The dorsomedial hypothalamus and the central pathways involved in the cardiovascular response to emotional stress.

Psychological stress elicits increases in sympathetic activity accompanied by a marked cardiovascular response. Revealing the relevant central mechanisms involved in this phenomenon could contribute significantly to our understanding of the pathogenesis of stress-related cardiovascular diseases, and the key to this understanding is the identification of the nuclei, pathways and neurotransmitters involved in the organization of the cardiovascular response to stress. The present review will focus specifically on the dorsomedial hypothalamus, a brain region now known to play a primary role in the synaptic integration underlying the cardiovascular response to emotional stress.

Dorsomedial hypothalamic sites where disinhibition evokes tachycardia correlate with location of raphe-projecting neurons.

Disinhibition of neurons in the region of the dorsomedial hypothalamus (DMH) elicits sympathetically mediated tachycardia in rats through activation of the brain stem raphe pallidus (RP), and this same mechanism appears to be largely responsible for the increases in heart rate (HR) seen in air jet stress in this species. Neurons projecting to the RP from the DMH are said to be concentrated in a specific subregion, the dorsal hypothalamic area (DA). Here, we examined the hypothesis that the location of RP-projecting neurons in the DA correspond to the sites at which microinjection of bicuculline methiodide (BMI) evokes the greatest increases in HR. To determine the distribution of RP-projecting neurons in the DA, cholera toxin B was injected in the RP in four rats. A consistent pattern of retrograde labeling was seen in every rat. In the hypothalamus, RP-projecting neurons were most heavily concentrated midway between the mammillothalamic tract and the dorsal tip of the third ventricle dorsal to the dorsomedial hypothalamic nucleus approximately 3.30 mm caudal to bregma. In a second series of experiments, the HR response to microinjections of BMI (2 pmol/5 nl; n = 76) was mapped at sites in the DA and surrounding areas in 22 urethane-anesthetized rats. All injection sites were located from 2.56 to 4.16 mm posterior to bregma, and the microinjections that evoked the largest increase in HR (i.e., >100 beats/min in some instances) were located in a region where RP-projecting neurons were most densely concentrated. Thus RP-projecting neurons in the DA may mediate DMH-induced tachycardia and thus play a role in stress-induced cardiac stimulation.

Tachycardia evoked by disinhibition of the dorsomedial hypothalamus in rats is mediated through medullary raphe.

Activation of neurons in the region of the dorsomedial hypothalamus (DMH) appears to generate the sympathetically mediated tachycardia seen in experimental stress in rats. The purpose of this study was to assess the role of neurons in the area of the medullary raphe pallidus (RP) in the tachycardia caused by stimulation of the DMH. The cardiovascular response to microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) 10 pmol (100 nl)(-1) into the DMH was assessed before, and after, injection of the GABA(A) receptor agonist muscimol 80 pmol (100 nl)(-1) or saline vehicle 100 nl into the RP in urethane-anaesthetized rats. Tachycardia evoked by microinjection of BMI into the DMH was mimicked by microinjection of BMI 30 pmol (75 nl)(-1) into the RP. This DMH-induced tachycardia was markedly suppressed after injection of muscimol into the RP, but the response was unaffected by injection of saline into the same region. Thus, DMH-induced tachycardia is mediated through activation of neurons in the area of the RP, suggesting that these neurons may play a previously unrecognized role in stress-induced cardiac stimulation.

Injection of muscimol in dorsomedial hypothalamus and stress-induced Fos expression in paraventricular nucleus.

Prior microinjection of the GABA(A)-receptor agonist muscimol into the dorsomedial hypothalamus (DMH) in conscious rats attenuates the increases in heart rate, blood pressure, and circulating adrenocorticotrophic hormone seen in air stress. Here, we examined the effect of similar treatment on air stress- or hemorrhage-induced Fos expression in the paraventricular nucleus (PVN). Muscimol (80 pmol/100 nl per side) or saline (100 nl per side) was microinjected bilaterally into the DMH in conscious rats before either air stress, an emotional or neurogenic stressor, or graded hemorrhage, a physiological stressor. Each stressor evoked a characteristic pattern of Fos expression in the parvocellular and magnocellular PVN after saline. Injection of muscimol into the DMH suppressed Fos expression in the PVN associated with air stress but not with hemorrhage. Injection of muscimol at sites anterior to the DMH and closer to the PVN had no effect on Fos expression in the PVN after air stress. Thus activation of neurons in the DMH is necessary for excitation of neurons in the PVN during air stress but not during hemorrhage.

Chemical stimulation of the dorsomedial hypothalamus elevates plasma ACTH in conscious rats.

The hallmark neuroendocrine response to stress is increased plasma ACTH. Inhibition of neurons in the region of the dorsomedial hypothalamus (DMH) attenuates experimental air stress-induced elevation of heart rate (HR), mean arterial pressure (MAP), and plasma ACTH. We hypothesized that, under basal conditions, stimulation of the DMH would mimic the neuroendocrine and cardiovascular response to air stress. We examined the effects of unilateral microinjection (100-nl vol) of bicuculline methiodide (BMI, 10 pmol), kainate (KA, 1 or 3 pmol), and N-methyl-D-aspartate (5 pmol) into the DMH or the paraventicular nucleus (PVN) on HR, MAP, locomotor activity, and plasma ACTH in conscious rats. Chemical stimulation of the DMH with KA or BMI produced increased locomotor activity and effects on HR, MAP, and plasma ACTH that together mimicked the pattern seen in experimental stress. Similar treatment in the PVN produced only small increases in MAP. Thus activation of neurons in the region of the DMH results in increased secretion of ACTH along with other changes typically seen in experimental stress.

GABAB receptors in the dorsomedial hypothalamus and heart rate in anesthetized rats.

Previous studies have shown that: (1) activation of neurons in the dorsomedial hypothalamus (DMH) of the rat by blockade of local GABAA receptors with bicuculline methiodide (BMI) elicits cardiovascular changes resembling those seen in experimental stress, including marked sympathetically-mediated tachycardia, and (2) inhibition of neurons in the same region by local microinjection of the GABAA receptor agonist muscimol can virtually abolish stress-induced tachycardia. This study examined the possibility that GABAB receptors exist in the neural circuitry of the DMH, and that stimulation of these receptors might suppress the cardiovascular response to local disinhibition with BMI. Microinjection of BMI 10 pmol into the DMH in urethane-anesthetized rats resulted in marked tachycardia with little or no effect on arterial pressure. Simultaneous injection of the GABAB receptor agonist baclofen at doses of 2.5, 5.0 and 10 pmol produced dose-related suppression of BMI induced tachycardia. Coinjection of the GABAB receptor antagonist 2-hydroxysaclofen 100 or 200 pmol had no significant effect on the heart rate response to BMI, but reversed the suppression elicited in the presence of baclofen. These findings indicate that (1) functional GABAB receptors exist in the DMH, and (2) stimulation of these receptors inhibits the tachycardia resulting from blockade of local GABAA receptors.

Effect of microinjection of muscimol into the dorsomedial or paraventricular hypothalamic nucleus on air stress-induced neuroendocrine and cardiovascular changes in rats.

The paraventricular nucleus (PVN) contains neurons that release corticotrophin-releasing factor (CRH) and thus provide the stimulus for the release of adrenocorticotrophic hormone (ACTH), the neuroendocrine hallmark of the response to stress. However, inhibition of neuronal activity in the nearby dorsomedial hypothalamic nucleus (DMH) by microinjection of the GABA(A) receptor agonist muscimol suppresses cardiovascular changes seen in air stress in conscious rats, while similar treatment in the PVN has no effect. Because the DMH projects to the PVN and also contains CRH neurons, we decided to investigate the role of neuronal activity in the DMH in the neuroendocrine response to stress. In control rats or after microinjection of saline vehicle into either the PVN or the DMH, air stress resulted in equivalent increases in plasma levels of ACTH, heart rate, and arterial pressure. Bilateral microinjection of muscimol 80 pmol/100 nl/side into either the PVN or the DMH prior to air stress reduced the associated increases in plasma ACTH (-37% and -71%, respectively), while only injection into the DMH attenuated the accompanying tachycardia (-62%) and pressor (-83%) effects. Thus, neurons in the DMH, but not in the PVN, play a role in both the cardiovascular and neuroendocrine response to air stress.

Cardiovascular effects of beta-carbolines in conscious rats.

The beta-carbolines have a high affinity for the benzodiazepine receptor, where they demonstrate actions opposite to those of the benzodiazepines and elicit anxiogenic effects. We tested the acute cardiovascular effects of beta-carbolines in conscious unrestrained rats. Intravenous infusion of ethyl-beta-carboline-3-carboxylate (BCCE) or methyl-beta-carboline-3-carboxylate (BCCM) caused dose-related decreases in heart rate. Pretreatment with RO 15-1788 (10.0 mg/kg, i.v.), a benzodiazepine receptor antagonist, or atropine (1.0 mg/kg, i.v.) prevented the bradycardia elicited by BCCE (3.0 mg/kg, i.v.). In contrast, tetrahydro-beta-carboline (THBC; 3.0 mg/kg, i.v.) increased both heart rate and blood pressure significantly as compared with controls. However, larger doses of THBC failed to elicit further increases in heart rate or blood pressure. These experiments indicate that in conscious unrestrained rats, beta-carbolines given acutely do not routinely elicit the cardiovascular changes normally associated with stress or anxiety. We next extended our observations to rats given the beta-carboline noreleagnine, 2 mg/kg, or vehicle twice daily intraperitoneally for 4 weeks. The rats were fed either a high salt (8%) or a low salt (0.9%) diet. At 4 weeks, rats given noreleagnine and high salt had higher tail cuff pressures (146 +/- 4 vs. 134 +/- 4 mmHg) than those given noreleagnine and low salt. However, with direct arterial measurement, these differences disappeared. These data suggest that beta-carbolines do not provide a useful model for investigating the effects of chronic stress on cardiovascular function in rats.

Stimulation of metabotropic glutamate receptors in the dorsomedial hypothalamus elevates heart rate in rats.

This study examined the potential role of metabotropic glutamate receptors (mGluRs) in the dorsomedial hypothalamus (DMH) by assessing the cardiovascular effects of microinjecting the agonist trans-1-aminocyclopentane-1, 3- dicarboxylate (tACPD) into this region in urethan-anesthetized rats. Dose-related tachycardia was observed after unilateral microinjection of 1S 3R-tACPD (10-200 pmol/50nl) but not after injection of 1R, 3S-tACPD, which has been reported to have little or no activity at mGluRs. Microinjection of dihydroxyphenylglycine, an agonist at mGluRs linked to phosphoinositide hydrolysis, resulted in increases in heart rate that correlated closely in magnitude to those seen after injection of the same dose of 1S, 3R-tACPD. Coinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2- amino-5-phosphonopentanoic acid, given at doses shown to elicit selective blockade of NMDA ionotropic glutamate receptors, reduced the increase in heart rate evoked by 100 pmol 1S, 3R-tACPD alone. Thus the DMH contains functional mGluRs, and stimulation of these receptors activates the same sympathoexcitatory mechanism characterized previously to provoke dose-related tachycardia.

Role of the dorsomedial hypothalamus in the cardiovascular response to stress.

1. Disinhibition of the dorsomedial hypothalamus (DMH) in rats by local microinjection of GABAA receptor antagonists evokes behavioural and physiological changes resembling those seen in acute experimental stress. 2. Conversely, similar microinjection of muscimol, a potent agonist at inhibitory GABAA receptors, virtually abolishes stress-induced increases in heart rate and arterial pressure. 3. Blockade of excitatory amino acid (EAA) receptors in the DMH also attenuates [correction of attentuates] stress-induced cardiovascular changes and microinjection of kainate, AMPA or NMDA at low doses elicits cardiovascular effects resembling those seen in stress. Paradoxically, injection of higher doses of NMDA or of glutamate into this region has no consistent effect. 4. The cardiovascular effects of bicuculline methiodide, a GABAA receptor antagonist, as well as those of NMDA and/or kainate were assessed after identical injection into either the DMH, the paraventricular nucleus (PVN) or the area between the two nuclei in both anaesthetized and conscious rats. For each agent, a similar pattern was seen, with the largest increases in heart rate and arterial pressure occurring after injection into the DMH and the smallest changes resulting from injection into the PVN. 5. In a parallel study, bilateral microinjection of muscimol into the DMH dramatically reduced air stress-induced cardiovascular changes; similar injection into the area of the PVN had no effect, while injection into the area between the nuclei produced an intermediate effect. 6. Our findings suggest that activation of neurons in the region of the DMH mediates stress-induced cardiovascular changes and that the activity of these neurons may be determined by the balance of tone at inhibitory GABAA receptors and EAA receptors.

Muscimol acts in dorsomedial but not paraventricular hypothalamic nucleus to suppress cardiovascular effects of stress.

Both the dorsomedial hypothalamic nucleus (DMH) and the paraventricular hypothalamic nucleus (PVN) have been implicated in the neural control of the cardiovascular response to stress. We used the GABAA agonist muscimol to inhibit neuronal activation and attempted to identify hypothalamic nuclei required for the cardiovascular response to air stress. Chronically instrumented rats received bilateral injections of either 80 pmol of muscimol or 100 nl of saline vehicle into the DMH, the PVN, or an intermediate area (including the rostral edge of the DMH and the region between the two nuclei) and were placed immediately in a restraining tube and subjected to 20 min of air stress. In all rats, air stress after vehicle injections caused marked increases in heart rate (137 +/- 6 beats/min) and blood pressure (26 +/- 2 mmHg). Microinjection of muscimol into the DMH suppressed the heart rate and blood pressure response by 85 and 68%, respectively. Identical microinjection of muscimol into the intermediate area between the DMH and the PVN attenuated the increases in heart rate by only 46% and in blood pressure by 52%. In contrast, similar injections into the vicinity of the PVN failed to alter the cardiovascular response to air stress. These findings demonstrate that muscimol-induced inhibition of neuronal activity in the region of the DMH blocks air stress-induced increases in heart rate and arterial pressure, whereas similar treatment in the area of the PVN has no effect.

Hypothalamic sites mediating cardiovascular effects of microinjected bicuculline and EAAs in rats.

Microinjection of gamma-aminobutyric acidA receptor antagonist bicuculline methiodide (BMI) into either the dorsomedial hypothalamic nucleus (DMH) or the nearby paraventricular hypothalamic nucleus (PVN) has been reported to evoke marked tachycardia and modest pressor effects. We compared the effects of microinjecting BMI and excitatory amino acids (EAAs) into 1) the DMH, 2) the PVN, and 3) an intermediate area between the two nuclei. In conscious rats, microinjection of (in pmol) 10 BMI, 0.5 kainic acid, or 5 N-methyl-D-aspartate into the DMH markedly increased heart rate and slightly elevated arterial pressure, whereas injections into other regions provoked changes that progressively declined in magnitude with increasing distance from the nucleus. A similar pattern was evident in urethan-anesthetized rats, where the shortest latency to onset of BMI-induced increases in heart rate was seen after injection into the DMH. These findings demonstrate that the cardiovascular changes seen after microinjection of BMI or EAAs into the medial hypothalamus result from an action in the DMH and not from spread to the PVN.

Activation of the hypothalamic dorsomedial nucleus stimulates intestinal motility in rats.

Blockade of gamma-aminobutyric acidA (GABAA) receptors in the dorsomedial nucleus of the hypothalamus (DMH) in rats induced cardiovascular and behavioral changes resembling those associated with emotional stress. The purpose of this study was to test the hypothesis that microinjection of the GABA antagonist bicuculline methiodide (BMI) into the DMH of anesthetized rats would produce increases in intestinal motility measured manometrically with saline-filled cannulas. Arterial pressure and heart rate were also recorded. Microinjection of BMI (15-30 pmol/15 nl) into the region of the DMH elicited reproducible and dose-related increases in jejunal motility, colonic motility, heart rate, and arterial pressure. Similar microinjection at sites anterior to the DMH into or nearer to the hypothalamic paraventricular nucleus elicited significantly attenuated cardiovascular effects accompanied by either no change in intestinal function or changes that were significantly reduced. Either vagotomy or treatment with atropine methyl bromide (1 mg/kg i.v.) blocked the increase in jejunal motility and reduced but did not abolish the colonic stimulation. Increases in heart rate and arterial pressure were essentially unaffected by either intervention. The observations suggest that disinhibition of neurons in the DMH increases jejunal motility through vagal cholinergic pathways and enhances colonic motility through vagal and nonvagal cholinergic and noncholinergic pathways.

Time course of effects of 3-mercaptopropionic acid on GABA levels in different brain regions in guinea pigs: possible relationship with associated cardiovascular changes.

In anesthetized guinea pigs, we examined heart rate, arterial pressure, and GABA levels in four brain regions after systemic administration of 3-mercaptopropionic acid, an inhibitor of GABA synthesis. After i.p. injection of 195 mg/kg, significant reductions in GABA were first noted at 15 minutes in the cerebellum (-39%), 30 minutes in the hypothalamus (-27%), 60 minutes in the medulla pons (-34%) and 90 minutes in the cerebral cortex (-43%). Cardiovascular function was unaltered at 15 minutes but heart rate and arterial pressure were both significantly elevated at 30 minutes. By 60 minutes, however, heart rate had fallen below control. Injection of a lower dose (97.5 mg/kg i.p.) of 3-MP produced significant increases in heart rate and arterial pressure in 4 of 11 guinea pigs tested. When GABA levels in the same four brain regions were examined at 90 minutes and compared to corresponding levels from vehicle-treated guinea pigs, significant reductions were seen only in the hypothalamus and only in those animals displaying tachycardia and pressor responses. These findings are consistent with our previous results indicating that decreased GABA levels in the hypothalamus and in the medulla pons are responsible for the increases and decreases in heart rate, respectively, seen after systemic administration of 3-mercaptopropionic acid.

Hypothalamic excitatory amino acid receptors mediate stress-induced tachycardia in rats.

The role of hypothalamic excitatory amino acid (EAA) receptors in mediating the cardiovascular response to stress was examined using conscious chronically instrumented rats. Microinjection of the EAA agonists N-methyl-D-aspartic acid (NMDA; 1-10 pmol), alpha-amino-3-hydroxy-5-methyl-4-isooxazolepropionic acid (AMPA; 0.3-3.0 pmol), or kainic acid (0.1-1.0 pmol) into the dorsomedial hypothalamus (DMH) elicited dose-related increases in heart rate and modest elevations in arterial pressure. Local microinjection of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (AP5; 100 pmol) selectively blocked NMDA-induced cardiovascular changes, whereas the non-NMDA EAA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 pmol) selectively blocked the responses to AMPA and kainic acid. In the stress trials, microinjection of the nonselective EAA antagonist kynurenic acid (1-10 nmol) into the DMH blocked air stress-induced tachycardia in a dose-related manner. Similar injection of kynurenic acid at sites lateral or posterior to the DMH or injection of xanthurenic acid (a structural analogue of kynurenic acid with no antagonistic properties at EAA receptors) into the DMH failed to influence air stress-induced cardiovascular changes. Injection of either AP5 or CNQX into the DMH at doses shown to be selective for their respective EAA receptor subtypes also attenuated air stress-induced tachycardia. Thus activity at EAA receptors in the DMH appears to be necessary for the generation of stress-induced changes in heart rate.

The use of microdialysis for studying the regional effects of pharmacological manipulation on extracellular levels of amino acids--some methodological aspects.

The purpose of this study was to examine and validate the use of microdialysis for sampling and pharmacologically manipulating extracellular amino acids in the brain. Repeated use of microdialysis probes in acute intracerebral experiments did not significantly alter the relative recovery in vitro for the amino acids quantitated (GABA, aspartate, glutamate, glycine, taurine, and alanine). Regional differences in basal levels of some of the amino acids were detected in dialysates collected from the dorsomedial hypothalamus, striatum, and frontal cortex. The percent in vitro recoveries for the amino acids from the probes used in the three regions were not significantly different suggesting that the regional differences in basal levels of amino acids were functionally derived and not a consequence of variations in probe recovery. Perfusion with nipecotic acid, an inhibitor of GABA uptake, resulted in selective elevations in extracellular GABA in the three regions studied. Conversely, perfusion with high-potassium, a depolarizing agent, resulted in significant elevations in not only extracellular GABA but also aspartate, glutamate, and taurine. Thus, microdialysis is a method which can be employed to assess and to pharmacologically manipulate extracellular amino acids in the rat brain.

Interaction of hypothalamic GABAA and excitatory amino acid receptors controlling heart rate in rats.

We have previously shown that microinjection of drugs that impair gamma-aminobutyric acid (GABA)-mediated synaptic inhibition into the dorsomedial hypothalamus (DMH) of rats generates cardiovascular and behavioral changes that mimic the response to stress. The purpose of this study was to examine the role of excitatory amino acid (EAA) receptors in the DMH in generating the cardiovascular changes caused by withdrawal of local GABAergic inhibition in urethan-anesthetized rats. Local treatment of the DMH with the nonselective EAA antagonist kynurenic acid blocked or reversed the increases in heart rate and blood pressure caused by microinjection of the GABAA antagonists bicuculline methiodide (BMI) or picrotoxin into the same region. Conversely, similar injection of xanthurenic acid, a structural analogue of kynurenic acid without significant effects on EAA receptors, did not significantly alter the cardiovascular changes produced by either GABAA antagonist. The tachycardic effects of BMI were also attenuated by injection of either the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid or the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. When the two EAA receptor antagonists were combined, their effects to suppress the BMI-induced tachycardia were additive. These findings suggest that the cardiovascular effects caused by blockade of GABAergic inhibition in the DMH of the rat are dependent on activation of local NMDA and non-NMDA EAA receptors.

GABAA and excitatory amino acid receptors in dorsomedial hypothalamus and heart rate in rats.

We have previously shown that microinjection of drugs that interfere with the function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into the hypothalamus produces cardiorespiratory and behavioral changes resembling those seen in emotional stress. The purpose of this study was to determine whether excitatory amino acids (EAAs) can produce a cardiovascular response similar to that caused by the GABAA receptor antagonist bicuculline methiodide (BMI) when microinjected at the same hypothalamic site in urethan-anesthetized rats and to clarify the precise locus of action of these agents. N-methyl-D-aspartic acid (NMDA, 0.68-6.8 pmol/50 nl) and kainic acid (KA, 0.47-4.7 pmol/50 nl) produced dose-related increases in heart rate and blood pressure when injected at sites in the dorsomedial hypothalamus reactive to BMI (20 pmol/50 nl). Higher doses of NMDA (68 pmol), however, failed to elicit consistent increases in heart rate and blood pressure when injected at these same sites. The effects of NMDA were selectively blocked by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid, whereas the effects of KA were selectively blocked by the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. These results demonstrate that 1) blockade of inhibitory amino acid receptors or stimulation of EAA receptors in the dorsomedial nucleus of the hypothalamus produces tachycardic and pressor responses in urethan-anesthetized rats and 2) use of high doses of EAAs may be an unreliable method of evoking local neuronal excitation in certain regions of the central nervous system.

Effect of local inhibition of gamma-aminobutyric acid uptake in the dorsomedial hypothalamus on extracellular levels of gamma-aminobutyric acid and on stress-induced tachycardia: a study using microdialysis.

Previous studies involving local microinjection of drugs that interfere with gamma-aminobutyric acid (GABA)A receptor-mediated synaptic inhibition have led to the suggestion that endogenous GABA suppresses the activity of a sympatho-excitatory mechanism in the dorsomedial hypothalamus in rats. In this study, microdialysis was used to assess and to alter pharmacologically extracellular-levels of GABA within this region while simultaneously monitoring heart rate and blood pressure. In anesthetized rats, local microdialysis for 15 min with 2.5, 10 and 40 mM nipecotic acid, an inhibitor of GABA uptake, caused concentration-related increases in GABA and taurine in the extracellular space, but no significant change in heart rate or arterial pressure. Similar perfusion with 37.5, 75 and 150 mM KCl caused concentration-related increases in GABA as well as aspartate, glutamate, taurine, glycine and alanine. Only modest, variable increases in heart rate and no effect on arterial pressure were observed during the perfusions with high potassium. In conscious rats, unilateral microdialysis of the dorsomedial hypothalamus with 0.5 mM nipecotic acid for 2 to 2.5 hr before stress coupled with contralateral microinjection of muscimol (88 pmol/250 nl) 5 min before stress significantly reduced air stress-induced tachycardia; this reduction in tachycardia was associated with markedly elevated levels of GABA in dialysates collected from the dorsomedial hypothalamus. Neither treatment alone significantly influenced stress-induced increases in heart rate, although perfusion with nipecotic acid alone evoked similar elevations in extracellular GABA. These results suggest that extracellular levels of endogenous GABA in the dorsomedial hypothalamus may regulate the cardiovascular response to stress.

Resolution of central sites involved in picrotoxin-induced vagal activation and vasopressin release.

This investigation tested the hypotheses that picrotoxin, a drug which blocks the inhibitory effect of gamma-aminobutyric acid (GABA), would, in spinal cord-transected rats, (1) suppress the cardiac vagus when localized to the forebrain and stimulate the cardiac vagus by acting in the brainstem and (2) stimulate the release of vasopressin into the systemic circulation through separate forebrain and brainstem GABAergic mechanisms. An intra-arterial infusion technique allowed for delivery of picrotoxin selectively to either forebrain or brainstem areas. Administration of picrotoxin via the vertebral artery decreased sinus rate and increased circulating levels of vasopressin. Infusion of picrotoxin into the internal carotid artery caused increases in sinus rate, blood pressure and plasma vasopressin. These data support the hypothesis that GABAergic mechanisms at different levels of the neuraxis exert opposite effects on cardiac vagal activity, and that GABAergic mechanisms in both the brainstem and forebrain inhibit the release of AVP into the systemic circulation.