Parabrachial complex glutamate receptors modulate the cardiorespiratory response evoked from hypothalamic defense area


      To characterize the possible role of glutamate in the interaction between Hypothalamic Defense Area (HDA) and Parabrachial complex (PBc) nuclei, cardiorespiratory changes were analyzed in response to electrical stimulation of the HDA (1 ms pulses, 30–50 μA given at 100 Hz for 5 s) before and after the microinjection of the nonspecific glutamate receptor antagonist kynurenic acid (50 nl, 5 nmol), NMDA receptor antagonist MK-801 (50 nl, 50 nmol), non-NMDA receptor antagonist CNQX (50 nl, 50 nmol) or metabotropic glutamate receptor antagonist MCPG (50 nl, 5 nmol) within the PBc. HDA stimulation evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (p<0.001) due to a decrease in expiratory time (p<0.01). The respiratory response was accompanied by a pressor (p<0.001) and a tachycardic response (p<0.001).
      Kynurenic acid within the lateral parabrachial region (lPB) abolished the tachycardia (p<0.001) and decreased the magnitude of blood pressure response (p<0.001) to HDA stimulation. Similarly, the magnitude of the tachycardia and the pressor response was decreased after the microinjection of MK-801 (p<0.01 and p<0.001, respectively) and CNQX (p<0.05 in both cases) into the lPB. Kynurenic acid microinjection in this region produced an inhibition of the tachypnea (p<0.001) to HDA stimulation but the respiratory response persisted unchanged after MK-801 or CNQX microinjection into the lPB.
      Kynurenic acid within the medial parabrachial region (mPB) abolished the tachycardia (p<0.01) and decreased the magnitude of the pressor response (p<0.001) to HDA stimulation. MK-801 and CNQX microinjection in this region decreased the magnitude of the tachycardia (p<0.05, in both cases) and pressor response (p<0.05, in both cases). The respiratory response evoked by HDA stimulation was not changed after the microinjection of kynurenic acid, MK-801 or CNQX within the mPB.
      No changes were observed in the cardiorespiratory response evoked to HDA stimulation after MCPG microinjection within lPB and mPB.
      These results indicate that glutamate PBc receptors are involved in the cardiorespiratory response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Alheid G.F.
        • Milsom W.K.
        • McCrimmon D.R.
        Pontine influences on breathing: an overview.
        Respir. Physiol. Neurobiol. 2004; 143: 105-114
        • Barnard E.A.
        Ionotropic glutamate receptors: new types and new concepts.
        Trends Pharmacol. Sci. 1997; 18: 141-148
        • Bazil M.K.
        • Gordon F.J.
        Blockade of parabrachial pressor responses by spinal administration of an N-methyl-d-aspartic acid receptor antagonist.
        Neuropharmacology. 1990; 29: 923-930
        • Biondolillo J.W.
        • Williams L.A.
        • King M.S.
        Blocking glutamate receptors in the waist area of the parabrachial nucleus decreases taste reactivity behaviors in conscious rats.
        Chem. Senses. 2009; 34: 221-230
        • Boon J.A.
        • Milsom W.K.
        NMDA receptor-mediated processes in the parabrachial/Kolliker fuse complex influence respiratory responses directly and indirectly via changes in cortical activation state.
        Respir. Physiol. Neurobiol. 2008; 162: 63-72
        • Chamberlin N.L.
        • Saper C.B.
        Topographic organization of cardiovascular responses to electrical and glutamate microstimulation of the parabrachial nucleus in the rat.
        J. Comp. Neurol. 1992; 326: 245-262
        • Chamberlin N.L.
        • Saper C.B.
        Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat.
        J. Neurosci. 1994; 14: 6500-6510
        • Chamberlin N.L.
        • Saper C.B.
        Differential distribution of AMPA-selective glutamate receptor subunits in the parabrachial nucleus of the rat.
        Neuroscience. 1995; 68: 435-443
        • Chamberlin N.L.
        • Saper C.B.
        A brainstem network mediating apneic reflexes in the rat.
        J. Neurosci. 1998; 18: 6048-6056
        • Coote J.H.
        • Hilton S.M.
        • Zbrozyna A.W.
        The ponto-medullary area integrating the defence reaction in the cat and its influence on muscle blood flow.
        J. Physiol. 1973; 229: 257-274
        • Dawid-Milner M.S.
        • Lara J.P.
        • Lopez de Miguel M.P.
        • Lopez-Gonzalez M.V.
        • Spyer K.M.
        • Gonzalez-Baron S.
        A5 region modulation of the cardiorespiratory responses evoked from parabrachial cell bodies in the anaesthetised rat.
        Brain Res. 2003; 982: 108-118
        • Dawid-Milner M.S.
        • Silva-Carvalho L.
        • Goldsmith G.E.
        • Spyer K.M.
        Hypothalamic modulation of laryngeal reflexes in the anaesthetized cat: role of the nucleus tractus solitarii.
        J. Physiol. 1995; : 739-749
        • Dawid-Milner M.S.
        • Lara J.P.
        • Gonzalez-Baron S.
        • Spyer K.M.
        Respiratory effects of stimulation of cell bodies of the A5 region in the anaesthetised rat.
        Pflugers Arch. 2001; 441: 434-443
        • De Gobbi J.I.
        • Beltz T.G.
        • Johnson R.F.
        • Menani J.V.
        • Thunhorst R.L.
        • Johnson A.K.
        Non-NMDA receptors in the lateral parabrachial nucleus modulate sodium appetite.
        Brain Res. 2009; 1301: 44-51
        • Diaz-Casares A.
        • Lopez-Gonzalez M.V.
        • Peinado-Aragones C.A.
        • Lara J.P.
        • Gonzalez-Baron S.
        • Dawid-Milner M.S.
        Role of the parabrachial complex in the cardiorespiratory response evoked from hypothalamic defense area stimulation in the anesthetized rat.
        Brain Res. 2009; : 58-70
        • Dutschmann M.
        • Herbert H.
        NMDA and GABAA receptors in the rat Kölliker-Fuse area control cardiorespiratory responses evoked by trigeminal ethmoidal nerve stimulation.
        J. Physiol. 1998; 510: 793-804
        • Felder R.B.
        • Mifflin S.W.
        Modulation of carotid sinus afferent input to nucleus tractus solitarius by parabrachial nucleus stimulation.
        Circ. Res. 1988; 63: 35-49
        • Feldmeyer D.
        • Cull-Candy S.
        Functional consequences of changes in NMDA receptor subunit expression during development.
        J. Neurocytol. 1996; 25: 857-867
        • Fontes M.A.
        • Tagawa T.
        • Polson J.W.
        • Cavanagh S.J.
        • Dampney R.A.
        Descending pathways mediating cardiovascular response from dorsomedial hypothalamic nucleus.
        Am. J. Physiol. Heart Circ. Physiol. 2001; 280: H2891-H2901
        • Fulwiler C.E.
        • Saper C.B.
        Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat.
        Brain Res. 1984; 319: 229-259
        • Guthmann A.
        • Herbert H.
        Distribution of metabotropic glutamate receptors in the parabrachial and Kölliker-Fuse nuclei of the rat.
        Neuroscience. 1999; 89: 873-881
        • Guthmann A.
        • Herbert H.
        Expression of N-methyl-d-aspartate receptor subunits in the rat parabrachial and Kölliker-Fuse nuclei and in selected pontomedullary brainstem nuclei.
        J. Comp. Neurol. 1999; 415: 501-517
        • Hayward L.F.
        Midbrain modulation of the cardiac baroreflex involves excitation of lateral parabrachial neurons in the rat.
        Brain Res. 2007; 1145: 117-127
        • Hayward L.F.
        • Castellanos M.
        • Davenport P.W.
        Parabrachial neurons mediate dorsal periaqueductal gray evoked respiratory responses in the rat.
        J. Appl. Physiol. 2004; 96: 1146-1154
        • Herbert H.
        • Moga M.M.
        • Saper C.B.
        Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat.
        J. Comp. Neurol. 1990; 293: 540-580
        • Hilton S.M.
        • Redfern W.S.
        A search for brain stem cell groups integrating the defence reaction in the rat.
        J. Physiol. 1986; 378: 213-228
        • Jhamandas J.H.
        • Harris K.H.
        Excitatory amino acids may mediate nucleus tractus solitarius input to rat parabrachial neurons.
        Am. J. Physiol. 1992; 263: R324-R330
        • Kemp J.A.
        • Leeson P.D.
        The glycine site of the NMDA receptor—five years on.
        Trends Pharmacol. Sci. 1993; 14: 20-25
        • Lara J.P.
        • Parkes M.J.
        • Silva-Carvhalo L.
        • Izzo P.
        • Dawid-Milner M.S.
        • Spyer K.M.
        Cardiovascular and respiratory effects of stimulation of cell bodies of the parabrachial nuclei in the anaesthetized rat.
        J. Physiol. 1994; 477: 321-329
        • Lara J.P.
        • Dawid-Milner M.S.
        • Lopez M.V.
        • Montes C.
        • Spyer K.M.
        • Gonzalez-Baron S.
        Laryngeal effects of stimulation of rostral and ventral pons in the anaesthetized rat.
        Brain Res. 2002; 934: 97-106
        • Lovick T.A.
        Inhibitory modulation of the cardiovascular defence response by the ventrolateral periaqueductal grey matter in rats.
        Exp. Brain Res. 1992; 89: 133-139
        • Miura M.
        • Takayama K.
        Circulatory and respiratory responses to glutamate stimulation of the lateral parabrachial nucleus of the cat.
        J. Auton. Nerv. Syst. 1991; 32: 121-133
        • Moga M.M.
        • Herbert H.
        • Hurley K.M.
        • Yasui Y.
        • Gray T.S.
        • Saper C.B.
        Organization of cortical, basal forebrain, and hypothalamic afferents to the parabrachial nucleus in the rat.
        J. Comp. Neurol. 1990; 295: 624-661
        • Moga M.M.
        • Saper C.B.
        • Gray T.S.
        Neuropeptide organization of the hypothalamic projection to the parabrachial nucleus in the rat.
        J. Comp. Neurol. 1990; 295: 662-682
        • Norgren R.
        • Pfaffmann C.
        The pontine taste area in the rat.
        Brain Res. 1975; 91: 99-117
        • Nosaka S.
        • Murata K.
        • Inui K.
        • Murase S.
        Arterial baroreflex inhibition by midbrain periaqueductal grey in anaesthetized rats.
        Pflugers Arch. 1993; 424: 266-275
        • Paxinos G.
        • Watson C.
        The rat brain in stereotaxic coordinates.
        • Saleh T.M.
        • Bauce L.G.
        • Pittman Q.J.
        Glutamate release in parabrachial nucleus and baroreflex alterations after vagal afferent activation.
        Am. J. Physiol. 1997; 272: R1631-R1640
        • Silva-Carvalho L.
        • Dawid-Milner M.S.
        • Goldsmith G.E.
        • Spyer K.M.
        Hypothalamic-evoked effects in cat nucleus tractus solitarius facilitating chemoreceptor reflexes.
        Exp. Physiol. 1993; 78: 425-428
        • Spyer K.M.
        The central nervous organisation of reflex circulatory control.
        in: Loewy A.D. Spyer K.M. In Central Regulation of Autonomic Functions. Oxford University Press, New York1990: 168-188
        • van den Pol A.N.
        • Wuarin J.P.
        • Dudek F.E.
        Glutamate, the dominant excitatory transmitter in neuroendocrine regulation.
        Science. 1990; 250: 1276-1278
        • van der Plas J.
        • Maes F.W.
        • Bohus B.
        Electrophysiological analysis of midbrain periaqueductal gray influence on cardiovascular neurons in the ventrolateral medulla oblongata.
        Brain Res. Bull. 1995; 38: 447-456
        • Verberne A.J.
        • Guyenet P.G.
        Midbrain central gray: influence on medullary sympathoexcitatory neurons and the baroreflex in rats.
        Am. J. Physiol. 1992; 263: R24-R33
        • Yardley C.P.
        • Hilton S.M.
        The hypothalamic and brainstem areas from which the cardiovascular and behavioural components of the defence reaction are elicited in the rat.
        J. Auton. Nerv. Syst. 1986; 15: 227-244
        • Zidichouski J.A.
        • Jhamandas J.H.
        Electrophysiological characterization of excitatory amino acid responses in rat lateral parabrachial neurons in vitro.
        Brain Res. 1993; 611: 313-321
        • Zidichouski J.A.
        • Easaw J.C.
        • Jhamandas J.H.
        Glutamate receptor subtypes mediate excitatory synaptic responses of rat lateral parabrachial neurons.
        Am. J. Physiol. 1996; 270: H1557-H1567