Biomedical subjects

A F Sved

Publications and source records attributed to A F Sved.

At least 37 records · Page 2Linked to original sources

PubMed2000

Mecamylamine prevents tolerance but enhances whole brain [3H]epibatidine binding in response to repeated nicotine administration in rats.

RATIONALE: Chronic administration of nicotine in rats results in upregulation of neuronal nicotinic receptors. Upregulation has been proposed to reflect receptor desensitization, which may underlie functional tolerance to nicotine's effects. However, evidence indicates that tolerance and upregulation do not always parallel each other, suggesting that either upregulation does not always reflect desensitization, or mechanisms other than receptor desensitization account for tolerance to nicotine. OBJECTIVES: The present studies examined tolerance to nicotine-induced antinociception and changes in receptor binding after two regimens of intermittent nicotine injections in rats. The role of receptor activation in upregulation and tolerance was also examined by co-administering nicotine with the non-competitive antagonist, mecamylamine. METHODS: Sprague-Dawley rats were administered a short (once-daily, s.c. for 6 days (0.35 mg/kg)) or long (twice-daily for 11 days (0.66 mg/kg)) series of injections and tolerance to nicotine-induced antinociception and [3H]epibatidine binding in whole brain were measured. RESULTS: The short series of injections resulted in tolerance to nicotine-induced antinociception, but failed to increase [3H]epibatidine binding. In contrast, the long series of injections resulted in both tolerance and increased receptor binding. Once-daily pairings of mecamylamine (1 mg/kg, s.c.) with nicotine (0.35 mg/kg) for 6 days blocked the development of tolerance, indicating receptor activation is necessary for tolerance to occur. Pairing mecamylamine with nicotine (0.66 mg/kg) twice daily for 11 days blocked tolerance but produced a greater increase in [3H]epibatidine binding than nicotine alone. CONCLUSIONS: A dissociation of tolerance from receptor upregulation was observed in the present study. The finding that receptor activation may be necessary for tolerance but not upregulation is discussed within the context of possible mechanisms controlling tolerance to nicotine.

Animals↗

PubMed2000

Increased transcription of the tyrosine hydroxylase gene in individual locus coeruleus neurons following footshock stress.

Footshock-evoked change in transcriptional activity of tyrosine hydroxylase in neurons of the locus coeruleus was examined using an intron-specific in situ hybridization histochemical technique. A significant increase in the cellular concentration of tyrosine hydroxylase primary transcripts was found in locus coeruleus neurons 3h following 30 min of intermittent footshock. However, the footshock-induced increase in tyrosine hydroxylase transcription was not homogeneously expressed in locus coeruleus neurons. Similarly, administration of the alpha(2)-adrenergic receptor antagonist idazoxan produced a significant increase in the cellular concentration of tyrosine hydroxylase primary transcripts that was heterogeneously distributed among locus coeruleus neurons. Both footshock and idazoxan significantly increased the regional levels of tyrosine hydroxylase messenger RNA in the locus coeruleus. The time-course of changes in tyrosine hydroxylase transcription rate and messenger RNA levels in the locus coeruleus was examined after a 15 min exposure to footshock. A robust increase in tyrosine hydroxylase transcription rate was found at the end of 15 min of footshock, which remained elevated for 6h and was back to the control levels by 24h. In contrast, in response to a 15 min period of footshock tyrosine hydroxylase messenger RNA concentrations in the locus coeruleus did not increase until 6h and remained elevated at 24h. These findings demonstrate that transcription of the tyrosine hydroxylase gene in locus coeruleus neurons in response to footshock stress occurs rapidly, is sustained for many hours and is heterogeneously distributed. These data also suggest that the increase in tyrosine hydroxylase messenger RNA following footshock is mediated, at least in part, by an increase in tyrosine hydroxylase gene transcription.

Animals↗

PubMed2000

Role of locus coeruleus in foot shock-evoked Fos expression in rat brain.

The robust activation of locus coeruleus neurons in response to a variety of stressors, in conjunction with the widespread outputs of the locus coeruleus, suggest that the locus coeruleus may be important in mediating responses to stress. Previous studies in rats have demonstrated that exposure to foot shock elicits Fos expression, a marker of neuronal activation, in the locus coeruleus and other brain sites. In order to evaluate the involvement of the locus coeruleus in foot shock-induced activation of other brain sites, shock-induced Fos expression was examined in the locus coeruleus and other brain areas known to be activated by foot shock, following direct inhibition of the locus coeruleus by local infusion of muscimol, a GABA agonist, prior to foot shock. Control rats received infusions of artificial cerebrospinal fluid into the locus coeruleus or muscimol into areas outside of locus coeruleus. Rats infused with artificial cerebrospinal fluid and then exposed to foot shock had significant increases in Fos expression in several brain areas, including locus coeruleus, nucleus O, several subdivisions of the hypothalamus, subnuclei of amygdala, bed nucleus of the stria terminalis and cingulate cortex. Inhibition of the locus coeruleus prior to foot shock significantly inhibited Fos expression in the locus coeruleus, nucleus O, some subdivisions of the hypothalamus including the magnocellular and medial parvicellular paraventricular hypothalamic nucleus, subnuclei of amygdala, and cingulate cortex. In contrast, inhibition of the locus coeruleus did not affect shock-induced Fos expression in other areas, including certain subdivisions of the hypothalamus and bed nucleus of the stria terminalis. We suggest that foot shock may activate multiple pathways, with activation of certain discrete nuclei requiring input from the locus coeruleus and activation of others occurring independently of locus coeruleus input.

Animals↗

PubMed2000

Thirst.

The homeostasis of body fluid traditionally is viewed as involving the regulation of its osmolality and of blood volume. However, the control of thirst is more complex than can be described in a two-factor model, and consideration of plasma sodium concentration and of arterial blood pressure also must be included in the discussion. This review is organized around those four variables and focuses on the seven distinct signals that appear to influence water intake in rats. These signals include four that are excitatory for thirst: increased plasma osmolality detected by cerebral osmoreceptors, decreased blood volume presumably detected by cardiac stretch receptors, increased circulating levels of angiotensin II detected by angiotensin II receptors in the subfornical organ, and increased gastric sodium load apparently detected by putative sodium receptors in the abdominal viscera. There also appear to be three signals that inhibit thirst: decreased plasma osmolality detected by cerebral osmoreceptors, increased arterial blood pressure detected by arterial baroreceptors, and increased gastric water load apparently detected by putative sodium receptors in the abdominal viscera.

Animals↗

PubMed2000

Pharmacological profile of depressor response elicited by sarthran in rat ventrolateral medulla.

Injection of sarthran, an angiotensin receptor antagonist, bilaterally into the rostral ventrolateral medulla (RVLM) of alpha-chloralose-anesthetized rats decreases arterial pressure (AP) to the same extent as total autonomic blockade. This response is not reproduced by selective AT(1) antagonists. To examine the pharmacological profile of the response elicited by [Sar(1), Thr(8)]ANG II (sarthran), the ability of angiotensin analogs to inhibit the effect of sarthran injected into the RVLM was tested. Coinjection of angiotensin II (ANG II) prevented the sarthran-evoked decrease in AP, but this action of ANG II was markedly attenuated by pretreatment of the RVLM with the aminopeptidase inhibitor amastatin. Coinjection of ANG(3-8) or a selective agonist of AT(4) receptors prevented the effect of sarthran injected into the RVLM. ANG(1-7) was also able to prevent the effect of sarthran. None of the angiotensin fragments tested substantially altered blood pressure when injected alone into the RVLM. These results suggest that the depressor action of sarthran injected into the RVLM is not dependent on ANG II receptors, though the nature of the site or sites of action of sarthran within the RVLM remains uncertain.

Angiotensin II↗

PubMed2000

Oxytocin-induced renin secretion in conscious rats.

Arterial hypotension and hypovolemia are known to stimulate neurohypophysial secretion of oxytocin (OT) in rats, although the physiological function of OT under these circumstances is uncertain. We now report that OT infused intravenously into conscious rats at 125 ng x kg(-1) x h(-1), a dose selected to mimic plasma OT levels during hypotension or hypovolemia, increased plasma renin concentration and plasma renin activity by twofold. This effect was prevented by systemic pretreatment with an OT receptor antagonist [[1-(3-mercaptopropionic acid)-2-O-ethyl-D-Tyr-Thr(4)-Orn(8)]-OT]. The OT antagonist did not block renin secretion induced by systemic injection of the beta-adrenergic receptor agonist isoproterenol, indicating that the OT antagonist does not interfere nonselectively with renin release. Pretreatment of rats with the beta-adrenergic receptor antagonist nadolol also prevented OT-induced renin secretion. Similarly, nadolol injected during infusion of OT markedly reduced the elevated plasma renin levels. These observations raise the possibility that pituitary OT secretion during hypotension or hypovolemia in rats may serve to support blood pressure by enhancing activation of the renin-angiotensin system via a beta-adrenergic receptor-dependent mechanism.

Adrenergic beta-Agonists↗

PubMed2000

Vasopressin and oxytocin release evoked by NaCl loads are selectively blunted by area postrema lesions.

The present study investigated the effect of area postrema lesions (APX) on stimulated neurohypophysial secretion of vasopressin (VP) and oxytocin (OT) in conscious rats. Blunted increases in plasma levels of both pituitary hormones were observed when rats with APX were infused intravenously with 1 M NaCl solution (2 ml/h for 6 h). In contrast, plasma VP and OT increased normally in rats with APX when equivalent increases in plasma osmolality (but not plasma Na(+)) resulted from intravenous infusion of an equiosmotic solution of 1 M mannitol and 0.5 M NaCl. Furthermore, APX did not affect increases in plasma VP and OT stimulated by plasma volume deficits, nor did APX disrupt OT secretion stimulated by intravenous injection of cholecystokinin. These findings suggest that the area postrema plays an important role in mediating secretion of VP and OT in response to an NaCl load, but not in response to an equiosmotic load that does not cause substantial hypernatremia, and not in response to other stimuli of neurohypophysial hormone secretion. Together with previous reports, these results suggest that APX impairs Na(+) regulation in rats.

Animals↗

PubMed2000

Nucleus of the solitary tract lesions enhance drinking, but not vasopressin release, induced by angiotensin.

Rats with chronic nucleus of the solitary tract lesions (NTS-X) drink water and release vasopressin (VP) in response to reduced blood volume despite an absence of neural signals from cardiac and arterial baroreceptors. The present study determined whether rats with NTS-X have a greater sensitivity to circulating ANG II, which may contribute to the drinking and VP responses to hypovolemia. In conscious control rats and rats with NTS-X, ANG II was infused intravenously for 1 h at 10, 100, or 250 ng. kg(-1). min(-1). At the two higher doses, ANG II stimulated more water intake with a shorter latency to drink in rats with NTS-X than in control rats. In contrast, infusion of ANG II produced comparable increases in plasma VP in the two groups. At the two higher doses, ANG II produced an enhanced increase in arterial pressure (AP) in rats with NTS-X, and the bradycardia seen in control rats was reversed to a tachycardia. Infusion of hypertonic saline, which did not alter AP or heart rate, produced comparable drinking and VP release in the two groups. These results demonstrate that chronic NTS-X increases the dipsogenic response of rats to systemic ANG II but has no effect on ANG II-induced VP release or the osmotic stimulation of these responses.

Angiotensin II↗

PubMed2000

Role of renin-angiotensin system in hypotension-evoked thirst: studies with hydralazine.

Injection of rats either with diazoxide (25 mg/kg iv), isoproterenol (0.33 mg/kg sc), or hydralazine (HDZ) (10 mg/kg ip) decreased arterial blood pressure from approximately 120 to 70-80 mmHg and stimulated renin secretion. However, diazoxide and isoproterenol treatments each stimulated water ingestion, whereas HDZ treatment did not. HDZ treatment did not reduce water intake evoked by systemic injection of hypertonic saline or 20% polyethylene glycol solution or by 24-h water deprivation, suggesting that HDZ treatment did not interfere with drinking behavior. In contrast, HDZ treatment markedly reduced water intake evoked by injection of diazoxide or isoproterenol or by intravenous infusion of renin. Furthermore, a highly significant correlation was observed when plasma ANG II levels were plotted as a function of plasma renin activity after intravenous infusion of renin and after diazoxide and isoproterenol treatments. However, values obtained after HDZ treatment alone or in combination with intravenous infusion of renin did not fall near the 99% confidence interval of the regression line, suggesting that HDZ treatment blocks ANG II production and/or promotes its clearance. Thus rats apparently do not increase water intake after HDZ treatment, because this drug interferes with the renin-angiotensin system. These results provide further evidence that arterial hypotension evokes thirst in rats predominantly by activation of the renin-angiotensin system.

Animals↗

PubMed2000

Water ingestion provides an early signal inhibiting osmotically stimulated vasopressin secretion in rats.

Dehydrated dogs are known to inhibit secretion of vasopressin (VP) within minutes after drinking water, before plasma osmolality (P(osmol)) diminishes. The present studies determined whether water ingestion causes a similar rapid inhibition of neurohypophyseal hormone secretion in rats. Adult rats were infused with 1 M NaCl (2 ml/h iv) for 240 min to stimulate VP and oxytocin (OT) secretion. After 220 min of infusion, rats were given water to drink for 5 min, and blood samples were taken 5 and 15 min later for RIA. Plasma VP (pVP) was much lower when rats ingested water than when they drank nothing even though P(osmol) was not significantly altered. Plasma OT (pOT) was affected similarly. In contrast, no effects on pVP or pOT occurred when rats drank isotonic NaCl solution for 5 min in amounts comparable to the water intakes (approximately 5.5 ml). These results suggest that neurohypophyseal secretion of VP and OT in rats is inhibited rapidly by water drinking, and that this inhibition is mediated by a visceral signal of osmotic dilution rather than by the act of drinking per se.

Animals↗

PubMed2000

Excitatory amino acids in the rostral ventrolateral medulla support blood pressure in spontaneously hypertensive rats.

Injection of the excitatory amino acid (EAA) antagonist kynurenic acid (KYN) into the rostral ventrolateral medulla (RVLM) of anesthetized rats has no effect on arterial pressure. However, we recently reported that after inhibition of the caudal ventrolateral medulla, injection of KYN into the RVLM decreased arterial pressure to the same level as produced by complete inhibition of the RVLM. We have suggested that these results reflect tonically active EAA-mediated inputs to the RVLM producing both direct excitation of RVLM vasomotor neurons and indirect inhibition of these neurons. On the basis of this model, we hypothesize that the balance between these EAA-driven direct excitatory and indirect inhibitory influences on the RVLM may be altered in models of experimental hypertension. To begin to test this hypothesis, the effects of injecting KYN into the RVLM of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were compared. In chloralose-anesthetized WKY, bilateral injection of KYN into the RVLM did not alter arterial pressure, whereas similar injections in SHR reduced mean arterial pressure by approximately 40 mm Hg. After inhibition of the caudal ventrolateral medulla, which similarly increased arterial pressure in both strains, injection of KYN into the RVLM reduced mean arterial pressure to the same level as produced by autonomic blockade. These results suggest that the balance of excitatory and inhibitory influences on RVLM vasomotor neurons driven by tonically active EAA-mediated inputs to the RVLM is disrupted in SHR and may contribute to the hypertension in SHR.

Animals↗

PubMed1999

Sensitization of norepinephrine release in medial prefrontal cortex: effect of different chronic stress protocols.

Previously, we demonstrated that continuous exposure of rats to cold (5 degrees C) for 2-3 weeks potentiates the increase in extracellular norepinephrine in the medial prefrontal cortex produced by acute tail shock. In the present study, we used in vivo microdialysis to examine whether this sensitization of evoked norepinephrine release also occurs in the medial prefrontal cortex following exposure to other chronic stress protocols. Rats exposed to 30 min of intermittent foot shock (0.6 mA) each day for 14 days, did not exhibit a greater increase in extracellular norepinephrine in response to acute tail shock. To determine whether this discrepancy between cold exposure and foot shock might be related to differences in the nature or the pattern of exposure to the chronic stressor, we also examined the effect of intermittent exposure to cold or continuous exposure to a foot shock protocol on tail shock-evoked norepinephrine release. Sensitized norepinephrine release did not develop following either intermittent exposure to cold (5 degrees C; 4 h/day for 14 days) or continuous exposure to a foot shock protocol (0.6 mA trains at random intervals 24 h/day for 14 days), suggesting that both the nature of the stressor as well as the pattern of exposure to the chronic stressor play a role in the development of sensitized norepinephrine release.

Animals↗

PubMed1999

Mecamylamine blocks the development of tolerance to nicotine in rats: implications for the mechanisms of tolerance.

Chronic injections of nicotine in rats produce upregulation of nicotinic cholinergic receptors. It has been proposed that this upregulation is a reflection of receptor desensitization and is the basis of functional tolerance. Mecamylamine, a non-competitive antagonist that blocks activation of nicotinic receptors, does not prevent upregulation produced by nicotine injections. This suggests that receptor activation is not a prerequisite for nicotine-induced receptor upregulation. Therefore, the present experiments tested whether mecamylamine would also fail to prevent the development of tolerance to nicotine. Six daily pairings of mecamylamine (1 mg/kg SC) with nicotine did block the development of tolerance to nicotine-induced antinociception (0.35 mg/kg) and to the ability of nicotine to suppress milk intake (0.66 mg/kg). In another experiment, six daily injections of mecamylamine, when given alone, did not alter the effects of a subsequent, acute injection of nicotine (0.35 mg/kg) in inducing antinociception in rats. There was no evidence that after six pairings of mecamylamine with nicotine, the cues associated with mecamylamine delivery took on conditioned antagonistic properties. These findings suggest that, unlike the receptor upregulation that results from either continuous or repeated nicotine administration, the tolerance following a short series of intermittent nicotine injections is dependent on receptor activation.

Analgesics↗

PubMed1999

Thirst and salt appetite elicited by hypovolemia in rats with chronic lesions of the nucleus of the solitary tract.

Cardiac vagal afferents terminating in the nucleus of the solitary tract (NTS) are believed to participate in stimulating neurohypophysial secretion of vasopressin as well as increased ingestion of water and NaCl solution in response to decreased blood volume. However, we recently reported that chronic lesions of NTS, which eliminate neural input from cardiac and arterial baroreceptors, do not impair hypovolemia-induced vasopressin secretion in rats. In the present investigation we sought to determine whether those sensory signals were necessary for hypovolemia-induced thirst and salt appetite. Rats with chronic lesions of the NTS increased consumption of water and NaCl solution normally when plasma volume was reduced isosmotically by subcutaneous injection of polyethylene glycol solution. These results were obtained whether rats were allowed to drink water or 0.15 M NaCl in one-bottle tests or water and 0.5 M NaCl in two-bottle tests. The induction of thirst and salt appetite by hypovolemia despite the apparent loss of neural input to the brain from cardiac volume-sensitive receptors indicates that other signals generated by plasma volume deficits can stimulate these behavioral responses in rats.

Animals↗

PubMed1999

GABA-mediated inhibition of raphe pallidus neurons regulates sympathetic outflow to brown adipose tissue.

Sympathetic nerve activity to brown adipose tissue (BAT) regulates adipocyte metabolism of its stored lipid fuel and thus the thermogenesis in BAT. To determine if the discharge of neurons in the rostral raphe pallidus (RPa) can influence BAT thermogenesis, changes in sympathetic nerve activity to BAT were recorded after microinjection (60 nl) of the GABAA receptor antagonist bicuculline (500 microM) into the RPa in chloralose-urethan-anesthetized, ventilated rats. Bicuculline caused a large, rapid rise in the sympathetic nerve activity to BAT (which had also increased during acute hypothermia) from very low, normothermic control levels to maximum values (mean: 1,949 +/- 604% control; n = 13) after 4-6 min. The sympathetic nerve discharge to BAT had a mean burst frequency (3. 5 +/- 0.3 Hz) that was significantly less than the heart rate (7.3 +/- 0.2 beats/min), and it was not inhibited during baroreceptor reflex activation. Bicuculline-stimulated increases in the sympathetic nerve activity to BAT and cold-evoked increases in neuronal fos expression were localized to the RPa at the level of the caudal half of the facial nucleus. This dramatic increase in sympathetic nerve activity to BAT after disinhibition of neurons in rostral RPa is consistent with a major role for RPa neurons, perhaps as sympathetic premotoneurons for BAT, in medullary control of BAT thermogenesis.

Adipose Tissue, Brown↗

PubMed1999

Dietary salt intake alters cardiovascular responses evoked from the rostral ventrolateral medulla.

The present experiments examined whether in rats consuming diets with either high NaCl content (8%) or low Na+ content (0.01%) for 2 wk excitatory inputs to the rostral ventrolateral medulla (RVLM) would be altered. In chloralose-anesthetized rats, injection of glutamate into the RVLM elicited a pressor response that, compared with rats fed a control diet, was 50% larger in rats fed a diet containing 8% NaCl and was 25% smaller in rats fed a diet containing 0.01% Na+. Pressor responses produced by electrical stimulation of sciatic nerve afferents, as well as by microinjections into the RVLM of L-dihydroxyphenylalanine or carbachol, were all potentiated by high dietary salt intake and reduced by low dietary salt intake. Dietary salt intake had no effect on pressor responses produced by intravenous injection of phenylephrine, indicating that salt-related alterations in cardiovascular responses produced by central activation could not be accounted for by changes in peripheral vascular reactivity. The decrease in arterial pressure produced by injection of glutamate into the nucleus of the solitary tract was also potentiated by the high salt diet, suggesting that the sensitivity of central baroreceptor reflex pathways may be altered by dietary NaCl. These results indicate that the amount of NaCl consumed in the diet can change the sensitivity of RVLM sympathoexcitatory neurons, and this change in sensitivity is not restricted to any particular class of cell surface receptors.

Adrenergic alpha-Agonists↗

PubMed1999

Impaired osmoregulatory responses in rats with area postrema lesions.

Area postrema lesions (APX) in adult male rats produced a robust spontaneous intake of 0.5 M NaCl, as reported previously. The largest NaCl intakes (up to 108 ml/day) were observed when there was little incidental damage in the medial subnucleus of the nucleus of the solitary tract adjacent to the caudal and middle portions of the area postrema. Rats with discrete APX also drank substantial amounts of 0.5 M NaCl when access to saline was restricted to 7 h/day (up to 30 ml in 1 h, 48 ml in 7 h). Such large NaCl intakes stimulated considerable water ingestion and renal sodium excretion, but together these responses usually were insufficient for osmoregulation during the 7-h test period. After systemic administration of hypertonic NaCl solution, rats with APX excreted less Na(+) in urine and secreted less vasopressin and oxytocin than control rats did. The prominent salt appetite, insufficient thirst and natriuresis in response to an ingested NaCl load, and blunted natriuresis and neurohypophysial hormone secretion in response to an injected NaCl load, all indicate that osmoregulatory responses are impaired in rats after APX.

Animals↗

PubMed1999

Lesions of the C1 catecholaminergic neurons of the ventrolateral medulla in rats using anti-DbetaH-saporin.

Phenylethanolamine-N-methyltransferase (PNMT)-containing neurons in the rostral ventrolateral medulla (RVLM) are believed to play a role in cardiovascular regulation. To determine whether injection of anti-dopamine beta-hydroxylase (DbetaH)-saporin directly into the RVLM in rats could selectively destroy these cells and thereby provide an approach for evaluating their role in cardiovascular regulation, we studied rats 2 wk after unilateral injection of 21 ng anti-DbetaH-saporin into the RVLM. There was an approximately 90% reduction in the number of PNMT-positive neurons in the RVLM, although the number of non-C1, spinally projecting barosensitive neurons of this area was not altered. The A5 cell group was the only other population of DbetaH-containing cells that was significantly depleted. The depressor response evoked by injection of tyramine into the RVLM was abolished by prior injection of toxin. The pressor response evoked by injection of glutamate into the RVLM was attenuated ipsilateral to the toxin injection but was potentiated contralateral to the toxin injection. Thus anti-DbetaH-saporin can be used to make selective lesions of PNMT-containing cells, allowing for the evaluation of their role in cardiovascular regulation.

Animals↗