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

Abstract

The parasympathetic control of heart rate arises from premotor cardiac vagal neurons (CVNs) located in the nucleus ambiguus. Previous microinjection studies in nucleus ambiguus show that dopamine evokes a decrease in heart rate, but the underlying mechanisms responsible for these responses were not identified. This study tested whether dopamine modulates inhibitory GABAergic and glycinergic and/or excitatory glutamatergic neurotransmission to CVNs. Retrogradely labeled CVNs were identified in an in-vitro rat brainstem slice preparation and synaptic events were recorded using whole cell voltage clamp techniques. Bath application of dopamine (100 M) had no effect on excitatory synaptic events, but reversibly inhibited the frequency (but not amplitude) of GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs. Similarly, dopamine (10 M & 100 M) inhibited glycinergic IPSC frequency by ~ 50% and 70% respectively. The reduction in inhibitory neurotransmission to CVNs by dopamine was prevented by the sodium channel blocker TTX (1μM) indicating that the dopamine mediated effects were action potential dependent. Dopamine evoked responses were mimicked by the D2-like receptor agonist, Quinpirole but not D1-like receptor agonist, SKF 38393. In addition, the dopamine mediated depression of inhibitory synaptic responses were prevented by the D2 receptor antagonist sulpiride, but not by D1-like or adrenergic or serotonergic receptor antagonists, suggesting that these responses were D2-like receptor mediated and not D1-like or adrenergic or 5-HT receptor mediated. These data suggest that dopamine acts via disinhibition, and diminishes inhibitory GABAergic and glycinergic neurotransmission to CVNs, which would be predicted to increase parasympathetic activity to the heart and evoke a bradycardia.

Circadian‐timed quick‐release bromocriptine lowers elevated resting heart rate in patients with type 2 diabetes mellitus

“…Such a SNS target of B‐QR would be consistent with the reported sympatholytic mechanism of action of circadian‐timed B‐QR therapy to improve glycaemic control and reduce CVD risk in type 2 diabetes subjects . However, although SNS innervation of the myocardium is extensive and exerts a prominent control of myocardial function, reduced parasympathetic drive to the heart may also contribute to elevated RHR and central dopamine action can function to reverse this vagal imbalance as well, an effect which may also participate in the observed B‐QR effects on elevated RHR in this study.…”

Mechanisms underlying the generation of autonomorespiratory coupling amongst the respiratory central pattern generator, sympathetic oscillators, and cardiovagal premotoneurons

“…Nucleus ambiguus (i.e., N.A.) and dorsal motor nucleus of the vagus (DMV) convey cardiovagal preganglionic neurons en route to cardiac plexus ganglia postganglionic parasympathetic neurons powerfully modulating sinoatrial chronotropy, atrioventricular dromotropy, and atrial inotropy (Dyavanapalli et al, 2013;Eckberg, 2003;Taylor et al, 2009), though a few fibers coordinately supply ventricular myocardium (Coote, 2013). Postganglionic sympathetic and parasympathetic cardiovagal axons modulate sinoatrial action potential frequency by influencing the slope of spontaneous depolarization mediated by persistent sodium channel current in sinoatrial nodal cells, atrioventricular conductivity by regulating the slope of voltage-gated calcium current rise in atrioventricular nodal cells, and atrial and ventricular contractility by determining magnitude and rate of rising of cytosolic calcium flux deriving from the extracellular space and sarcoplasmic reticulum stores (Ghali, 2017a.…”

Brain Stem Mechanisms Responsible for the Trigeminocardiac Reflex

“…As an example, the acetylcholinesterase inhibitor neostigmine inhibits the glutamatergic neurotransmission to CVNs upon stimulation of trigeminal fibers. 4,9,10 The synaptic transmission onto neurons in the trigeminal nucleus remains unaffected by isoflurane or fentanyl, suggesting that both of these agents either act on receptors that are more densely localized to the synapses surrounding CVNs or more readily modify the subunit composition of receptors involved in neurotransmission to CVNs than they modify receptors involved in neurotransmission to spinal trigeminal neurons. However, the peak amplitude of EPSC evoked by trigeminal stimulation was inhibited by the muscarinic acetylcholine receptor (mAChR) agonist bethenecol and facilitated by the mAChR antagonist atropine, providing additional evidence for endogenous inhibition of this reflex pathway by acetylcholine, specifically via activation of mAChRs.…”