Clonidine, an α2-receptor agonist, diminishes GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus

Abstract

In hypertension there is an autonomic imbalance in which sympathetic activity dominates over parasympathetic control. Parasympathetic activity to the heart originates from cardiac vagal neurons located in the nucleus ambiguus. Pre-sympathetic neurons that project to sympathetic neurons in the spinal cord are located in the ventral brainstem in close proximity to cardiac vagal neurons, and many of these pre-sympathetic neurons are catecholaminergic. In addition to their projection to the spinal cord, many of these pre-sympathetic neurons have axon collaterals that arborize into neighboring cardio-respiratory locations and likely release norepinephrine onto nearby neurons. Activation of α 2 adrenergic receptors in the central nervous system evokes a diverse range of physiological effects, including reducing blood pressure. This study tests whether clonidine, an α 2 adrenergic receptor agonist, alters excitatory glutamatergic, and/or inhibitory GABAergic or glycinergic synaptic neurotransmission to cardiac vagal neurons in the nucleus ambiguus. Cardiac vagal neurons were identified in a in-vitro brainstem slice preparation and synaptic events were recording using whole cell voltage clamp methodologies. Clonidine significantly inhibited GABAergic neurotransmission, but had no effect on glycinergic or glutamatergic pathways to cardiac vagal neurons. This diminished inhibitory GABAergic neurotransmission to cardiac vagal neurons would increase parasympathetic activity to the heart, decreasing heart rate and blood pressure. The results presented here provide a cellular substrate for the clinical use of clonidine as a treatment for hypertension as well as a role in alleviating posttraumatic stress disorder by evoking an increase in parasympathetic cardiac vagal activity, and a decrease in heart rate and blood pressure.

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

“…Hence it was important to test whether dopamine induced effects on inhibitory neurotransmission to CVNs were mediated due to the activation of 5-HT and noradrenergic receptors. The concentrations of 5-HT antagonists and adrenergic receptor antagonists used in this study are consistent with the previous studies (Dergacheva et al, 2007, Dergacheva et al, 2009, Gorini et al, 2009, Philbin et al, 2010, Boychuk et al, 2011) and the data in this study indicates that the effects of dopamine in this study were mediated independent from adrenergic or serotonergic receptor activation and involved D 2 –like, but not D 1 –like, receptor activation.…”

“…Dopamine has been shown to interact with various 5-HT receptors such as 5-HT 1A/1C , 5-HT 2A/2C and 5-HT 3 (Woodward et al, 1992, Oz et al, 2003, Bhattacharyya et al, 2006) and adrenergic receptors (Cornil et al, 2002, Cornil and Ball, 2008, Alberto et al, 2011). Activation of 5-HT 1A/7 and 5-HT 2 receptors (Dergacheva et al, 2007, Wang et al, 2007) and adrenergic receptors (Philbin et al, 2010, Bateman et al, 2012) inhibits the frequency of spontaneous GABAergic IPSCs to CVNs. Hence it was important to test whether dopamine induced effects on inhibitory neurotransmission to CVNs were mediated due to the activation of 5-HT and noradrenergic receptors.…”

“…CVNs are intrinsically silent and receive numerous synaptic inputs including those from GABAergic, glycinergic, glutamatergic, serotonergic and purinergic pathways (Neff et al, 1998, Mendelowitz, 1999, Wang et al, 2003, Dergacheva et al, 2010). Synaptic activity to CVNs is modulated by catecholaminergic pathways and receptors (Philbin et al, 2010, Boychuk et al, 2011, Bateman et al, 2012) and these targets likely act as links between depression and cardiovascular disease. However one still unstudied catecholamine that has strong potential to modulate the neurotransmission to CVNs is dopamine.…”

Dexmedetomidine decreases inhibitory but not excitatory neurotransmission to cardiac vagal neurons in the nucleus ambiguus

“…Clonidine, a less specific α2 adrenergic agonist than dexmedetomidine, has been shown to increase the excitability of cardiac vagal neurons via decreased inhibitory neurotransmission [10] suggesting a likely similar target for the effects of dexmedetomidine on cardiac vagal neurons. The purpose of this study is to test if synaptic neurotransmission to cardiac vagal neurons are altered by clinically relevant concentrations of dexmedetomidine.…”

Use of tetrahydrozoline for chemical submission

“…The alpha 2-adrenoceptor acts as an agonist thereby activating pre or postsynaptic receptors and the associated neurotransmitter(s). Alpha 2-adrenoceptors located in the presynaptic membrane of adrenergic neurons inhibit the release of various neurotransmitters such as noradrenaline or adrenaline [9], serotonin [10,11], gamma-aminobutyric acid (GABA) [12][13][14] and dopamine [15] producing a negative feedback loop. In vivo, the alpha 2-adrenoceptor agonists elicit a wide range of effects including hypotension and bradycardia, analgesia, hypothermia, sedation, hypnosis and anesthetic-sparing [15][16][17][18][19][20][21][22][23].…”