Biomedical subjects

A F Sved

Publications and source records attributed to A F Sved.

At least 19 recordsLinked to original sources

PubMed2001

Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing.

Splenic immune function is modulated by sympathetic innervation, which in turn is controlled by inputs from supraspinal regions. In the present study, the characterization of central circuits involved in the control of splenic function was accomplished by injecting pseudorabies virus (PRV), a retrograde transynaptic tracer, into the spleen and conducting a temporal analysis of the progression of the infection from 60 hours to 110 hours postinoculation. In addition, central noradrenergic cell groups involved in splenic innervation were characterized by dual immunohistochemical detection of dopamine-beta-hydroxylase and PRV. Infection in the CNS first appeared in the spinal cord. Splenic sympathetic preganglionic neurons, identified in rats injected with Fluoro-Gold i.p. prior to PRV inoculation of the spleen, were located in T(3)-T(12) bilaterally; numerous infected interneurons were also found in the thoracic spinal cord (T(1)-T(13)). Infected neurons in the brain were first observed in the A5 region, ventromedial medulla, rostral ventrolateral medulla, paraventricular hypothalamic nucleus, Barrington's nucleus, and caudal raphe. At intermediate survival times, the number of infected cells increased in previously infected areas, and infected neurons also appeared in lateral hypothalamus, A7 region, locus coeruleus, subcoeruleus region, nucleus of the solitary tract, and C3 cell group. At longer postinoculation intervals, infected neurons were found in additional hypothalamic areas, Edinger-Westphal nucleus, periaqueductal gray, pedunculopontine tegmental nucleus, caudal ventrolateral medulla, and area postrema. These results demonstrate that the sympathetic outflow to the spleen is controlled by a complex multisynaptic pathway that involves several brainstem and forebrain nuclei.

Animals↗

PubMed2001

The area postrema lesions alter the inhibitory effects of peripherally infused pancreatic polypeptide on pancreatic secretion.

Circulating PP binds to specific receptors in the DVC through the AP, but the mechanism through which these brain receptors affect pancreatic secretion is not clear. We hypothesize that the removal of the AP (APX) will alter the effects of PP on pancreatic secretion. APX or sham procedures were performed in anesthetized male Wistar rats. After a 1-month recovery, one group of rats were infused with either PP (30 or 100 pmol/kg per h) or vehicle under basal or 2-DG-stimulated (75 mg/kg, i.v. bolus) conditions for studying pancreatic exocrine secretion. A second parallel group was sacrificed for examination of PP receptor binding in the brain stem. A third group received an intraperitoneal injection of PP at the dose of 4.15x10(4) pmol/kg (200 microg/kg) and c-fos expression in the brain stem was examined. APX eliminated PP binding sites in the DVC as assessed by autoradiography. PP infusion caused a dose-dependent decrease in basal protein secretion. APX partially reversed PP inhibition of basal protein secretion when infused at 30 pmol/kg per h, and at 100 pmol/kg per h stimulated pancreatic fluid secretion and reversed the inhibition of protein secretion. During 2-DG stimulation the effects of PP and 2-DG on pancreatic fluid and protein secretion were parallel. PP dose-dependently inhibited 2-DG-stimulated secretion in sham rats. APX reduced the pancreatic fluid (54%) and protein (46%) secretory response to 2-DG. However, PP at 30 pmol/kg per h remained a potent inhibitor of 2-DG-stimulated pancreatic secretion in APX rats. This effect was blunted with PP at 100 pmol/kg per h in APX rats, possibly related to the stimulatory effect of high-dose PP in APX rats without 2-DG. Furthermore, i.p. PP induced significantly greater c-fos activation of NTS neurons in APX rats than sham rats, despite the apparent absence of PP binding sites in the DVC. We conclude that in awake rats, PP inhibits basal secretion, in part, through the AP. Furthermore, and unlike PYY, PP inhibits 2-DG-stimulated pancreatic secretion, and it does so through an AP-independent mechanism. The possibility that the mechanism may involve the DVC cannot be excluded since i.p. injection of PP activates c-fos expression in DVC neurons. Thus, PP and PYY may regulate different components of the pancreatic secretory control system through unique pathways.

Animals↗

PubMed2001

Chronic cold exposure potentiates CRH-evoked increases in electrophysiologic activity of locus coeruleus neurons.

BACKGROUND: Chronic stress exposure can produce sensitization of norepinephrine release in the forebrain in response to subsequent stressors. Furthermore, the increase in norepinephrine release in response to the stress-related peptide corticotropin-releasing hormone (CRH) is potentiated by prior chronic stress exposure. To explore possible mechanisms underlying these alterations in norepinephrine release, we examined the effect of chronic stress on the electrophysiologic activity of locus coeruleus (LC) neurons in response to centrally applied CRH. METHODS: Single-unit recordings of LC neurons in halothane-anesthetized rats were used to compare the effect of intraventricular administration of CRH (0.3-3.0 microg) in control and previously cold-exposed (2 weeks at 5 degrees C) rats. RESULTS: The CRH-evoked increase in LC neuron activity was enhanced following chronic cold exposure, without alteration in basal activity of LC neurons. The enhanced CRH-evoked activation was apparent at higher doses of CRH but not at lower ones, resulting in an increased slope of the dose-response curve for CRH in previously cold-exposed rats. CONCLUSIONS: These data, in combination with previous data, suggest that the sensitivity of LC neurons to excitatory inputs is increased following chronic cold exposure. The altered functional capacity of LC neurons in rats after continuous cold exposure may represent an experimental model to examine the role of central noradrenergic neurons in anxiety and mood disorders.

Animals↗

PubMed2001

Cue dependency of nicotine self-administration and smoking.

A paradox exists regarding the reinforcing properties of nicotine. The abuse liability associated with smoking equals or exceeds that of other addictive drugs, yet the euphoric, reinforcing and other psychological effects of nicotine, compared to these other drugs, are more subtle, are manifest under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence. One possible resolution to this apparent inconsistency is that environmental cues associated with drug delivery become conditioned reinforcers and take on powerful incentive properties that are critically important for sustaining smoking in humans and nicotine self-administration in animals. We tested this hypothesis by using a widely employed self-administration paradigm in which rats press a lever at high rates for 1 h/day to obtain intravenous infusions of nicotine that are paired with two types of visual stimuli: a chamber light that when turned on signals drug availability and a 1-s cue light that signals drug delivery. We show that these visual cues are at least as important as nicotine in sustaining a high rate of responding once self-administration has been established, in the degree to which withdrawing nicotine extinguishes the behavior, and in the reinstatement of lever pressing after extinction. Additional studies demonstrated that the importance of these cues was manifest under both fixed ratio and progressive ratio (PR) schedules of reinforcement. The possibility that nicotine-paired cues are as important as nicotine in smoking behavior should refocus our attention on the psychology and neurobiology of conditioned reinforcers in order to stimulate the development of more effective treatment programs for smoking cessation.

Animals↗

PubMed2001

Area postrema lesion alters the effects of peptide YY on 2-DG-stimulated pancreatic exocrine secretion.

Previously we demonstrated that circulating peptide YY (PYY), which inhibits pancreatic exocrine secretion, binds to specific receptors in the area postrema (AP); therefore we have tested the hypothesis that the removal of the AP (APX) will alter the effects of PYY on pancreatic secretion in awake rats. One-month after AP lesion or sham lesion, rats were implanted with pancreatic, biliary, duodenal, and intravenous catheters. After recovery from the surgery, unanesthetized rats were infused with vehicle or PYY (30 pmol/kg/hr or 100 pmol/kg/hr) under basal or 2-deoxy-D-glucose (2-DG) stimulated (75 mg/kg, intravenous bolus) conditions. PYY at 30 pmol/kg/hr inhibited basal pancreatic fluid secretion in sham-operated rats, but not APX rats. PYY at 100 pmol/kg/hr stimulated basal pancreatic protein secretion in sham-operated rats, and this effect was also lost in APX rats. PYY at 30 and 100 pmol/kg/hr inhibited peak 2-DG stimulated protein secretion to a greater extent in APX rats as compared to sham-operated rats (P < 0.05). Since PYY inhibition of basal pancreatic secretion is AP dependent and inhibition of 2-DG stimulated pancreatic secretion is AP independent, we conclude that the 2-DG pathway of pancreatic secretion differs from the pathway responsible for basal secretion, and that APX potentiates the inhibitory effect of PYY on the 2-DG pathway.

Animals↗

PubMed2001

Excitatory inputs to the RVLM in the context of the baroreceptor reflex.

The central neural circuit mediating baroreceptor control of sympathetic vasomotor outflow involves an excitatory projection from arterial baroreceptors to nucleus tractus solitarius, an excitatory projection from nucleus tractus solitarius to the caudal ventrolateral medulla, an inhibitory projection from the caudal ventrolateral medulla to the rostral ventrolateral medulla (RVLM), and an excitatory projection from the RVLM to sympathetic preganglionic neurons in the spinal cord. For this circuit to be operational, the relevant neurons in the RVLM must be tonically active. Indeed, numerous studies have demonstrated that RVLM vasomotor neurons are tonically active; however, little is known regarding the nature of the tonic excitatory drive to these neurons. We present a model in which RVLM vasomotor neurons are tonically excited by inputs to the RVLM that can be blocked by the excitatory amino acid receptor antagonist, kynurenic acid, as well as an input from the caudal ventrolateral medulla that is not sensitive to kynurenic acid.

Animals↗

PubMed2001

Acute hypertension inhibits thirst stimulated by ANG II, hyperosmolality, or hypovolemia in rats.

The present study sought to determine whether increases in arterial blood pressure inhibited drinking behavior evoked by ANG II, hyperosmolality, or hypovolemia in rats. Cumulative water intakes in 60- or 90-min tests and latency to the first lick were recorded as indexes of thirst. During intravenous infusions of 100 ng. kg(-1). min(-1) ANG II, attenuation of the induced increases in arterial pressure with the arteriolar vasodilator diazoxide resulted in greater water intakes and shorter latencies to drink. Drinking behavior stimulated by intravenous infusion of hypertonic saline was significantly inhibited by increases in arterial pressure caused by intravenous infusion of phenylephrine or endothelin-1, and this inhibition of drinking was proportional to the induced increase in pressure. Upon termination of the phenylephrine infusion, mean arterial pressure returned to basal values, and drinking was restored. Phenylephrine-induced increases in arterial pressure also inhibited drinking behavior in response to hypovolemia that could not be explained by differences in plasma renin activity, plasma protein concentration, or plasma osmolality. Thus increases in arterial pressure inhibit water drinking behavior in response to each of these three thirst stimuli in rats.

Acute Disease↗

PubMed2001

Oxytocin antagonist disrupts hypotension-evoked renin secretion and other responses in conscious rats.

Previous experiments have indicated that arterial hypotension increases plasma oxytocin (OT) levels in rats and that OT infused intravenously causes an increase in plasma renin activity (PRA). The goal of the present study was to determine whether systemic administration of an OT receptor antagonist would attenuate the increase in PRA that is normally evoked by arterial hypotension in rats. In conscious male rats, intravenous injection of hydralazine or diazoxide produced sustained hypotension and evoked a significant increase in PRA, as expected. Intravenous infusion of an OT receptor antagonist did not alter the hypotension induced by hydralazine or diazoxide, but it did markedly blunt the induced increase in PRA. The OT receptor antagonist also blunted the hypotension-evoked increase in heart rate and plasma vasopressin levels, suggesting that the antagonist may have generally disrupted afferent signaling of hypotension. Thus hypotension-evoked OT secretion may contribute to cardiovascular homeostasis by enhancing baroreceptor signals that stimulate increases in renin secretion, vasopressin secretion, and heart rate during arterial hypotension in rats.

Animals↗

PubMed2001

Osmoregulation in water-deprived rats drinking hypertonic saline: effect of area postrema lesions.

Rats drank rapidly when 0.3 M NaCl was the only drinking fluid available after overnight water deprivation, consuming approximately 200 ml/24 h. Although such large intakes of this hypertonic solution initially elevated plasma osmolality, excretion of comparable volumes of urine more concentrated than 300 meq Na(+)/l ultimately appears to restore plasma osmolality to normal levels. Rats drank approximately 100 ml of 0.5 M NaCl after overnight water deprivation, but urine Na(+) concentration (U(Na)) did not increase sufficiently to achieve osmoregulation. When an injected salt load exacerbated the initial dehydration caused by water deprivation, rats increased U(Na) to void the injected load and did not significantly alter 24-h intake of 0.3 or 0.5 M NaCl. Rats with lesions of area postrema had much higher saline intakes and lower U(Na) than did intact control rats; nonetheless, they appeared to osmoregulate well while drinking 0.3 M NaCl but not while drinking 0.5 M NaCl. Detailed analyses of drinking behavior by intact rats suggest that individual bouts were terminated by some rapid postabsorptive consequence of the ingested NaCl load that inhibited further NaCl intake, not by a fixed intake volume or number of licks that temporarily satiated thirst.

Animals↗

PubMed2001

PYY inhibits CCK-stimulated pancreatic secretion through the area postrema in unanesthetized rats.

Peptide YY (PYY) inhibits CCK-8-secretin-stimulated pancreatic secretion in vivo. To investigate whether CCK-8-secretin-stimulated pancreatic secretion is mediated through a vago-vagal pathway and whether PYY inhibits this pathway through the area postrema (AP), chronic pancreatic, biliary, and duodenal catheters were implanted in AP-lesioned (APX) or sham-operated rats. The effects of APX on pancreatic secretion stimulated by bethanechol, pancreatic juice diversion (PJD), or CCK-8-secretin, were tested, with and without background PYY infusion, in unanesthetized rats. APX reduced basal pancreatic secretion by 15-20% (P < 0.01). APX had no effect on bethanechol-stimulated secretion and potentiated protein secretion stimulated by PJD (396 vs. 284%) and exogenous CCK-8-secretin. In sham-operated rats, background PYY potently inhibited CCK-8-secretin-stimulated pancreatic fluid (1.8 vs. 48.2%) and protein secretion (3.7 vs. 45.8%) but potentiated fluid (52.9 vs. 43.1%) and protein (132.9 vs. 68.9%) secretion in APX rats. Our findings demonstrate that PYY inhibits CCK-8-secretin-stimulated pancreatic secretion through an AP-dependent mechanism in sham-operated rats. The AP also contributes to basal pancreatic secretion.

Animals↗

PubMed2001

Tonic excitatory input to the rostral ventrolateral medulla in Dahl salt-sensitive rats.

The goal of the present study was to test the hypothesis that the balance of tonic excitation and inhibition of vasomotor neurons in the rostral ventrolateral medulla (RVLM) driven by excitatory amino acid (EAA)-mediated inputs to the RVLM is shifted toward excitation in Dahl salt-sensitive (DS) rats compared with Dahl salt-resistant (DR) rats. Glutamate and the EAA antagonist kynurenic acid were microinjected into the RVLM of chloralose-anesthetized DS and DR rats maintained on diets containing either 0.3% NaCl or 8.0% NaCl. DS rats had a higher arterial pressure than DR rats, and this difference was greatly exaggerated by high dietary salt intake. Bilateral injection of kynurenic acid (2.7 nmol) into the RVLM decreased mean arterial pressure by 16+/-2 mm Hg in DS rats fed a diet containing 0.3% NaCl, and this effect was significantly larger in DS rats fed the high-salt diet (40+/-2 mm Hg). In contrast, injections of kynurenic acid into the RVLM did not significantly decrease arterial pressure in DR rats fed either diet. In DR rats, the pressor response elicited by the injection of glutamate into the RVLM was potentiated in rats fed the high-salt diet. The glutamate-evoked pressor response was greater in DS rats compared with DR rats, and the response in DS rats was not influenced by the salt content of the diet. These data suggest that tonically active EAA inputs to the RVLM may contribute to salt-sensitive hypertension in the Dahl model.

Animals↗

PubMed2001

Tonic excitatory input to the rostral ventrolateral medulla in Dahl salt-sensitive rats.

Analysis of Variance↗

PubMed2000

Differential effects of response-contingent and response-independent nicotine in rats.

Passive administration of nicotine activates the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system. However, little is known about the effects of self-administered nicotine. Drug-naive rats were trained to respond for food reinforcement and then tested in one, 1-h session in which they received response-contingent i.v. nicotine or response-independent i.v. nicotine or saline. Blood draws were taken immediately prior to the session, 15 min after the first infusion and immediately after the session. Both response-contingent and response-independent nicotine (RI/N) increased corticosterone within 15 min, however, corticosterone levels returned to baseline in animals receiving response-contingent nicotine (RC/N) by the end of the session while remaining elevated in those receiving RI/N. Furthermore, only RI/N increased plasma epinephrine and norepinephrine levels; RC/N produced no effect. These differences indicate that nicotine's acute effects are powerfully modified by the presence of a contingency relationship between drug administration and the animal's behavior and that this relationship develops very rapidly.

Animals↗

PubMed2000

Enhanced serotonin-mediated responses in the nucleus tractus solitarius of spontaneously hypertensive rats.

Previous studies have demonstrated that injection of serotonin into the nucleus tractus solitarius (NTS) elicits hypotension and bradycardia in rats. The present study sought to further characterize this response and to examine the role of serotonergic mechanisms in the NTS in cardiovascular regulation in spontaneously hypertensive (SHR) rats. Injections of picomole amounts of serotonin into the NTS of chloralose-anesthetized normotensive Sprague-Dawley (S-D) or Wistar-Kyoto (WKY) rats produced hypotension and bradycardia that were eliminated by prior injection into the NTS of the selective 5HT(2) antagonist sarpogrelate. Bilateral injection of sarpogrelate did not alter blood pressure or reflex changes in heart rate in response to phenylephrine-induced increases in blood pressure or nitroprusside-induced decreases in blood pressure. In SHR rats, the depressor response produced by injection of serotonin into the NTS was markedly larger than in WKY rats, and was larger than depressor responses previously reported for other excitatory substances injected into the NTS. In SHR rats bilateral injection of sarpogrelate produced an increase in blood pressure, although it did not alter baroreceptor-evoked changes in heart rate. These results provide further support for the hypothesis that stimulation of 5HT(2) receptors in the NTS contributes to cardiovascular regulation independent of the baroreceptor reflex. Furthermore, this serotonergic system is altered in SHR rats, apparently acting tonically to reduce blood pressure.

Animals↗

PubMed2000

Connections of Barrington's nucleus to the sympathetic nervous system in rats.

Barrington's nucleus (BN) has been considered a pontine center related exclusively to the control of pelvic parasympathetic activity. The present study demonstrates an anatomical linkage between BN and autonomic outflow to visceral targets innervated exclusively by the sympathetic division of the autonomic nervous system. Temporal analysis of infection after injection of pseudorabies virus (PRV), a retrograde transynaptic tracer, into two sympathetically innervated organs, the spleen and the kidney, revealed the presence of infected neurons in BN at early post-inoculation survival intervals. Immunohistochemical localization of PRV after spleen injections showed that a small subpopulation of BN neurons became labeled in a time frame coincident with the appearance of infected neurons in other brain regions known to project to sympathetic preganglionic neurons (SPNs) in the thoracic spinal cord; a larger number of infected neurons appeared in BN at intermediate intervals after PRV injections into the spleen or kidney. Coinjection of the retrograde tracer Fluoro-Gold i.p. and PRV into the spleen demonstrated that parasympathetic preganglionic neurons in the caudal medulla or lumbo-sacral spinal cord were not infected, indicating that infected BN neurons were not infected via a parasympathetic route. Thus, BN neurons become infected after PRV injections into the spleen or kidney either directly through BN projections to SPNs, or secondarily via BN projections to infected pre-preganglionic neurons. These results demonstrate an anatomical linkage, either direct or indirect, between BN and sympathetic activity. Because BN receives numerous inputs from diverse brain regions, the relation of BN with both branches of the autonomic nervous system suggests that this nucleus might play a role in the integration of supraspinal inputs relevant to the central coordination of sympathetic and parasympathetic activity.

Animals↗

PubMed2000

Analysis of tyrosine hydroxylase gene transcription using an intron specific probe.

The nuclear run-on assay is the most commonly used technique to determine transcription rates of specific genes such as tyrosine hydroxylase. Its application to studies in the nervous system is problematic, however, as a result of limitations in sensitivity and the loss of anatomical integrity. We observed that the relative levels of tyrosine hydroxylase intron 2-containing RNA using a ribonuclease protection assay in the adrenal medulla changed in response to pharmacological treatments consistently with changes shown by the nuclear run-on assay. Our results indicate that measures of tyrosine hydroxylase primary transcript levels offer an alternative to the nuclear run-on assay and validate the application of intron-specific in situ hybridization as a means of assessing the relative transcriptional activity of the tyrosine hydroxylase gene. Similar quantitative results were obtained using intron-specific in situ hybridization with oligonucleotide probes specific for rat tyrosine hydroxylase intron 2. Furthermore, we observed that intron-specific in situ hybridization could be used to measure tyrosine hydroxylase transcription rates in the locus coeruleus, providing resolution at the level of single neurons. Thus, measuring the levels of tyrosine hydroxylase intron 2 provides a sensitive measure of tyrosine hydroxylase transcription rate that can be applied to the study of brain catecholaminergic neurons.

Adrenal Medulla↗

PubMed2000

Baroreflex dependent and independent roles of the caudal ventrolateral medulla in cardiovascular regulation.

The caudal ventrolateral medulla (CVLM) plays a critical role in cardiovascular regulation. Convincing data now support the hypothesis that inhibition of sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM) by CVLM neurons constitutes the necessary inhibitory link in baroreceptor reflex mediated control of sympathetic vasomotor outflow. Inhibition or destruction of the CVLM produces severe acute hypertension, consistent with blockade of baroreceptor reflexes and withdrawal of inhibition of RVLM sympathoexcitatory neurons. However, other data indicate that the CVLM also tonically inhibits RVLM sympathoexcitatory neurons in a manner not driven by baroreceptor input. In some studies, inhibition of the CVLM results in an increase in arterial pressure (AP) without inhibiting baroreceptor reflexes, possibly reflecting baroreceptor-independent and baroreceptor-dependent sub-regions of the CVLM. Furthermore, in baroreceptor-denervated rats, inhibition of the CVLM still leads to large increases in AP. In addition, in spontaneously hypertensive rats (SHR) central processing of baroreceptor reflexes appears normal but CVLM-mediated inhibition of the RVLM seems to be attenuated, suggesting that it is specifically a baroreceptor-independent mechanism of cardiovascular regulation in SHR that is altered. Taken together, these findings support an important, tonic, baroreceptor-independent inhibition of RVLM sympathoexcitatory neurons exerted by the CVLM.

Animals↗

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↗