5-HT_1A/7receptor agonist excites cardiac vagal neurons via inhibition of both GABAergic and glycinergic inputs

Abstract

Aim: To study the synaptic mechanisms involved in the 5-hydroxytryptamine1A/7 (5-HT 1A/7 ) receptor-mediated reflex control of cardiac vagal preganglionic neurons (CVPN). Methods: CVPN were retrogradely labeled and identified in brain stem slices of newborn rats, and their synaptic activity was examined using whole-cell patch-clamp. Results: 8-Hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), an agonist of 5-HT 1A/7 receptors, had no effect on the glutamatergic inputs of CVPN. In contrast, it significantly decreased the frequency and the amplitude of both the GABAergic and the glycinergic spontaneous inhibitory postsynaptic currents (sIPSC). 8-OH-DPAT also caused significant amplitude decrease of the GABAergic currents evoked by stimulation of the nucleus tractus solitarius. Both the frequency inhibition and the amplitude inhibition of the GABAergic and the glycinergic sIPSC by 8-OH-DPAT had dose-dependent tendencies and could be reversed by WAY-100635, an antagonist of 5-HT 1A/7 receptors. In the pre-existence of tetrodotoxin, 8-OH-DPAT had no effect on the GABAergic or the glycinergic miniature inhibitory postsynaptic currents, and had no effect on the GABAergic or the glycinergic currents evoked by exogenous GABA or glycine. Conclusion:The 5-HT 1A/7 receptor agonist excites CVPN indirectly via the inhibition of both the GABAergic and glycinergic inputs. These findings have at least in part revealed the synaptic mechanisms involved in the 5-HT 1A/7 receptor-mediated reflex control of cardiac vagal nerves in intact animals. Key words5 -h y d r o x y t r y p t a m i n e ; c a r d i a c v a g a l preganglionic neurons; 8-hydroxy-2-(di-Np r o p y l a m i n o ) t e t r a l i n ; s p o n t a n e o u s inhibitory postsynaptic currents

Activation of D2-like dopamine receptors inhibits GABA and glycinergic neurotransmission to pre-motor cardiac vagal neurons in the nucleus ambiguus

“…However, a recent study in rats reported that strychnine sensitive glycine receptors are not involved in tonic or reflex control of cardiac vagal output (Hildreth and Goodchild, 2010) but are needed for 5H 1A receptor activation induced facilitation of bradycardia and changes in heart rate (Hildreth and Goodchild, 2010). In support of the current findings differential sensitivity of GABA and glycinergic neurons and inputs projecting to CVNs has been reported previously in which spontaneous glycinergic IPSCs were more sensitive to neuromodulators such as orexin-A (Wang et al, 2005) and 5HT 1A/7 receptor agonists (Chen et al, 2008) compared to GABA IPSCs. These reports indicate that GABA and glycine inputs to CVNs are likely differentially regulated, including their modulation by dopamine.…”

Role of ionotropic GABA, glutamate and glycine receptors in the tonic and reflex control of cardiac vagal outflow in the rat

“…In support of this hypothesis, in slice preparation, application of 8-OH-DPAT inhibits both GABAergic and glycinergic inputs to CVPN [26,27]. To confirm the physiological relevance of these findings we blocked GABA A receptors or strychnine-sensitive glycine receptor in the vicinity of CVPN and examined the response of systemic 8-OH-DPAT on the tonic and reflex bradycardia evoked.…”

“…Speculation suggests that as the 5-HT 1A receptor is an inhibitory GPCR, the mechanism must involve an interaction with inhibitory ionotropic inputs to CVPN [25]. In keeping with this hypothesis, application of 8-OH-DPAT in vitro attenuates presynaptic GABAergic and glycinergic inputs to CVPN [26,27]; however the functional significance of these inputs is unknown. Whether or not the effects of 5-HT 1A activation on HR or BRS are mediated by GABAergic and/or glycinergic inhibition of CVPN in the ventrolateral medulla has not been investigated in vivo .…”

Developmental exposure to paracetamol causes biochemical alterations in medulla oblongata

“…Activation of 5-HT 1A and 5-HT 1B receptors leads to the hyperpolarization of the neurons and reduction of the GABA release in different parts of CNS e.g. cerebellum or dorsal raphe nucleus (Chen et al, 2008;Ostrowski et al, 2014).…”