Presynaptic a1 adrenergic receptors differentially regulate synaptic glutamate and GABA release to hypothalamic presympathetic neurons

The hypothalamic paraventricular nucleus (PVN) neurons that project to the spinal intermediolateral cell column and brainstem are important for the control of sympathetic outflow. Stimulation of a1 adrenergic receptors in the PVN increases sympathetic outflow, but the cellular mechanisms remain unclear. In this study, we determined the role of a1 adrenergic receptors in the regulation of glutamatergic and GABAergic synaptic inputs to spinally projecting PVN neurons. Whole-cell and cell-attached patch-clamp recordings were performed on retrogradely labeled PVN-spinal neurons in rat brain slices. Bath application of 10 to 100 µM phenylephrine, an a1 adrenergic receptor agonist, significantly increased the frequency of spontaneous excitatory postsynaptic currents in a concentration-dependent manner. This effect was blocked by the a1 adrenergic receptor antagonists prazosin or corynanthine. Phenylephrine also significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) but not the amplitude and decay constant of mEPSCs. Furthermore, activation of a1 adrenergic receptors with phenylephrine or cirazoline significantly decreased the frequency of spontaneous inhibitory postsynaptic currents and miniature inhibitory postsynaptic currents, and this effect also was blocked by corynanthine. In addition, 50 µM phenylephrine significantly increased the firing rate of 13 labeled PVN neurons from 3.16 ± 0.42 to 5.83 ± 0.65 Hz. However, phenylephrine failed to increase the firing of most labeled PVN neurons in the presence of GABAA and ionotropic glutamate receptor antagonists. Thus, these data suggest that activation of a1 adrenergic receptors increases the excitability of PVN presympathetic neurons primarily through augmentation of glutamatergic tone and attenuation of GABAergic inputs. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.