Brain Research 973 (2003) 161–170 www.elsevier.com / locate / brainres Research report Estrogen-induced autonomic effects are mediated by NMDA and GABA receptors in the parabrachial nucleus A a,b, a * Tarek M. Saleh , Barry J. Connell a Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI C1A 4P3, Canada b PEI Health Research Institute, University of Prince Edward Island, Charlottetown, PEI C1A 4P3, Canada Accepted 5 February 2003 Abstract The present study was done to determine if estrogen interacts with excitatory and / or inhibitory amino acid neurotransmitters to alter neuronal excitability within the parabrachial nucleus (PBN) and modulate autonomic tone. First, the role of estrogen in modulating autonomic tone was investigated in male rats anesthetized with Inactin (100 mg / kg). Animals were instrumented to record blood pressure, heart rate, vagal parasympathetic and renal sympathetic nerve activities as well as baroreflex sensitivity. Direct, bilateral injection of 17b-estradiol (0.5 mM; 200 nl / side) into the PBN resulted in a significant decrease in blood pressure (1764 mmHg), sympathetic tone (2065%) and heart rate (2265 beats / min) while increasing parasympathetic tone (3464%) 30 min post-injection. These estrogen- induced effects were completely blocked by the co-injection of estrogen with the estrogen receptor antagonist, ICI 182,780 (20 mM; 200 nl/side). Co-injection of the NMDA receptor antagonist, (6)-3-(2-carboxypiperazine-4-yl) propyl-1-phosphonic acid (CPP; 10 mM; 200 nl / side), with estradiol resulted in complete blockade of the estrogen-induced decrease in heart rate and increase in parasympathetic tone only. Co-injection of estradiol with the GABA receptor antagonist, (1)-bicuculline (0.1 mM; 200 nl/side), resulted in complete blockade A of the estrogen-induced decrease in blood pressure and sympathetic nerve activity only. These results suggest that estrogen acts on estrogen receptors on neurons in the PBN to modulate GABA -receptor mediated inhibitory neurotransmission to alter sympathetic tone A and blood pressure and on neurons in a separate, parallel pathway to modulate NMDA-receptor mediated neurotransmission to alter parasympathetic tone and heart rate.  2003 Elsevier Science B.V. All rights reserved. Keywords: GABA; NMDA; Autonomic effect; Parabrachial nucleus; Estrogen receptor 1. Introduction cardiovascular pathology [2,17,32]. Our laboratory has shown that the prior intravenous administration of estrogen Estrogen is well established as a central modulator of blocked the MCAO-induced sympatho-excitation and autonomic nervous system health and has been shown to parasympathoinhibition in male rats [27,28]. Interestingly, prevent pathology-induced alterations in sympatho-vagal these beneficial effects of systemic estrogen administration balance. Sympatho-vagal imbalance leads to autonomic prior to MCAO could be blocked with the prior mi- dysfunction which plays an important role in the patho- croinjection of the estrogen receptor antagonist, ICI genesis of cardiac arrhythmias, particularly following 182,780, directly into central autonomic nuclei implicating ischemic heart disease or stroke. Animal models of either a centrally-mediated mechanism of action in male rats increased visceral afferent activation or permanent middle [19]. cerebral artery occlusion (MCAO), have mimicked the Estrogen-like immunoreactivity and estrogen receptors elevated sympathetic output and / or parasympathetic with- (ERa and ERb) have been localized throughout the central drawal seen clinically shortly following the onset of nervous system and in nuclei responsible for autonomic regulation. Both estrogen receptor subtypes are found in particular dense distribution within the lateral subnuclei of *Corresponding author. Department of Biomedical Sciences, Atlantic the parabrachial nucleus of the pons (PBN) [29,35]. The Veterinary College, University of Prince Edward Island, Charlottetown, lateral PBN has been demonstrated to play an integral role PEI C1A 4P3 Canada. Tel.: 11-902-566-0819; fax: 11-902-566-0832. E-mail address: tsaleh@upei.ca (T.M. Saleh). in modulating neurotransmission of cardiovascular infor- 0006-8993 / 03 / $ – see front matter  2003 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0006-8993(03)02432-6