Noradrenergic Excitation of Magnocellular Neurons in the Rat Hypothalamic Paraventricular Nucleus via Intranuclear Glutamatergic Circuits

Abstract

Noradrenergic projections to the hypothalamus play a critical role in the afferent control of oxytocin and vasopressin release. Recent evidence for intrahypothalamic glutamatergic circuits prompted us to test the hypothesis that the excitatory effect of noradrenergic inputs on oxytocin and vasopressin release is mediated in part by local glutamatergic interneurons. The voltage response to norepinephrine (30-300 M) was tested with whole-cell recordings in putative magnocellular neurons of the paraventricular nucleus (PVN) in hypothalamic slices (400 m). Norepinephrine elicited an ␣ 1 receptor-mediated direct depolarization in 23% of the magnocellular neurons tested; however, the most prominent response, seen in 42% of the magnocellular neurons, was an ␣ 1 receptor-mediated increase in the frequency of EPSPs. The norepinephrine-induced increase in EPSPs was blocked by tetrodotoxin and by ionotropic glutamate receptor antagonists, suggesting that norepinephrine excited presynaptic glutamate neurons to cause an increase in spike-mediated transmitter release. The increase in EPSPs also was observed in a surgically isolated PVN preparation (64% of cells) and with microdrop applications of norepinephrine (1 mM, 33% of cells) and glutamate (0.5-1 mM, 28%) in the PVN, indicating that the norepinephrine-sensitive presynaptic glutamate neurons are located within the PVN. Biocytin injection and subsequent immunohistochemical labeling revealed that both oxytocin and vasopressin neurons responded to norepinephrine. Our data indicate that magnocellular neurons of the PVN receive excitatory inputs from intranuclear glutamatergic neurons that express ␣ 1 -adrenoreceptors. These glutamatergic interneurons may serve as an excitatory relay in the afferent noradrenergic control of oxytocin and vasopressin release under certain physiological conditions.

The Role of the Amygdala in Regulating the Hypothalamic-Pituitary-Adrenal Axis

“…In a recent study, it was found that the NE-induced increase of excitatory postsynaptic potentials was blocked by ionotropic glutamate receptor antagonists. This result suggests that spike-mediated transmiter release in the hypothalamus resulted from presynaptic efect of NE on glutamate neurons [36].…”

“…For example, the efect of hypothalamic NE on CRH release is mediated by intrahypothalamic glutamatergic interneurons [36]. Also, the activation of the HPA axis by electrical stimulation of the VNAB, or by direct PVN injection of, phenylephrine (an agonist with high ainity to α1-adrenergic receptors) was markedly inhibited by PVN administration of selective ionotropic glutamate receptor antagonists [37].…”

Group III Metabotropic Glutamate Receptors Maintain Tonic Inhibition of Excitatory Synaptic Input to Hypocretin/Orexin Neurons

“…In these experiments, 30 M bicuculline (BIC) was bath applied to block inhibitory transmission. The chemical stimulation experiments were made by pressure application (10 -20 psi, 5-10 msec) (Picospritzer II; Parker-Hannefin, Fairfield, NJ) of a small microdrop of L-glutamate (5-10 mM) to the surface of the lateral hypothalamus, using a broken patch pipette of 50 -100 m tip diameter, as described previously (Belousov and van den Pol, 1997;Daftary et al, 1998;Smith and Dudek, 2001). These experiments were conducted in a slice preparation in which the lateral hypothalamic area was surgically isolated by cutting away and removing the rest of the tissue.…”

The paraventricular nucleus of the hypothalamus – a potential target for integrative treatment of autonomic dysfunction

“…Noradrenergic effects on magnocellular PVN neurons were demonstrated to be the result of catecholamine actions on glutamate interneurons rather than direct effects on the magnocellular neuron itself [46]. Subsequently, a number of studies which have suggested important roles for glutamate interneurons in mediating the excitatory effects of ANG [25], orexin [33], and prokineticin 2 [47] on magnocellular neurons, capsaicin on preautonomic neurons [48], and on the response of neuroendocrine CRH neurons to restraint stress [49].…”