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At least 649 records · Page 36Linked to original sources
PubMed2000

Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus.

The present study examined the regional localization of corticotropin-releasing factor (CRF)- and 5-hydroxytryptamine (5-HT)-immunoreactive (IR) fibers within the rat dorsal raphe nucleus (DRN) using immunohistochemistry. Additionally, the effects of CRF, administered intracerebroventricularly (0.1-3.0 micrograms) or intraraphe (0.3-30 ng), on discharge rates of putative 5-HT DRN neurons were quantified using in vivo single unit recording in halothane-anesthetized rats. CRF-IR fibers were present at all rostrocaudal levels of the DRN and exhibited a topographical distribution. CRF produced predominantly inhibitory effects on DRN discharge at lower doses and these effects diminished or became excitatory at higher doses. Inhibition of DRN discharge by CRF was attenuated by the nonselective CRF antagonist, DPheCRF12-41 and the CRF-R1-selective antagonist, antalarmin, implicating the CRF-R1 receptor subtype in these electrophysiological effects. The present findings provide anatomical and physiological evidence for an impact of CRF on the DRN-5HT system.

Animals↗
PubMed1986

Transmitter-replacement therapy in Alzheimer's disease using intracerebroventricular infusions of receptor agonists.

Neurotransmitter replacement therapy in Alzheimer's Disease is currently being attempted using bethanechol chloride (Urecholine) infused intracerebroventricularly with an Infusaid continuous infusion pump. The rationale of this therapy is based on the severe cortical pre-synaptic cholinergic deficit in the presence of relatively normal post-synaptic muscarinic receptor density. Patients are selected on the basis of strict clinical criteria at a functional stage 4 or 5 of Reisberg. A cortical biopsy at the time of pump and catheter implantation confirms the diagnosis by histological and biochemical examination. Pre-operative, post-operative and serial mental status assessments combined with functional ADL assessments monitor changes in behavior. A 6 months double-blind treatment period is done in every patient, who is then free to continue if he has improved on active treatment. This specific study is part of a multi-centre trial. Other therapeutic trials using somatostatin analogs, such as Sandostatin, could then be done. The biological effects of the latter compound are being studied currently in adult Green Vervet monkeys, prior to its use in Alzheimer patients. Furthermore autoradiography of bethanechol and peptides labeled with 14C administered in these animals by intracerebroventricular infusion will allow a better knowledge of their pharmacological site of action.

Alzheimer Disease↗
PubMed1997

Microdialysis studies of the distribution of stavudine into the central nervous system in the freely-moving rat.

PURPOSE: To study the extent and time course of distribution of stavudine (d4T) into the central nervous system (CNS) and to investigate the transport mechanisms of antiviral nucleosides in the CNS. METHODS: Microdialysis with on-line HPLC analysis was used to measure drug concentrations in the brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) in the freely-moving rat. The in vivo recovery of d4T and zidovudine (AZT) was estimated by retrodialysis, which was validated by the zero-net flux method. The CNS distribution of d4T was investigated during iv and intracerebroventricular (icv) infusion. In the subsequent studies, the effect of AZT on CNS distribution of d4T was examined. RESULTS: During iv infusion, d4T distributed rapidly into the CNS. Its brain ECF/plasma and CSF/plasma steady-state concentration ratios were 0.33 +/- 0.06 and 0.49 +/- 0.12, respectively (n = 15). During icv infusion, the steady-state d4T concentrations in the brain ECF were 23-fold higher than those during iv infusion, whereas its steady-state plasma levels were about the same for these two routes. Coadministration of AZT with d4T did not alter their respective brain distribution and systemic clearance at the concentrations examined. More importantly, the steady-state brain ECF/plasma and CSF/plasma concentration ratios of d4T were about 2-fold higher than those of AZT (0.15 +/- 0.04 and 0.25 +/- 0.08) determined in the same animals. CONCLUSIONS: d4T readily crosses the blood-brain barrier (BBB) and blood-CSF barrier. An active efflux transport system in the BBB and blood-CSF barrier may be involved in transporting d4T out of the CNS. Direct icv administration of d4T can be used to enhance its brain delivery. Moreover, d4T exhibits a more favorable penetration into the CNS than AZT and therefore may be useful in the treatment of AIDS dementia complex.

Animals↗
PubMed2002

Subcellular biodistribution of sodium borocaptate (BSH: Na2B12H11SH) in a rat glioma model in boron neutron capture therapy.

Mercaptoundecahydrododecaborate (Na2B12H111SH, sodium borocaptate or 'BSH') has been used clinically as a boron compound for boron neutron capture therapy (BNCT) in patients with malignant glioma in Japan and Europe. Boron-10 is known to accumulate selectively only in brain tumor cells. This work was aimed to clarify the subcellular biodistribution of BSH in a rat glioma model using immunohistochemical approach. Wistar rats were used for this experiment. An intracerebral injection of 5.0 x 10(6) C6 glioma cells was introduced into the region of cerebral hemisphere. Fifty milligrams of "'B/kg BSH was infused intravenously two weeks after implantation. Host rats were divided into six groups according to the sampling time: 1, 4, 8, 16, 24 and 48 h after the start of BSH infusion. Immunohistochemical study was carried out using anti-BSH antibody. Boron was already found in a whole cell 1 h after BSH infusion, and then seemed to collect in a cell nuclei around 8-16 h after infusion. It was still recognized in tumor cell 48 h after infusion. This study supports the following hypothesis on selective boron uptake in a tumor. BSH can pass through the disrupted blood-brain barrier (BBB) easily and can come in contact with tumor cells; there, BSH can bind on the extracellular surface of plasma membrane to choline residues. After binding to the plasma membrane, boron with choline residues may be internalized into the cell by endocytic pathways and eventually travel to cell nuclei, and then stay there for a long time.

Animals↗
PubMed1994

Effects of central losartan on plasma renin and centrally mediated natriuresis.

Because intracerebroventricular (ICV) infusion of hypertonic saline or angiotensin II (Ang II) both induce water drinking, vasopressin secretion, natriuresis and increased arterial pressure, the possibility that common neural pathways mediate responses to ICV Ang II and hypertonic saline has been investigated. This was done by testing the effect of ICV infusion of the Ang II antagonist losartan on the natriuretic and pressor responses to ICV hypertonic NaCl in sheep. The effect of ICV losartan on plasma renin concentration (PRC) was also investigated. Infusion of losartan (1 mg/hr) into a lateral ventricle prevented both natriuretic and pressor responses to infusion of 0.6 mol/liter NaCl into a lateral ventricle at 1 ml/hr. In another experiment, ICV losartan at 1 mg/hr caused a pronounced increase in the PRC of Na-depleted sheep, while ICV Ang II at 3 micrograms/hr decreased PRC. The results suggest that: (i) a central angiotensinergic pathway may mediate osmoregulatory responses to centrally administered hypertonic saline, and (ii) a central angiotensinergic pathway may have a tonic inhibitory influence on renin secretion in Na-depleted animals.

Angiotensin II↗
PubMed2006

Disruption of prepulse inhibition after stimulation of central but not peripheral alpha-1 adrenergic receptors.

Prepulse inhibition (PPI) refers to the attenuation of startle when a weak prestimulus precedes the startling stimulus. PPI is deficient in several psychiatric illnesses involving poor sensorimotor gating. Previous studies indicate that alpha1 adrenergic receptors regulate PPI, yet the extent to which these effects are mediated by central vs peripheral receptors is unclear. The present studies compared the effects of intracerebroventricular (ICV) vs intraperitoneal (IP) delivery of several alpha1 receptor agonists on PPI. Male Sprague-Dawley rats received either cirazoline (0, 10, 25, 50 microg/5 microl), methoxamine (0, 30, 100 microg/5 microl), or phenylephrine (0, 3, 10, 30 microg/5 microl) ICV immediately before testing. Separate groups received either cirazoline (0, 0.25, 0.50, 0.75 mg/kg), methoxamine (0, 2, 5, 10 mg/kg), or phenylephrine (0, 0.1, 2.0 mg/kg) IP 5 min before testing. PPI, baseline startle responses, and piloerection, an index of autonomic arousal, were measured. Cirazoline disrupted PPI; effective ICV doses were approximately six times lower than effective IP doses. Methoxamine disrupted PPI after ICV infusion but failed to affect PPI with IP doses that were up to 30-fold higher than the effective ICV dose. Phenylephrine disrupted PPI with ICV administration, but did not alter PPI after IP injection of even a 20-fold higher dose. None of the ICV treatments altered baseline startle magnitude, but phenylephrine and methoxamine lowered startle after administration of high systemic doses. Piloerection was induced by cirazoline via either route of administration, and by IP methoxamine and phenylephrine, but not by ICV infusion of methoxamine or phenylephrine. These findings indicate that alpha1 receptor-mediated PPI disruption occurs exclusively through stimulation of central receptors and is dissociable from alterations in baseline startle or autonomic effects.

Acoustic Stimulation↗
PubMed1989

Evidence that intravenous morphine stimulates central opiate receptors to increase sympatho-adrenal outflow and cause hypertension in conscious rabbits.

1. In conscious rabbits, intravenous morphine caused hypertension, bradycardia, hyperglycaemia and increased plasma adrenaline and noradrenaline. These effects were prevented by ganglionic blockade with pentolinium. 2. The cardiovascular responses to morphine were not altered by pretreatment with a vasopressin V1-receptor antagonist. 3. After bilateral adrenalectomy morphine caused a similar rise in noradrenaline but no increase in adrenaline. The rise in blood pressure was attenuated and the hyperglycaemia was abolished. 4. Adrenaline infused intravenously to mimic the levels that occurred after morphine caused a similar degree of hyperglycaemia but only a small increase in blood pressure. 5. Pretreatment with intracerebroventricular naloxone prevented the morphine-induced hypertension, hyperglycaemia, increase in plasma catecholamines, respiratory depression and sedation. 6. These results demonstrate that, in conscious rabbits, intravenous morphine causes hypertension by increasing sympathetic vasoconstrictor nerve activity and elevating plasma adrenaline levels; the latter alone produces the hyperglycaemia. Vasopressin release is not involved in the hypertensive response to morphine. The effects of morphine appear to result from stimulation of central opiate receptors leading to enhanced sympathoadrenal outflow.

Adrenalectomy↗
PubMed1996

Effect of CRH on the preovulatory LH and FSH surge in the cyclic rat: a role for arginine vasopressin?

The effect of intracerebroventricular (i.c.v.) injection or infusion of various doses of corticotropin-releasing hormone (CRH) on the LH and FSH surge was studied in pro-oestrous rats supplied with a jugular vein and an i.c.v. cannula. Additionally, we investigated if arginine vasopressin (AVP) was involved in the CRH-induced alterations to the surge of gonadotropins. I.c.v. injection of 10 micrograms CRH given 5 min before the presumed onset of the LH surge caused a strong inhibition of the LH surge and a slight inhibition of the FSH surge. Three to four h after CRH injection, its inhibitory effect diminished. A 6'h i.c.v. infusion of CRH started 1 h before the presumed onset of the LH surge, caused a dose-related inhibition of the LH and FSH surge. Infusion of 1 micrograms/h CRH did not suppress the surge of both hormones while infusion of 5 or 10 micrograms/h CRH inhibited the LH surge. Infusion of 10 micrograms/h CRH caused a strong suppression of plasma LH during the first 3 h of the LH surge. Despite continuation of CRH infusion, the inhibitory effect disappeared and plasma LH increased to similar levels as in controls at corresponding points of time of the LH surge. The FSH surge was also suppressed by infusion of 10 micrograms/h CRH. The surge of LH and FSH was not affected by a 9-h infusion of 10 micrograms/h CRH started 4 h before the presumed onset of the LH surge. This observation also indicates that the inhibitory effect of CRH may last for only 3-4 h. The surge of LH and FSH was not affected by i.c.v. injections of AVP-antiserum. However, pretreatment with AVP-antiserum prolonged the inhibitory effect of CRH on the LH surge. In conclusion, CRH can inhibit the pro-oestrous LH and to a lesser extent the FSH rise for only 3-4 h after the beginning of CRH administration. AVP may play a role in limiting the inhibitory effect of CRH on LH to 3-4 h.

Animals↗
PubMed2000

Dexmedetomidine and haemodynamic responses to acute central hypovolaemia in conscious rabbits.

1. Effects of the alpha2-adrenoceptor agonist dexmedetomidine on vasoconstrictor and heart rate (HR) responses to acute central hypovolaemia were studied in eight chronically instrumented rabbits. We compared intravenous (i.v.) and fourth ventricular (V4) dexmedetomidine (0.1-10 microg/kg) and the reversal of effects by the alpha2-adrenoceptor antagonist idazoxan and the opioid agonist alfentanil. 2. Gradual inflation of an inferior vena cava (IVC) cuff reduced cardiac index (CI) by 8%/min, with progressive vasoconstriction and increased HR. In control rabbits, at approximately 40% baseline CI, there was sudden decompensation with failure of vasoconstriction and a fall in mean arterial pressure (MAP). 3. Dexmedetomidine (i.v. and V4) reduced resting MAP and HR and caused an earlier decompensation during central hypovolaemia. Intravenous dexmedetomidine (3 and 10 microg/kg) also reduced the slope of the initial vasoconstrictor response and the maximum HR. 4. The effects of dexmedetomidine were reversed by the antagonist idazoxan, which prevented the decompensation phase. Intravenous alfentanil was also effective in restoring the vasoconstrictor response and delaying decompensation with hypovolaemia after dexmedetomidine. Combining dexmedetomidine with an opioid, such as alfentanil, may provide the benefit of reduced sympathetic tone without increased risk of cardiovascular collapse.

Acute Disease↗
PubMed2002

Dendroaspis natriuretic peptide administered intracerebroventricularly increases renal water excretion.

1. The effects of intracerebroventricular (i.c.v.) infusion of Dendroaspis natriuretic peptide (DNP) on renal function were examined in anaesthetized rats. The results were compared with those obtained following intravenous (i.v.) infusion of the same dose of DNP. 2. Urine volume was increased four- to six-fold over basal values by i.c.v. infusion of DNP (6 pmol/min). Urine osmolality was decreased, whereas sodium excretion was not significantly altered. Intravenous infusion of the same dose of DNP had little effect on urinary water excretion. Neither arterial pressure nor heart rate was changed significantly by either i.v. or i.c.v. infusion of DNP. Glomerular filtration rate, measured by creatinine clearance, remained unaltered. 3. The diuretic response to i.c.v. DNP was markedly attenuated in rats that were deprived of their water supply for 3 days before the experiment. 4. These results suggest that DNP can act within the central nervous system to increase renal water excretion.

Animals↗
PubMed1998

Stimulation of neuropeptide Y overflow in the rat paraventricular nucleus by corticotropin-releasing factor.

Neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) are present at high concentrations in the hypothalamus where they mediate important endocrine and autonomic functions. Morphological and physiological studies have suggested an interaction between these peptides, and opposing actions of CRF and NPY have been reported on feeding and other behaviors. This study investigated the effect of CRF on NPY release in vivo, measured by push-pull techniques, in the anesthetized rat. Push-pull probes implanted into the paraventricular nucleus of the hypothalamus (PVN) were perfused with modified Ringer solution containing bovine serum albumin at 15 microl/min, and the perfusate was lyophilized prior to NPY radioimmunoassay. NPY overflow from the rat PVN was increased threefold by perfusion of a depolarizing concentration of potassium (50 mmol/L KCl). When CRF was administered into the PVN via the push-pull cannula at 1 or 5 microg/ml, dose-dependent increases in NPY overflow of two- and fivefold were observed (p < 0.05). These increases were abolished by prior intracerebroventricular (i.c.v.) administration of the CRF antagonist [D-Phe12,Nle(21,38),C(alpha)MeLeu32]CRF (12-41) at 1 or 5 microg/microl, respectively. NPY overflow returned promptly to resting levels following CRF administration. In contrast, when CRF was administered by i.c.v. bolus at a similar total dose (2 microg), no significant effect on NPY overflow was observed. These data provide in vivo evidence for an interaction between CRF and NPY at the level of the PVN.

Animals↗
PubMed2004

Rat brain arachidonic acid metabolism is increased by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide.

In a rat model of acute neuroinflammation, produced by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide (LPS), we measured brain activities and protein levels of three phospholipases A2 (PLA2) and of cyclo-oxygenase-1 and -2, and quantified other aspects of brain phospholipid and fatty acid metabolism. The 6-day intracerebral ventricular infusion increased lectin-reactive microglia in the cerebral ventricles, pia mater, and the glial membrane of the cortex and resulted in morphological changes of glial fibrillary acidic protein (GFAP)-positive astrocytes in the cortical mantel and areas surrounding the cerebral ventricles. LPS infusion increased brain cytosolic and secretory PLA2 activities by 71% and 47%, respectively, as well as the brain concentrations of non-esterified linoleic and arachidonic acids, and of prostaglandins E2 and D2. LPS infusion also increased rates of incorporation and turnover of arachidonic acid in phosphatidylethanolamine, plasmenylethanolamine, phosphatidylcholine, and plasmenylcholine by 1.5- to 2.8-fold, without changing these rates in phosphatidylserine or phosphatidylinositol. These observations suggest that selective alterations in brain arachidonic acid metabolism involving cytosolic and secretory PLA2 contribute to early pathology in neuroinflammation.

Animals↗
PubMed1991

Inhibition of sleep in rats by inorganic selenium compounds, inhibitors of prostaglandin D synthase.

Prostaglandin (PG) D2 has been postulated to be an endogenous sleep-promoting factor in rats, and SeCl4 and Na2SeO3 recently have been shown to inhibit the PGD synthase (prostaglandin-H2 D-isomerase, EC 5.3.99.2) activity of rat brain. The effect of these selenium compounds on sleep-wake activities was examined in freely moving rats along with their effects on brain temperature, food and water intake, and behavior. Test substances were administered for 6 hr into the third ventricle of rats, using a microdialysis technique. SeCl4, time- and dose-dependently, inhibited sleep at perfusion rates of 60 pmol/0.2 microliter per min and higher, and the inhibition was almost complete at rates greater than 200 pmol/0.2 microliter per min. The effect was reversible and was followed by a rebound. Na2SeO3 exhibited similar effects, but Na2SO3 did not show any effect on sleep. Simultaneous administration of dithiothreitol eliminated the sleep-inhibiting effects of these selenium compounds. These findings indicate that the decrease in sleep is due to inhibition of the PGD synthase activity in the brain by SeCl4 as well as Na2SeO3. During the inhibition of sleep, the rats in general showed an activation of behavior with moderate elevation of brain temperature and a detectable increase in food and water intake, suggesting that the sleep-inhibited state of the rats was similar to the physiological state of wakefulness and that the inhibitory effect was not due to the general toxicity of selenium.

Animals↗
PubMed1996

Corticotropin-releasing factor-binding protein ligand inhibitor blunts excessive weight gain in genetically obese Zucker rats and rats during nicotine withdrawal.

Elevation of the neuropeptide corticotropin-releasing factor (CRF) in the brain is associated with a reduction of food intake and body weight gain in normal and obese animals. A protein that binds CRF and the related peptide, urocortin, with high affinity, CRF-binding protein (CRF-BP), may play a role in energy homeostasis by inactivating members of this peptide family in ingestive and metabolic regulatory brain regions. Intracerebroventricular administration in rats of the high-affinity CRF-BP ligand inhibitor, rat/human CRF (6-33), which dissociates CRF or urocortin from CRF-BP and increases endogenous brain levels of "free" CRF or urocortin significantly blunted exaggerated weight gain in Zucker obese subjects and in animals withdrawn from chronic nicotine. Chronic administration of CRF suppressed weight gain nonselectively by 60% in both Zucker obese and lean control rats, whereas CRF-BP ligand inhibitor treatment significantly reduced weight gain in obese subjects, without altering weight gain in lean control subjects. Nicotine abstinent subjects, but not nicotine-naive controls, experienced a 35% appetite suppression and a 25% weight gain reduction following acute and chronic administration, respectively, of CRF-BP ligand inhibitor. In marked contrast to the effects of a CRF-receptor agonist, the CRF-BP ligand inhibitor did not stimulate adrenocorticotropic hormone secretion or elevate heart rate and blood pressure. These results provide support for the hypothesis that the CRF-BP may function within the brain to limit selected actions of CRF and/or urocortin. Furthermore, CRF-BP may represent a novel and functionally selective target for the symptomatic treatment of excessive weight gain associated with obesity of multiple etiology.

Animals↗
PubMed1990

Intracerebroventricular infusion but not bolus injection of vasopressin increases the cerebrospinal fluid pressure in awake rabbits.

The effect of intracerebroventricular infusion or injection of arginine vasopressin (AVP) was examined in awake rabbits with permanent ventricular cannulae. Intracerebroventricular infusion of artificial cerebrospinal fluid (CSF) 43 microliters min-1 containing AVP concentrations exceeding 0.4 ng ml-1, equivalent to an AVP infusion rate of 17.2 pg min-1, caused a dose-dependent increase in intracranial pressure (ICP) of 3 to 5 mmHg after 30-50 min of AVP infusion. Intracerebroventricular bolus injection of equivalent doses of AVP did not provoke changes in ICP. At the end of the experiments cisternal CSF concentrations of AVP were higher after infusion of AVP than after injection of the same amount of AVP. The mean arterial blood pressure increased slightly in the group of animals infused with AVP at rates above 17.2 pg min-1. It is concluded that intracerebroventricular infusion of AVP increases ICP in awake rabbits but the mechanism responsible for the elevation of ICP remains speculative.

Animals↗
PubMed1980

Central pyrogenic activity of muramyl dipeptide.

Fever can be elicited in the rabbit by the intravenous administration of relatively large doses of a synthetic immunoadjuvant, N-acetylmuramyl-L-alanyl-D-isoglutamine, or muramyl dipeptide (MDP). This response could be mediated by endogenous pyrogen because MDP has been shown to induce their production both in vivo and in vitro. The results reported here show that intracisternal injection of minute amounts of MDP could elevate fever without activating the release of endogenous pyrogen in the plasma or in the cerebrospinal fluid. Moreover, indomethacin inhibited hyperthermia produced by intracerebroventricular administration of MDP. Therefore, our findings argue in favor of a direct effect of the glycopeptide on the thermoregulatory centers besides its indirect effect through the production of leukocytic pyrogen. This molecule apparently represents the minimal requirement for the pyrogenicity of bacterial peptidoglycan because administration, even by the intracerebral route, of a mixture of muramic acid and of its dipeptide moiety did not elicit fever.

Acetylmuramyl-Alanyl-Isoglutamine↗