Role of serotonergic input to the ventrolateral medulla in expression of the 10-Hz sympathetic nerve rhythm

We studied the changes in inferior cardiac sympathetic nerve discharge (SND) produced by unilateral microinjections of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists into the ventrolateral medulla (VLM) of urethane-anesthetized, baroreceptor-denervated cats. Microinjection of the 5-HT2 receptor antagonist LY-53857 (10 mM) into either the rostral or caudal VLM significantly reduced (P < or = 0.05) the 10-Hz rhythmic component of basal SND without affecting its lower-frequency, aperiodic component. The selective depression of 10-Hz power was accompanied by a statistically significant decrease in mean arterial pressure (MAP). Microinjection of LY-53857 into the VLM also attenuated the increase in 10-Hz power that followed tetanic stimulation of depressor sites in the caudal medullary raphé nuclei. Microinjection of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-amino-propane (DOI; 10 microM) into the VLM selectively enhanced 10-Hz SND, and intravenous DOI (1 mg/kg) partially reversed the reduction in 10-Hz SND produced by 5-HT2 receptor blockade in the VLM. Microinjection of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT; 10 mM), into either the rostral or caudal VLM also selectively attenuated 10-Hz SND and significantly reduced MAP. The reduction in 10-Hz SND produced by 8-OHDPAT was partially reversed by intravenous WAY-100635 (1 mg/kg), which selectively blocks 5-HT1A receptors. These results support the view that serotonergic inputs to the VLM play an important role in expression of the 10-Hz rhythm in SND.     

Does angiotensin II have a significant tonic action on cardiovascular neurons in the rostral and caudal VLM?

The peptidic ANG II receptor antagonists [Sar(1),Ile(8)]ANG II (sarile) or [Sar(1),Thr(8)]ANG II (sarthran) are known to decrease arterial pressure and sympathetic activity when injected into the rostral part of the ventrolateral medulla (VLM). In anesthetized rabbits and rats, the profound depressor and sympathoinhibitory response after bilateral microinjections of sarile or sarthran into the rostral VLM was unchanged after prior selective blockade of angiotensin type 1 (AT(1)) and ANG-(1---7) receptors, although this abolished the effects of exogenous ANG II. Unlike the neuroinhibitory compounds muscimol or lignocaine, microinjections of sarile in the rostral VLM did not affect respiratory activity. Sarile or sarthran in the caudal VLM resulted in a large pressor and sympathoexcitatory response, which was also unaffected by prior blockade of AT(1) and ANG-(1---7) receptors. The results indicate that the peptidic ANG receptor antagonists profoundly inhibit the tonic activity of cardiovascular but not respiratory neurons in the VLM and that these effects are independent of ANG II or ANG-(1---7) receptors.     

Is visceral sympathoexcitation to heat stress dependent on activation of ionotropic excitatory amino acid receptors in the rostral ventrolateral medulla?

Acute heat stress activates visceral sympathetic nerve discharge (SND) in young rats, and the functional integrity of the rostral ventrolateral medulla (RVLM) is required for sustaining visceral sympathoexcitation during peak increases in internal body temperature (T(c)). However, RVLM mechanisms mediating SND activation to hyperthermia remain unknown. In the present study, we investigated the role of RVLM ionotropic excitatory amino acid receptors in mediating visceral SND activation to heat stress in anesthetized, young rats. The effects of bilateral RVLM kynurenic acid (Kyn; 2.7 and 5.4 nmol), saline, or muscimol (400-800 pmol) microinjections on renal SND and splenic SND responses to heat stress were determined at peak hyperthermia (T(c) 41.5°C), during progressive hyperthermia (T(c) 40°C), and at the initiation of heating (T(c) increased from 38 to 38.5°C). RVLM Kyn microinjections did not reduce renal and splenic SND recorded during progressive or peak hyperthermia and did not attenuate SND activation at the initiation of heating. In fact, renal and splenic SND tended to be or were significantly increased following RVLM Kyn microinjections at the initiation of heating and during hyperthermia (40 and 41.5°C). RVLM muscimol microinjections at 39, 40, and 41.5°C resulted in immediate reductions in SND. These data indicate that RVLM ionotropic glutamate receptors are required for mediating visceral sympathoexcitation to acute heating and suggest that acute heating activates an RVLM ionotropic excitatory amino acid receptor dependent inhibitory input, which reduces the level of visceral SND to heating.     

Vav3 is involved in GABAergic axon guidance events important for the proper function of brainstem neurons controlling cardiovascular, respiratory, and renal parameters

Vav3 is a phosphorylation-dependent activator of Rho/Rac GTPases that has been implicated in hematopoietic, bone, cerebellar, and cardiovascular roles. Consistent with the latter function, Vav3-deficient mice develop hypertension, tachycardia, and renocardiovascular dysfunctions. The cause of those defects remains unknown as yet. Here, we show that Vav3 is expressed in GABAegic neurons of the ventrolateral medulla (VLM), a brainstem area that modulates respiratory rates and, via sympathetic efferents, a large number of physiological circuits controlling blood pressure. On Vav3 loss, GABAergic cells of the caudal VLM cannot innervate properly their postsynaptic targets in the rostral VLM, leading to reduced GABAergic transmission between these two areas. This results in an abnormal regulation of catecholamine blood levels and in improper control of blood pressure and respiration rates to GABAergic signals. By contrast, the reaction of the rostral VLM to excitatory signals is not impaired. Consistent with those observations, we also demonstrate that Vav3 plays important roles in axon branching and growth cone morphology in primary GABAergic cells. Our study discloses an essential and nonredundant role for this Vav family member in axon guidance events in brainstem neurons that control blood pressure and respiratory rates.     

Fast-acting excitatory amino acids are involved in the enhancement of the aversiveness of the electrical stimulation of the inferior colliculus by systemic injections of muscimol

Gradual increases in the electrical stimulation of the inferior colliculus produces progressive aversive responses from vigilance, through freezing, until escape. These responses are probably mediated by excitatory amino acids (EAA) mechanisms as microinjection of glutamate into the inferior colliculus can trigger freezing responses while microinjections of NMDA cause a mixture of immobility and escape responses. Moreover, it has been shown that the neural substrates for defensive behavior in this structure are regulated by GABA-benzodiazepine mechanisms. Indeed, these responses are depressed by muscimol and midazolam locally injected into the inferior colliculus. In this work we were interested in knowing how GABAergic mechanisms interact with the EAA-mediated neural substrates of aversion generated at the inferior colliculus level. We found that while intraperitoneal injections of muscimol caused the expected antiaversive effects, unexpectedly systemic injections of muscimol enhanced the aversive reactions induced by electrical stimulation of the inferior colliculus of rats. Local injections into the central nucleus of the inferior colliculus of GDEE-an AMPA/kainate receptor antagonist-inhibited whereas AP7-a NMDA receptor antagonist-did not influence these responses. It is suggested that systemic injections of muscimol inhibit GABAergic inputs to the inferior colliculus. The removal of these inhibitory influences reduce the well-known tonic inhibitory control exerted by GABAergic mechanisms on the neural substrates of aversion of the inferior colliculus. Activation of these neural substrates by fast-acting AMPA/kainate receptors trigger the initial steps of the defense reaction in the central nucleus of the inferior colliculus.     

Breathing of awake goats during prolonged dysfunction of caudal M ventrolateral medullary neurons

Forster, H. V., L. G. Pan, T. F. Lowry, T. Feroah, W. M. Gershan, A. A. Whaley, M. M. Forster, and B. Sprtel. Breathing ofawake goats during prolonged dysfunction of caudal M ventrolateral medullary neurons. J. Appl. Physiol.84(1): 129-140, 1998.Cooling the caudal M ventrolateralmedullary (VLM) surface for 30 s results in a sustained apnea inanesthetized goats but only a 30% decrease in breathing in awakegoats. The purpose of the present study was to determine, in the awakestate, the effect of prolonged (minutes, hours) caudal M neuronaldysfunction on eupneic breathing andCO₂ sensitivity. Dysfunction wascreated by ejecting excitatory amino acid receptor antagonists or aneurotoxin on the VLM surface through guide tubes chronically implantedbilaterally on a 10- to 12-mm²portion of the caudal M VLM surface of 12 goats. Unilateral and bilateral ejections (1 µl) of selective antagonists forN-methyl-D-aspartic acid ornon-N-methyl-D-asparticacid receptors had no significant effect on eupneic breathing orCO₂ sensitivity. Unilateralejection of a nonselective excitatory amino acid receptor antagonistgenerally had no effect on eupneic breathing orCO₂ sensitivity. However, bilateral ejection of this antagonist resulted in a significant 2-Torrhypoventilation during eupnea and a significant reduction inCO₂ sensitivity to 60 ± 9% ofcontrol. Unilateral ejection of the neurotoxin kainic acid initiallystimulated breathing; however, breathing then returned to near controlwith no incidence of apnea. After the kainic acid ejection,CO₂ sensitivity was reducedsignificantly to 60 ± 7% of control. We conclude that in the awakestate a prolonged dysfunction of caudal M VLM neurons results incompensation by other mechanisms (e.g., carotid chemoreceptors, wakefulness) to maintain near-normal eupneic breathing, butcompensation is more limited for maintainingCO₂ sensitivity.

     

Medullary lateral tegmental field: an important source of basal sympathetic nerve discharge in the cat

We used blockade of excitatory amino acid (EAA) neurotransmission in the medullary lateral tegmental field (LTF) and rostral ventrolateral medulla (RVLM) to assess the roles of these regions in the control of inferior cardiac sympathetic nerve discharge (SND) and mean arterial pressure (MAP) in urethan-anesthetized, baroreceptor-denervated cats. Bilateral microinjection of a non-N-methyl-D-aspartate (NMDA)-receptor antagonist [1,2,3, 4-tetrahydro-6-nitro-2,3-dioxobenzo-[f]quinoxaline-7-sulfonamide (NBQX)] into the LTF significantly decreased SND to 46 +/- 4% of control (as demonstrated with power-density spectral analysis) and MAP by 16 +/- 6 mmHg. In contrast, bilateral microinjection of an NMDA-receptor antagonist [D(-)-2-amino-5-phosphonopentanoic acid (D-AP5)] into the LTF did not decrease SND or MAP. These results demonstrate that the LTF is an important synaptic relay in the pathway responsible for basal SND in the cat. Bilateral microinjection of NBQX or D-AP5 into the RVLM significantly decreased power in SND to 48 +/- 5 or 61 +/- 5% of control, respectively, and reduced MAP by 15 +/- 2 or 8 +/- 4 mmHg, respectively. These data indicate that EAA-mediated synaptic drive to RVLM-spinal sympathoexcitatory neurons accounts for a significant component of their basal activity.     

Effect of furosemide on changes in the rat behavior produced by intrastriatal GABA or picrotoxin microinjections

It was shown in chronic rat experiments that multiple microinjections of furosemide into the rostral region of the neostriatum facilitated avoidance conditioning in a shuttle box and prevented from GABA-induced deviant freezing, but did not abolish the choreic hyperkinesis produced by picrotoxine (GABA-A receptors antagonist) intrastriatal microinjections. Simultaneous microinjections of furosemide and picrotoxine into the neostriatum increased differences in parameters of picrotoxine-induced hyperkinesis between rat groups capable and incapable (extinct reflex) for conditioned avoidance. These findings point to a certain correlation between the intensity of hyperkinesis, capability for acquisition and realization of avoidance conditioning, and activity of neostriatal neurotransmitter systems involved in neuronal homeostasis. The findings suggest an involvement of neostriatal GABAergic system in conditioning and organization of free locomotor behavioral acts.     

Sympathetic nerve and cardiovascular responses to chemical activation of the midbrain defense region

The changes in mean arterial pressure (MAP), renal (RBF) and femoral (FBF) blood flows, and inferior cardiac (CN) and vertebral nerve (VN) sympathetic nerve discharges (SND) produced by chemical activation (D,L-homocysteic acid) of the midbrain periaqueductal gray (PAG) were compared in baroreceptor-denervated and -innervated cats anesthetized with urethan. Defenselike cardiovascular responses in both states were similar in magnitude and consisted of increased MAP and FBF and decreased RBF; however, the nerve responses differed. In baroreceptor-denervated cats, PAG activation increased CN 10-Hz activity, decreased VN 10-Hz activity, and lengthened the CN-VN phase angle. In baroreceptor-innervated cats in which the rhythm in SND was cardiac related, PAG activation increased CN activity, but VN activity and the CN-VN phase angle were unchanged. These results demonstrate that chemical activation of PAG neurons induces differential patterns of sympathetic outflow generally consistent with accompanying defenselike cardiovascular responses. However, the mechanisms responsible for the changes in 10-Hz and cardiac-related SND appear to be different.     

Glutamate receptors in RVLM modulate sympathetic baroreflex in conscious rabbits

In this study, we examined the effect of excitatory amino acid (EAA) receptor blockade in the rostral ventrolateral medulla (RVLM) on the renal sympathetic baroreflex in conscious rabbits. Rabbits were implanted with guide cannulas for bilateral microinjections into the RVLM (+2 to +3 mm from the obex, n = 8) or into the intermediate ventrolateral medulla (IVLM; 0 to +1 mm from the obex, n = 5) and with an electrode for measuring renal sympathetic nerve activity (RSNA). After 7 days of recovery, microinjection of the EAA receptor antagonist kynurenate (10 nmol) into the RVLM did not affect resting RSNA or arterial pressure. Kynurenate decreased the gain of the RSNA baroreflex by 53% but did not change the reflex range. By contrast, injection of kynurenate into the IVLM increased resting arterial pressure and RSNA by 27 mmHg and 88%, respectively, but did not alter the RSNA baroreflex gain or range. Pentobarbital sodium anesthesia attenuated the gain and range of the RSNA baroreflex by 78 and 40%, respectively. Under these conditions, microinjection of kynurenate into the RVLM did not cause any further change in the gain of this reflex. These results suggest that endogenous EAA neurotransmitters in the RVLM are important in modulating the sympathetic baroreflex in conscious rabbits. Anesthesia can mask the functional significance of EAAs in the RVLM in modulating the baroreflexes, which may explain why previous studies in anesthetized animals found no effect of blocking EAA receptors in the RVLM on sympathetic baroreflexes.     

Retrofacial lesions: effects on CO2-sensitive phrenic and sympathetic nerve activity.

We made unilateral chemical (10- or 50-nl microinjections; 4.7 mM kainic acid) or electrolytic (5-15 mA; 15 s) lesions in a region of the rostral ventrolateral medulla (VLM) caudal to the retrotrapezoid nucleus in 10 decerebrate, paralyzed, vagotomized, and servo-ventilated cats. The lesions were 3.0-4.2 mm lateral to the midline, within 2 mm caudal to the facial nucleus, and within 2.5 mm of the VLM surface. Four control injections (mock cerebrospinal fluid and fluorescent beads alone) produced small and inconsistent effects over 3-5 h. The predominant effect of the lesions was a significant decrease in baseline integrated phrenic nerve amplitude (PNA) (apnea in 2 cases), total respiratory cycle duration, and the response to increased CO2 (slope < 15% of control in 3 cases). The respiratory-related peak amplitude of the integrated sympathetic signal, blood pressure, and the sympathetic nerve activity response to CO2 were also decreased after the majority of lesions. Not all lesions produced all effects, and some lesions resulted in increased PNA and respiratory cycle duration. The lesioned region appears functionally to represent a caudal extension of the retrotrapezoid nucleus containing neurons necessary for normal baseline PNA and CO2 sensitivity. In addition, it contains neurons involved in the determination of resting respiratory frequency and normal sympathetic activity and blood pressure. The pattern of mixed responses among animals suggests that a heterogeneity of function is present within a relatively small VLM region.     

NMDA as well as non-NMDA receptor antagonists can prevent the phase-shifting effects of light on the circadian system of the golden hamster.

The present experiments were designed to evaluate whether the intraventricular administration of excitatory amino acid (EAA) receptor antagonists would prevent light-induced phase shifts of the circadian rhythm of wheel-running activity in the hamster. Administration of the non-N-methyl-D-aspartate (non-NMDA) antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) blocked light-induced phase advances and delays. Similarly, administration of the competitive NMDA receptor antagonist, 3(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP), prevented light-induced phase advances and delays. Neither drug by itself caused any consistent effect on the phase of the rhythm. These data provide further evidence that EAA receptors mediate the effects of light on the circadian system, and suggest that both NMDA and non-NMDA receptor types may be involved.     

Sympathoinhibitory pathway from caudal midline medulla to RVLM is independent of baroreceptor reflex pathway

Glutamate stimulation of the caudal midline medulla (CMM) causes profound sympathoinhibition due to GABAergic inhibition of presympathetic neurons in the rostral ventrolateral medulla (RVLM). We investigated whether the sympathoinhibitory pathway from CMM to RVLM, like the central baroreceptor reflex pathway, includes a glutamatergic synapse in the caudal ventrolateral medulla (CVLM). In pentobarbital sodium-anesthetized rats, the RVLM on one side was inhibited by a muscimol microinjection. Then the response evoked by glutamate microinjections into the CMM or by baroreceptor stimulation was determined before and after 1) microinjection of the GABA receptor antagonist bicuculline into the RVLM on the other side or 2) microinjections of the glutamate receptor antagonist kynurenate bilaterally into the CVLM. Bicuculline in the RVLM greatly reduced both CMM- and baroreceptor-evoked sympathoinhibition. Compared with the effect of vehicle solution, kynurenate in the CVLM greatly reduced baroreceptor-evoked sympathoinhibition, whereas its effect on CMM-evoked sympathoinhibition was not different from that of the vehicle solution. These findings indicate that the output pathway from CMM sympathoinhibitory neurons, unlike the baroreceptor and other reflex sympathoinhibitory pathways, does not include a glutamatergic synapse in the CVLM.     

Neurokinin-1 receptor-expressing cells regulate depressor region of rat ventrolateral medulla

Intraparenchymal injection of the saporin conjugate [Sar9, Met (O2)11] substance P-saporin (SSP-SAP) into the ventrolateral medulla (VLM) destroys neurokinin-1 receptor-immunoreactivity (NK1R-ir) neurons selectively. This treatment attenuates the hypotension caused by injection of DL-homocysteic acid (DLH) into the caudal VLM (CVLM). Here we ask whether SSP-SAP creates this deficit by destroying the CVLM GABAergic interneurons that mediate the sympathetic baroreflex (baroactivated depressor neurons) or by destroying other VLM neurons. Two weeks after unilateral SSP-SAP treatment (97% loss of VLM NK1R-ir neurons) DLH-induced hypotension and sympathetic tone inhibition were blunted on the lesioned side. Unlesioned or unilaterally lesioned rats received phenylephrine (PE) while awake to identify CVLM baroactivated depressor neurons by the presence of Fos-ir nuclei. Although CVLM Fos-ir cells were not NK1R-ir, their number was reduced approximately 60-70% on the SSP-SAP-injected side. SSP-SAP spared VLM neurons devoid of NK1R-ir, such as the catecholaminergic cells and the precerebellar glutamatergic neurons. In the pre-B?tzinger region of the VLM the toxin killed glutamatergic neurons while sparing glycinergic and GABAergic inhibitory neurons. In the CVLM region approximately 26% of the inhibitory cells were destroyed. In conclusion, the baroactivated depressor neurons of the CVLM do not appear to express NK1Rs but their activity is probably modulated by a population of excitatory NK1R-ir cells located in the VLM. The results also suggest that a region located below the CVLM (subCVLM) may contain an unrelated population of GABAergic depressor neurons that are NK1R-ir but are either not barosensitive or do not express Fos during baroreceptor stimulation.     

A role for GABAergic inhibition in electrosensory processing and common mode rejection in the dorsal nucleus of the little skate, Raja erinacea

The electrosensory primary afferents in elasmobranchs are responsive to electric potentials created by the animal's own ventilation, while the second-order neurons (AENs) which receive this afferent input in the medulla suppress responses to ventilatory potentials but retain their extreme sensitivity to electric signals in the environment. Ventilatory potentials are common mode signals in elasmobranchs and a common mode rejection mechanism is one way the AENs suppress ventilatory noise. By pressure injecting the GABA-A receptor antagonist SR95531 while extracellularly recording from AENs, we tested the hypothesis that the subtractive circuitry that selectively reduces common mode signals in AENs utilizes GABA, and that a GAB-Aergic component of the dorsal nucleus commissural pathway mediates crossed inhibition of AENs. Local application of SR95531 increased the spontaneous activity and the responsiveness of AENs to electrosensory stimuli. AEN responses to a common mode stimulus were selectively increased compared to responses to a localized stimulus due to SR95531 application. Contralateral inhibition of AENs was blocked by SR95531, indicating that GABAergic commissural cells may inhibit AENs when the contralateral side of the body is stimulated, as with common mode stimulation. We conclude that GABAergic inhibition contributes significantly to the shaping of AEN responses including common mode rejection.Abbreviations AENs ascending efferent neurons - GABA gamma-aminobutyric acid     

Role of paraventricular nucleus in regulation of sympathetic nerve frequency components

Autospectral and coherence analyses were used to determine the role of and interactions between paraventricular nucleus (PVN) nitric oxide, gamma-aminobutyric acid (GABA), and the N-methyl-D-aspartic acid (NMDA)-glutamate receptor in regulation of sympathetic nerve discharge (SND) frequency components in anesthetized rats. Four observations were made. First, PVN microinjection of bicuculline (BIC) (GABA(A) receptor antagonist), but not single PVN injections of NMDA (excitatory amino acid) or N(G)-monomethyl-L-arginine (L-NMMA; a nitric oxide synthase inhibitor), altered SND frequency components. Second, combined PVN microinjections of L-NMMA and NMDA changed the SND bursting pattern; however, the observed pattern change was different from that produced by PVN BIC and not observed after sinoaortic denervation. Third, PVN microinjection of kynurenic acid prevented and reversed BIC-induced changes in the SND bursting pattern. Finally, vascular resistance (renal and splenic) was significantly increased after PVN BIC microinjection despite the lack of change in the level of renal and splenic SND. These data demonstrate that the PVN contains the neural substrate for altering SND frequency components and suggest complex interactions between specific PVN neurotransmitters and between PVN neurotransmitters and the arterial baroreceptor reflex in SND regulation.     

GABAergic mediation of stress-induced secretion of corticosterone and oxytocin, but not prolactin, by the hypothalamic paraventricular nucleus

The hypothalamus-pituitary-adrenal axis (HPA) participates in mediating the response to stressful stimuli. Within the HPA, neurons in the medial parvocellular region of paraventricular nucleus (PVN) of the hypothalamus integrate excitatory and inhibitory signals triggering secretion of corticotropin-releasing hormone (CRH), the main secretagogue of adrenocorticotropic hormone (ACTH). Stressful situations alter CRH secretion as well as other hormones, including prolactin and oxytocin. Most inputs to the PVN are of local origin, half of which are GABAergic neurons, and both GABA-A and GABA-B receptors are present in the PVN. The objective of the present study was to investigate the role of GABA-A and GABA-B receptors in the PVN's control of stress-induced corticosterone, oxytocin and prolactin secretion. Rats were microinjected with saline or different doses (0.5, 5 and 50 pmol) of GABA-A (bicuculine) or GABA-B (phaclofen) antagonists in the PVN. Ten minutes later, they were subjected to a stressor (ether inhalation) and blood samples were collected 30 min before and 10, 30, 60, 90 and 120 min after the stressful stimulus to measure hormone levels by radioimmunoassay. Our results indicate that GABA acts in the PVN to inhibit stress-induced corticosterone secretion via both its receptor subtypes, especially GABA-B. In contrast, GABA in the PVN stimulates oxytocin secretion through GABA-B receptors and does not alter prolactin secretion.     

Central nervous mechanisms in the generation of the pattern of breathing

The role of the B?tzinger complex (B?tC) and the pre-B?tzinger complex (pre-B?tC) in the genesis of the breathing pattern was investigated in anesthetized, vagotomized, paralysed and artificially ventilated rabbits making use of bilateral microinjections of kainic acid (KA) and excitatory amino acid (EAA) receptor antagonists. KA microinjections into either the B?tC or the pre-B?tC transiently eliminated respiratory rhythmicity in the presence of tonic phrenic activity (tonic apnea). Rhythmic activity resumed as low-amplitude, high-frequency irregular oscillations, superimposed on tonic inspiratory activity and displayed a progressive, although incomplete recovery. Microinjections of kynurenic acid (KYN) and D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) into the B?tC caused a pattern of breathing characterized by low-amplitude, high-frequency irregular oscillations and subsequently tonic apnea. Responses to KYN and D-AP5 in the pre-B?tC were similar, although less pronounced than those elicited by these drugs in the B?tC and never characterized by tonic apnea. Microinjections of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) into the B?tC and the pre-B?tC induced much less intense responses mainly consisting of increases in respiratory frequency. The results show that the investigated medullary regions play a prominent role in the genesis of the normal pattern of breathing through the endogenous activation of EAA receptors.     

Differential pattern of spinal sympathetic outflow in response to stimulation of the caudal medullary raphe

In urethan-anesthetized cats, frequency domain analysis was used to explore the mechanisms of differential responses of inferior cardiac (CN), vertebral (VN), and renal (RN) sympathetic nerves to electrical stimulation of a discrete region of the medullary raphe (0-2 mm caudal to the obex). Raphe stimulation in baroreceptor-denervated cats at frequencies (7-12 Hz) that entrained the 10-Hz rhythm in nerve activity decreased CN and RN activities but increased VN activity. The reductions in CN and RN discharges were associated with decreased low-frequency (相似文献   

Excitatory Amino Acid Receptors in the Ventral Tegmental Area Regulate Dopamine Release in the Ventral Striatum

Abstract: The role of excitatory amino acid (EAA) receptors located in the ventral tegmental area (VTA) in tonic and phasic regulation of dopamine release in the ventral striatum was investigated. Microdialysis in conscious rats was used to assess dopamine release primarily from the nucleus accumbens shell region of the ventral striatum while applying EAA antagonists or agonists to the VTA. Infusion of the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (25 and 100 µ M ) into the VTA did not affect dopamine release in the ventral striatum. In contrast, intra-VTA infusion of the NMDA receptor antagonist 2-amino-5-phosphopentanoic acid (100 and 500 µ M ) dose-dependently decreased the striatal release of dopamine. Intra-VTA application of the ionotropic EAA receptor agonists NMDA and AMPA dose-dependently (10 and 100 µ M ) increased dopamine efflux in the ventral striatum. However, infusion of 50 or 500 µ M trans -(±)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD), a metabotropic EAA receptor agonist, did not significantly affect these levels. These data suggest that NMDA receptors in the VTA exert a tonic excitatory influence on dopamine release in the ventral striatum. Furthermore, dopamine neurotransmission in this region may be enhanced by activation of NMDA and AMPA receptors, but not ACPD-sensitive metabotropic receptors, located in the VTA. These data further suggest that EAA regulation of dopamine release primarily occurs in the VTA as opposed to presynaptically at the terminal level.