Stocker SD, Gordon KW. Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation. J Neurophysiol 113: 1302-1309, 2015. First published December 4, 2014 doi:10.1152/jn.00764.2014.-The sympathoexcitatory response to insulin is mediated by neurons in the arcuate nucleus (ARC) and hypothalamic paraventricular nucleus (PVH). Previous studies have reported that stimulation of ARC neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through glutamate receptor activation in the PVH. Therefore, the purpose of the present study was to determine whether glutamatergic neurotransmission in the PVH contributes to insulin-induced sympathoexcitation. Male Sprague-Dawley rats (275-400 g) were infused with isotonic saline or insulin (3.75 mU·kg Ϫ1 ·min Ϫ1 ) plus 50% dextrose to maintain euglycemia. Intravenous infusion of insulin significantly increased lumbar SNA without a significant change in mean ABP, renal SNA, heart rate, or blood glucose. Bilateral PVH injection of the excitatory amino acid antagonist kynurenic acid (KYN) lowered lumbar SNA and ABP of animals infused with insulin. Similarly, a cocktail of the NMDA antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) and non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced lumbar SNA and mean ABP during infusion of insulin. In a final experiment, bilateral PVH injection of AP5 only, but not CNQX, lowered lumbar SNA and mean ABP of animals infused with insulin. The peak changes in lumbar SNA and mean ABP of insulin-treated animals were not different between KYN, AP5 plus CNQX, or AP5 alone. These drug treatments did not alter any variable in animals infused with saline. Altogether, these findings suggest that glutamatergic NMDA neurotransmission in the PVH contributes to insulin-induced sympathoexcitation.hypothalamus; lumbar; sympathetic nerve activity; NMDA; blood pressure ACCUMULATING EVIDENCE INDICATES insulin acts within the hypothalamic arcuate nucleus (ARC) to activate downstream pathways including neurons of the hypothalamic paraventricular nucleus (PVH) and rostral ventrolateral medulla (RVLM) to increase sympathetic nerve activity (SNA) and alter baroreflex function (Bardgett et al.