Effects of estrogen on acetylcholine release in frontal cortex of female rats: involvement of serotonergic neuronal systems

The effects of estrogen on cortically projecting cholinergic neurons were investigated using in vivo microdialysis to measure cortical basal acetylcholine (ACh) levels and serotonin (5-HT)-stimulated ACh release in frontal cortex of freely moving Wistar female rats. Bilateral ovariectomy (OVX) or sham operations were performed under anesthesia. Immediately after surgery, each OVX animal was subcutaneously implanted with pellet containing 0.1/0.5 mg of 17beta-estradiol (E(2)) or a vehicle. Nineteen days later, a transverse microdialysis probe was stereotaxically implanted in the frontal cortex (AP: +2.7 mm, DV: -2.5 mm relative to bregma). Two days later (21 days after beginning of estrogen treatment), in vivo microdialysis experimentation was conducted. Serum E(2) levels of animals with 0.1 and 0.5 mg-pellets were equivalent to those levels during diestrous and proestrous, respectively. Although the replacement of different amounts of E(2) produced significant changes in body weight, it failed to affect basal ACh levels in the frontal cortex. Systemically administered serotonin releasing agent, fenfluramine, significantly increased cortical ACh release in all animal groups. The fenfluramine's ability to increase ACh release was potentiated by E(2) replacement with a 0.5 mg-pellet. E(2)-induced enhancement was also observed when the selective 5-HT(1A) agonist, 8-hydroxy-2-(di-n-propylamino) tetralin, but not the 5-HT(2A/2C) agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, was administered. Therefore, the effect of estrogen on 5-HT-stimulated ACh release might be exerted partly via 5-HT(1A) receptors, and not via 5-HT(2) receptors. These results suggest that the positive effects of estrogen on cognitive functions might be mediated through the ACh-5-HT interactions.     

Selective suppression of hippocampal region hyperexcitability related to seizure susceptibility in epileptic El mice by the GABA-transporter inhibitor tiagabine

High seizure susceptibility in El mice is associated with disinhibition in the dentate gyrus (DG) and paired-pulse facilitation in the CA3 area in hippocampal slices [Brain Res. 745 (1997) 165; Brain Res. 779 (1998) 324]. A decrease in gamma-aminobutyric acid (GABA)-mediated inhibition and an increase in excitatory inputs to the major neurons seem to be the responsible mechanisms, respectively, for these phenomena. In this study, we examined the effects of tiagabine, an inhibitor of GABA transporter, on hyperexcitation in vivo and in slice preparations. Tiagabine (0.3-0.5 mg/kg) suppressed the occurrence of seizures to about 20% of controls with an ED(50) value of about 0.17 mg/kg. In addition, perfusion of hippocampal slices with tiagabine (20 microM) counteracted the paired-pulse facilitation in the CA3 region over the entire range of interpulse intervals (P<0.05, two-way ANOVA) and reduced the disinhibition in the DG measured at 10 and 20 ms during short interpulse intervals (P<0.005, paired t-test). The CA1 region in the El mice, as well as in a non-epileptic parental strain of ddY mice did not respond to the drug. However, frequency potentiation of CA3 was enhanced in both strains (P<0.05, paired t-test). Our results suggest that within the hippocampus the antiepileptic action of tiagabine is selectively suppressive for hyperexcitability of DG and CA3, which are responsible for seizure-susceptibility in El mice.     

Adenosine triphosphate accelerates recovery from hypoxic/hypoglycemic perturbation of guinea pig hippocampal neurotransmission via a P(2) receptor

The present study was designed to assess the effects of adenosine triphosphate (ATP) on hippocampal neurotransmissions under the normal and hypoxic/hypoglycemic conditions. ATP reversely depressed population spikes (PSs), which were monitored in the dentate gyrus of guinea pig hippocampal slices, in a dose-dependent manner at concentrations ranged from 0.1 micro M to 1 mM. A similar depression was obtained with the P(2) receptor agonist, alpha,beta-methylene ATP (alpha,beta-MeATP), and the effect was inhibited by the P(2) receptor antagonists, suramin and PPADS. The inhibitory action of ATP or alpha,beta-MeATP was inhibited by the gamma-aminobutyric acid(A) (GABA(A)) receptor antagonist, bicuculline, but it was not affected by theophylline, a broad inhibitor of adenosine (P(1)) receptors, tetraethylammonium, a broad inhibitor of K(+) channels, or ecto-protein kinase inhibitors. ATP or alpha,beta-MeATP enhanced GABA release from guinea pig hippocampal slices, that was inhibited by deleting extracellular Ca(2+) or in the presence of tetrodotoxin, while ATP had no effect on GABA release from cultured rat hippocampal astrocytes or postsynaptic GABA-gated channel currents in cultured rat hippocampal neurons. Twenty-minutes deprivation of glucose and oxygen from extracellular solution abolished PSs, the amplitude recovering to about 30% of basal levels 50 min after returning to normal conditions. ATP or alpha,beta-MeATP accelerated the recovery after hypoxic/hypoglycemic insult (approximately 80% of basal levels). Adenosine diphosphate and adenosine monophosphate accelerated the recovery, but to a much lesser extent, and adenosine had no effect. The results of the present study thus suggest that ATP inhibits neuronal activity by enhancing neuronal GABA release via a P(2) receptor, perhaps a P2X receptor, thereby protecting against hypoxic/hypoglycemic perturbation of hippocampal neurotransmission.     

Activation of hypothalamic angiotensin receptors produces pressor responses via cholinergic inputs to the rostral ventrolateral medulla in normotensive and hypertensive rats

We have previously reported that the angiotensin system in the anterior hypothalamic area (AHA) is enhanced in spontaneously hypertensive rats (SHR) and that this enhancement is involved in hypertension in SHR. In addition, acetylcholine (ACh) release is increased in the rostral ventrolateral medulla (RVLM) of SHR, which has also been shown to be involved in hypertension in SHR. In this study, we examined whether the enhanced angiotensin system in the AHA of SHR is related to the increase in cholinergic inputs to the RVLM. Electrical stimulation in the AHA produced a pressor response and an increase in firing rate of RVLM barosensitive neurons. These responses were inhibited and enhanced by RVLM application of the muscarinic receptor antagonist scopolamine and the cholinesterase inhibitor physostigmine, respectively. AHA stimulation also produced release of ACh in the RVLM. Microinjections of angiotensin II and carbachol into the AHA produced pressor responses. The pressor response to angiotensin II was inhibited by scopolamine microinjected into the RVLM, although this produced no effect on the response to carbachol. In SHR, although not in Wistar-Kyoto rats, microinjection of losartan into the AHA inhibited pressor responses to physostigmine. However inhibition was not observed in response to the directly acting muscarinic receptor agonist carbachol, injected into the RVLM. These findings demonstrate that angiotensin receptor activation or electrical stimulation in the AHA produce a pressor response via an increase in ACh release in the RVLM. In addition, the present study suggests that the enhanced angiotensin system in the AHA of SHR increases cholinergic inputs to the RVLM, which leads to increases in blood pressure.     

The anti-dementia drug FK960 stimulates glial glutamate release via a PKA pathway

The present study was conducted to understand the mechanism underlying the facilitatory action of FK960, an anti-dementia drug, on hippocampal neurotransmission. FK960 facilitated hippocampal neurotransmission in normal mice, and also in mice lacking the glial glutamate transporter, GLT-1 (glut-1(-/-)), but to a lesser extent. FK960 enhanced glutamate release from cultured hippocampal astrocytes from normal rats and mice, while the drug had no effect on the release from cultured rat hippocampal neurons. The glutamate release was still obtained with cultured hippocampal astrocytes from glut-1(-/-) mice, suggesting that the release is not due to GLT-1-mediated counter transport of glutamate. The FK960 action was inhibited by H-89, a selective inhibitor of cAMP-dependent protein kinase (PKA), bafilomycin A1, an inhibitor of vesicular transport, or BAPTA-AM, a chelator of intracellular Ca(2+). FK960 caused an increase in intracellular Ca(2+) concentrations by stored Ca(2+) release in cultured rat hippocampal astrocytes, and H-89 abolished the increase. Forskolin, a PKA activator, mimicked the effect of FK960 on intracellular Ca(2+) mobilizations. Taken together, it appears that FK960 stimulates glutamate release from astrocytes, likely as a result of raising intracellular Ca(2+) concentrations via a PKA pathway. The FK960 action would increase synaptic glutamate concentrations, in part responsible for the facilitation of hippocampal neurotransmission. The results of the present study may provide a new idea that agents targeting astrocytes could serve as anti-dementia drugs.     

Association between -1438G/A promoter polymorphism in the 5-HT(2A) receptor gene and fluvoxamine response in Japanese patients with major depressive disorder

Genetic polymorphism of the serotonin 5-HT(2A) receptor seems to be associated with therapeutic response to selective serotonin reuptake inhibitors (SSRIs). The present study investigated whether a novel -1438G/A polymorphism in the promoter region of the 5-HT(2A )receptor gene is associated with therapeutic response to fluvoxamine (an SSRI) in 66 Japanese patients with major depressive disorder. Fluvoxamine (50 to 200 mg) was administered twice daily for 6 weeks. Fifty-four patients completed this study. The genotype distribution and the allele frequencies showed no significant difference between responders and non-responders. The time-course of the Montgomery-Asberg Depression Rating Scale scores showed no significant difference among -1438G/G, -1438G/A, and -1438A/A genotype groups. The results demonstrated that the -1438G/A promoter polymorphism in the 5-HT(2A) receptor gene was unlikely to have a major role in therapeutic response to fluvoxamine in Japanese patients with major depressive disorder.     

A case of intracoronary stent implanted for acute myocardial infarction in an elderly patient with idiopathic thrombocytopenic purpura

A 68-year-old woman with idiopathic thrombocytopenic purpura (ITP) was admitted to our hospital with acute myocardial infarction on 7 February 1999. She had been treated since 1991 for mitral stenosis and regurgitation, atrial fibrillation due to mitralism, diabetes mellitus, hypertension, hyperlipidemia. Chest radiograph on admission showed cardiomegaly with congestion and cardiothoracic ratio was 63%. The platelet count on admission was 22,000/microliter, but she did not have petechia or purpura. Urgent coronary angiography revealed total occlusion in segment 7, and 13 and 75% stenosis in segment 4PD, 9 and 10. Subsequently, direct percutaneous transluminal coronary angioplasty (PTCA) was performed in segment 7. Dissection occurred during the intervention, and a coronary stent was implanted, we started heparin infusion and medication with ticlopidine hydrochloride as post-stenting therapy after the intervention, and there was no bleeding tendency.     

Early diagnosis and radical surgical treatment of Budd-Chiari syndrome

We report a 26-year-old woman who was diagnosed with Budd-Chiari syndrome following consultation for a skin nodule in the lower extremity. Histopathological examination of a biopsy specimen showed features of erythema induratum. As part of the diagnostic work-up, chest roentgenography performed to rule out possible tuberculosis showed enlarged right lower mediastinum. Computed tomography identified a dilated azygos vein and obstruction of the inferior vena cava near the liver. Liver function tests and blood cell counts were all within normal limit and no sign of portal hypertension was noted except for mild splenomegaly. Although angioplasty by balloon catheter resulted in recanalization of the obstructed inferior vena cava, obstruction of the inferior vena cava appeared again 2 months later. One-stage surgical reconstruction of the vascular abnormalities affecting inferior vena cava and hepatic vein using autologous pericardial patch was performed 11 months after angioplasty, which resulted in normalization of blood flow. Examination of a liver biopsy obtained intraoperatively revealed hepatic fibrosis compatible with early-stage Budd-Chiari syndrome. No complications were noted postoperatively and the nodular lesion in the lower extremity disappeared after surgery.     

Oral L-arginine prevents murine coxsackievirus B3 myocarditis

We have previously demonstrated that administration of nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), aggravated murine coxsackievirus B3 myocarditis. In the present study, we evaluated the effects of L-arginine, a precursor of NO, upon acute and chronic myocarditis. Dietary L-arginine and L-arginine plus L-NAME (L-arginine+L-NAME group) were administered to coxsackievirus B3 (CB3)-infected C(3)H/He mice for 2 weeks (experiment I), and to CB3-infected mice from the second week until the fourth week after virus inoculation (experiment II). Infected control was prepared in each experiment. In experiment I, survival was higher in the L-arginine group compared with the other two groups, and cardiac damage was less. In addition, plasma concentrations of L-arginine and NO were elevated in the L-arginine group. In experiment II, cardiomyopathic lesion in the L-arginine group was less prominent associated with lower plasma catecholamine and lower myocardial collagen concentrations compared with the other two groups. Thus, L-arginine treatment may be effective not only in preventing the development of acute CB3 myocarditis but in ameliorating cardiac dysfunction in chronic myocarditis.     

Current status of nuclear medicine clinical application of FDG-PET for cancer diagnosis. Head and neck cancer

Accurate detection of head and neck cancer is crucial in patients' quality of life. The head and neck area consists of many complicated anatomical structures. Conventional imaging procedures such as CT and MRI provide much detailed information, but accurate estimation of the spread of cancer is still limited. Positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) is clinically useful in detecting head and neck cancer, providing accurate estimates of head and neck primary cancer especially in cases that are equivocal on CT and/or MRI. FDG-PET is able to show metastatic lymph nodes that may appear normal on CT and/or MRI. Further, whole body FDG-PET makes it possible to detect distant metastases. The clinical usefulness of FDG-PET in head and neck cancer is discussed in this review.