. In the lamprey, 5-HT1A receptors are involved in the neural control of locomotion, but their role in the respiratory regulation, particularly at the level of the putative respiratory rhythm generator, the paratrigeminal respiratory group (pTRG), is not known. We here investigate the respiratory function of inhibitory 5-HT1A receptors within the pTRG of the isolated brainstem of the adult lamprey. The 5-HT1A receptor agonists either bath applied or microinjected into the pTRG did not cause significant effects. However, the selective 5-HT1A receptor antagonist (S)-WAY 100135 bath applied or microinjected into the pTRG induced depressing respiratory effects or even apnoea, thus revealing that 5-HT exerts a 5-HT1A receptor-mediated potent tonic influence on respiration and contributes to maintain baseline levels of respiratory activity. Microinjections of strychnine or bicuculline, either alone or in combination, into the pTRG prevented (S)-WAY 100135-induced apnoea. In addition, immunohistochemical studies corroborate the present findings suggesting that 5-HT1A receptors are widely expressed in close apposition to the soma of glycine-immunoreactive cells located within the pTRG region. The results show that in the lamprey respiratory network, 5-HT exerts a tonic influence on respiration by a potent inhibitory control on both GABAergic and glycinergic mechanisms. The observed disinhibitory effects resemble the excitatory respiratory modulation exerted by 5-HT1A receptor-mediated inhibition of glycinergic and/or GABAergic neurons present in mammals, supporting the notion that some features of the neuronal network subserving respiratory rhythm generation are highly conserved throughout phylogeny.