Biomedical subjects

T Kakiuchi

Publications and source records attributed to T Kakiuchi.

At least 37 records · Page 2Linked to original sources

PubMed2000

Age-related reduction of [11C]MDL100,907 binding to central 5-HT(2A) receptors: PET study in the conscious monkey brain.

Age-related alterations of serotonin (5-hydroxytryptamine; 5-HT) type 2A receptors (5-HT(2A)) in the living brains of young (6.0+/-1. 3 years old) and aged (19.2+/-3.0 years old) monkeys (Macaca mulatta) were evaluated with [11C]MDL100,907 in the conscious state using high-resolution positron emission tomography (PET). For quantitative analysis of 5-HT(2A) binding in vivo, PET scan of [11C]MDL100,907 was performed with arterial blood sampling in each animal, and the metabolic-corrected arterial input function was used for Logan graphical analysis. Higher cerebral binding of [11C]MDL100, 907 was observed in the hippocampus, cingulate gyrus, frontal, temporal and occipital cortices, regions known to contain high densities of 5-HT(2A), by in vitro assay. Binding was intermediate in the striatum and thalamus, and lower in the pons and cerebellum in both young and aged monkeys. The age-related decrease in [11C]MDL100,907 binding to 5-HT(2A) receptors was prominent in the hippocampus, cingulate gyrus, frontal, temporal and occipital cortices, but not in the striatum, thalamus and pons. These observation demonstrated the usefulness of [11C]MDL100,907 as an labeled compound for assessment of the aging process of the cortical 5-HT(2A) measured by PET.

Aging↗

PubMed2000

Cholinergic neuronal modulation alters dopamine D2 receptor availability in vivo by regulating receptor affinity induced by facilitated synaptic dopamine turnover: positron emission tomography studies with microdialysis in the conscious monkey brain.

To evaluate the cholinergic and dopaminergic neuronal interaction in the striatum, the effects of scopolamine, a muscarinic cholinergic antagonist, on the striatal dopaminergic system were evaluated multi-parametrically in the conscious monkey brain using high-resolution positron emission tomography in combination with microdialysis. l-3,4-Dihydroxyphenylalanine (l-[beta-(11)C]DOPA) and 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([beta-(11)C]CFT) were used to measure dopamine synthesis rate and dopamine transporter (DAT) availability, respectively. For assessment of dopamine D(2) receptor binding in vivo, [(11)C]raclopride was applied because this labeled compound, which has relatively low affinity to dopamine D(2) receptors, was hypothesized to be sensitive to the striatal synaptic dopamine concentration. Systemic administration of scopolamine at doses of 10 and 100 microg/kg dose-dependently increased both dopamine synthesis and DAT availability as measured by l-[beta-(11)C]DOPA and [beta-(11)C]CFT, respectively. Scopolamine decreased the binding of [(11)C]raclopride in a dose-dependent manner. Scopolamine induced no significant changes in dopamine concentration in the striatal extracellular fluid (ECF) as determined by microdialysis. However, scopolamine dose-dependently facilitated the striatal ECF dopamine induced by the DAT inhibitor GBR12909 at a dose of 0.5 mg/kg. Scatchard plot analysis in vivo of [(11)C]raclopride revealed that scopolamine reduced the apparent affinity of dopamine D(2) receptors. These results suggested that the inhibition of muscarinic cholinergic neuronal activity modulates dopamine turnover in the striatum by simultaneous enhancement of the dynamics of dopamine synthesis and DAT availability, resulting in no significant changes in apparent "static" ECF dopamine level but showing a decrease in [(11)C]raclopride binding in vivo attributable to the reduction of affinity of dopamine D(2) receptors.

Animals↗

PubMed2000

Changes in local cerebral blood flow in photochemically induced thrombotic occlusion model in rats.

We demonstrated earlier that in a photochemically induced thrombotic occlusion model, a reperfusion-like phenomenon may be involved in the progress of brain damage. Therefore, we now investigated changes in local cerebral blood flow in a photochemical model compared with changes in a thermocoagulated occlusion model, using autoradiography. At 5 min, and 3, 6 and 24 h after middle cerebral artery occlusion, local cerebral blood flow was measured by intravenous injection of 4-iodo[N-methyl-14C]antipyrine (20 mu Ci). In the ischemic core zone, the reduction in blood flow was similar in the two models. However, blood flow in the ischemic border zone in the photochemical model decreased transiently in the third hour after ischemia and then increased again, while the blood flow in a thermocoagulated model continued to decrease. Time courses of brain damage formation in both models were no different up to 24 h. These findings suggest that the transient reduction in cerebral blood flow in the third hour following ischemia may contribute to a reperfusion-like phenomenon in a photochemical model.

Animals↗

PubMed2000

Docosahexaenoic acid (DHA) improves the age-related impairment of the coupling mechanism between neuronal activation and functional cerebral blood flow response: a PET study in conscious monkeys.

The regional cerebral blood flow (rCBF) response to vibrotactile stimulation was compared in conscious young (5.9+/-1.8 years old) and aged (18.0+/-3.3 years old) monkeys using [15O]H(2)O and high-resolution positron emission tomography (PET). In addition, the effects of docosahexaenoic acid (DAH), an n-3 polyunsaturated fatty acid (PUFA), on the rCBF response to stimulation were evaluated in aged monkeys. Soybean milk (SBM) or DHA-containing SBM (DHA/SBM) was supplied to aged monkeys for 1 and 4 weeks. Under control conditions, vibrotactile stimulation elicited an increase in the rCBF response in the contralateral somatosensory cortices of both young and aged monkeys, but the degree of increase in the rCBF response was significantly lower in aged monkeys (116% of corresponding 'rest' condition) than that in young animals (141%). The regional cerebral metabolic rate of glucose (rCMRglc) response to the stimulation, an index of neuronal activation, was not significantly different between young and aged monkeys as measured by [18F]-2-fluoro-2-deoxy-D-glucose (FDG). Supply of DHA/SBM at a dose of 150 mg/kg/day as DHA for 1 week resulted in a significant increase in rCBF response to stimulation (127%) in aged monkeys, and 4-week supply of DHA induced further facilitation of the rCBF response (133%). In contrast, the reduced rCBF response in the aged monkeys was not affected by SBM alone for either 1 or 4 weeks. The neuronal activation itself elicited by the stimulation, as measured by [18F]FDG, was not affected by SBM or DHA/SBM. These results suggested the involvement of DHA in the coupling mechanism between the neuronal activation and rCBF response, possibly by modulation of cholinergic neuronal transmission.

Aging↗

PubMed2000

Dose-response and duration effects of acute administrations of cocaine and GBR12909 on dopamine synthesis and transporter in the conscious monkey brain: PET studies combined with microdialysis.

The dose-response and duration effects of acute administration of the dopamine transporter (DAT) blocker cocaine and GBR12909 on dopamine synthesis and transporter availability were evaluated in the brains of conscious monkeys using high-resolution positron emission tomography (PET) in combination with microdialysis. Rate of dopamine synthesis and DAT availability were evaluated using L-[beta-11C]DOPA and [11C]beta-CFT (WIN35,428), respectively. Administration of cocaine (0.5, 2 and 5 mg/kg) resulted in dose-dependent elevation of dopamine level in the striatal extracellular fluid (ECF) at 0.5 h after injection, and returned to the baseline level within 1.5 h post-injection. At 0.5 post-injection, cocaine reduced dopamine synthesis rate and DAT availability in a dose-dependent manner. The reduction of DAT availability by cocaine (2 mg/kg) returned to baseline level at 3 h post-injection and thereafter. Interestingly, dopamine synthesis rate was significantly higher at 3 h than baseline level and returned to baseline level 5.5 h post-injection. When GBR12909 (0.5, 2 and 5 mg/kg) was administered 0.5 h before tracer injection, dopamine synthesis rate and DAT availability were significantly decreased in a dose-dependent manner. These reductions induced by GBR12909 (2 mg/kg) lasted at least until 5.5 h post-injection. GBR12909 induced dose-dependent elevation of dopamine level in ECF, and the elevation lasted up to 7 h. The present results indicated that cocaine and GBR12909 affect dopamine synthesis rate and DAT availability in the striatum with difference time courses as measured by PET in the conscious monkey brains.

Animals↗

PubMed2000

Decline of the monkey's limbic and prefrontal activity during task repetition.

In order to investigate the neural mechanism underlying the motivation, we measured the regional cerebral blood flow (rCBF) by positron emission tomography in a monkey that was repeatedly engaged in cognito-behavioural tasks. The rCBF of the anterior cingulate area, medial parts of prefrontal area, and hippocampal region decreased significantly with the succession of tasks within a day. The activity was restored abruptly when the reward was then increased, but decreased again on further repetition of the tasks. These findings suggest that the limbic and prefrontal areas are the regions involved in motivational function in the brain.

Animals↗

PubMed2000

Age-related impairment of coupling mechanism between neuronal activation and functional cerebral blood flow response was restored by cholinesterase inhibition: PET study with microdialysis in the awake monkey brain.

The effects of three cholinesterase inhibitors (physostigmine, E2020, and Tacrine), all of which are to be cognitive enhancers, on the functional regional cerebral blood flow (rCBF) response were studied in young (5.9+/-1.8 years old) and aged (18.0+/-3.3 years old) monkeys under awake conditions using high-resolution positron emission tomography (PET). Under control condition, vibrotactile stimulation elicited increases in the rCBF response in the contralateral somatosensory cortices of both young and aged monkeys, but the degree of increase in rCBF response was significantly lower in aged (115.8%) than that in young monkeys (139.9%). Regional cerebral metabolic rate of glucose (rCMRglc) response to the stimulation, measured using [18F]-2-fluoro-2-deoxy-Dphysostigmine) were consistent with the data obtained by microdialysis. In contrast, the cognitive enhancers did not alter rCBF response to stimulation in young monkeys. The present results demonstrated that the functional change in rCBF response to the stimulation was induced during the aging process by impairment of the coupling mechanism between the neuronal activation and rCBF response. Furthermore, the observation that cognitive enhancers partly restored the functional rCBF response suggested that the coupling mechanism might be regulated via cholinergic neuronal transmission.

Acetylcholine↗

PubMed2000

Ketamine decreased striatal [(11)C]raclopride binding with no alterations in static dopamine concentrations in the striatal extracellular fluid in the monkey brain: multiparametric PET studies combined with microdialysis analysis.

The effects of ketamine, a noncompetitive antagonist of NMDA receptors, on the striatal dopaminergic system were evaluated multiparametrically in the monkey brain using high-resolution positron emission tomography (PET) in combination with microdialysis. L-[beta-(11)C]DOPA, [(11)C]raclopride, and [(11)C]beta-CFT were used to evaluate dopamine synthesis rate, D(2) receptor binding, and transporter availability, respectively, in conscious and ketamine-anesthetized animals. Dopamine concentrations in the striatal extracellular fluid (ECF) were simultaneously measured by PET. Thirty minutes prior to PET scan, intravenous administration of ketamine was started by continuous infusion at a rate of 3 or 10 mg/kg/h. Ketamine infusion dose-dependently decreased [(11)C]raclopride binding, but induced no significant changes in dopamine concentration in the striatal ECF as measured by microdialysis at any dose used. In contrast, ketamine increased both dopamine synthesis and DAT availability as measured by L-[beta-(11)C]DOPA and [(11)C]beta-CFT, respectively, in a dose-dependent manner. These results suggest that the inhibition of glutamatergic neuronal activity modulates dopamine turnover in the striatum by simultaneous enhancement of the dynamics of dopamine synthesis and DAT availability to the same extent, resulting in no apparent changes in ECF dopamine concentration as measured by microdialysis. It also suggests that the alteration of [(11)C]raclopride binding in vivo as measured by PET might not simply be modulated by the static synaptic concentration of dopamine.

Animals↗

PubMed2000

A novel PAX6 gene mutation (P118R) in a family with congenital nystagmus associated with a variant form of aniridia.

BACKGROUND: A variety of PAX6 gene mutations were identified in patients with aniridia and/or allied ocular dysgenesis such as keratopathy, Peters' anomaly, foveal hypoplasia, and nystagmus. To scrutinize the etiology of a four-generation Japanese family with autosomal dominant nystagmus associated with anterior and posterior segment anomalies, the PAX6 gene was examined. PATIENTS AND METHODS: A Japanese family showed a variant aniridia phenotype in four successive generations. Affected individuals had congenital nystagmus, microcornea with shortened axial length, superficial peripheral corneal opacification with pannus formation, dislocated pupil, and foveal hypoplasia. Analysis of the PAX6 gene mutation was performed in affected and unaffected individuals. RESULTS: A novel missense mutation in the PAX6 gene was found in all affected individuals examined, but neither in unaffected individuals nor in unrelated healthy individuals. This mutation predicted a proline to arginine change at codon 118 (P118R) in the paired domain of PAX6 protein. CONCLUSION: The reported family illustrates that mutations in the PAX6 gene, in particular missense mutations, may manifest atypical clinical expression or forme fruste of aniridia.

Adult↗

PubMed2000

Development and evaluation of muscarinic cholinergic receptor ligands N-[11C]ethyl-4-piperidyl benzilate and N-[11C]propyl-4-piperidyl benzilate: a PET study in comparison with N-[11C]methyl-4-piperidyl benzilate in the conscious monkey brain.

The muscarinic cholinergic receptor ligands N-[(11)C]ethyl-4-piperidyl benzilate (4-EPB) and N-[(11)C]propyl-4-piperidyl benzilate (4-PPB) were developed and evaluated in comparison with N-[(11)C]methyl-4-piperidyl benzilate (4-MPB) in the conscious monkey brain using positron emission tomography (PET). Time-activity curves of [(11)C]4-EPB, unlike [(11)C]4-MPB, showed peaks within 91 min in regions rich in muscarinic receptors. [(11)C]4-PPB showed no specific binding even in the regions rich in these receptors. These observation demonstrated that increases in [(11)C]alkyl chain length could alter the kinetic properties of receptor ligands for PET.

Animals↗

PubMed2000

Unresponsiveness of intrahepatic lymphocytes to bacterial superantigen: rapid development of suppressive Mac-1(high) cells in the mouse liver.

We previously found that a small dose (2 microg per mouse) of staphylococcal enterotoxin B (SEB) induced early emerging unresponsiveness in intrahepatic-lymphocyte populations (IHLs). The purpose of this study was to reveal the inducing role of accessory cells involved in IHLs in this phenomenon. IHLs prepared at 3 to 24 hours after SEB injection failed to proliferate in response not only to SEB but also to SEA, representing ligand-nonspecific unresponsiveness, whereas spleen cells (SPCs) and mesenteric lymph-node cells showed transient proliferation. Unresponsiveness in IHLs was related to a deficit of their accessory cell function as measured by coculture of irradiated IHLs and antigen-specific, type 1 T-helper (Th1) clone cells. High levels of nitrite were detected in the culture supernatant. Supplement of N(G)-monomethyl-L-arginine lowered nitrite levels and concurrently restored the proliferative response of Th1 cells, indicating the involvement of nitric oxide in suppression. Adherent cells prepared from IHLs well reproduced these results. As shown by flow cytometry, Mac-1(high) Ia(+) cells, which mainly included F4/80(+) cells (macrophages) and a minor population of CD11c(+) cells (dendritic cells), increased in proportion in IHLs but not in SPCs at 6 to 24 hours. Depletion of Mac-1(high) cells from IHLs with antibody-coated magnetic beads recovered the proliferative response. Depleted Mac-1(high) cells had a monocytoid appearance. In immunostained sections, Kupffer cells came to highly express both Mac-1 and Ia at 12 hours. These results indicate that Mac-1(high)Ia(+) adherent cells, largely Kupffer cells activated by SEB, nonspecifically suppress the proliferation of Th1 cells via nitric oxide production before manifestation of ligand-specific unresponsiveness.

Animals↗

PubMed2000

Improvement in cerebral blood flow and metabolism following subarachnoid hemorrhage in response to prophylactic administration of the hydroxyl radical scavenger, AVS, (+/-)-N,N'-propylenedinicotinamide: a positron emission tomography study in rats.

OBJECT: The hydroxyl radical scavenger (+/-)-N,N'-propylenedinicotinamide (AVS) has been shown to ameliorate the occurrence of vasospasm following experimental subarachnoid hemorrhage (SAH) and to reduce the incidence of delayed ischemic neurological deficits (DINDs) in patients with SAH. The authors investigated whether prophylactic administration of AVS could improve cerebral blood flow (CBF) and cerebral glucose utilization (CGU) following SAH in rats. METHODS: Anesthetized rats were subjected to intracisternal injection of blood (SAH group) or saline (control group). Either AVS (1 mg/kg/min) or saline (vehicle group) was continuously injected into the rat femoral vein. Forty-eight hours later, positron emission tomography scanning was used with the tracers 15O-H2O and 18F-2-fluoro-D-glucose to analyze quantitatively CBF and CGU, respectively, in the frontoparietal and occipital regions (12 regions of interest/group). In SAH rats receiving only vehicle, CBF decreased significantly (p < 0.05, Tukey's test) and CGU tended to decrease, compared with values obtained in control (non-SAH) rats receiving vehicle. In rats that were subjected to SAH, administration of AVS significantly (p < 0.05, Tukey's test) improved CBF and CGU in both the frontoparietal and occipital regions compared with administration of vehicle alone. CONCLUSIONS: Prophylactic administration of AVS improves CBF and CGU in the rat brain subjected to SAH, and can be a good pharmacological treatment for the prevention of DINDs following SAH.

Animals↗

PubMed2000

Detection of reperfusion injury using PET in a monkey model of cerebral ischemia.

UNLABELLED: Several studies of focal ischemia and reperfusion in animal models have proposed that reperfusion contributes to brain damage. However, the extent to which reperfusion affects the brain, especially in acute stroke patients, remains unclear. Our purpose in this study was to determine whether reperfusion injury can be detected with PET and to clarify the extent to which reperfusion contributes to brain damage. METHODS: The right middle cerebral artery (MCA) of cynomolgus monkeys was occluded for 3 h (n = 8) or permanently (n = 5) by a transorbital device. Four consecutive PET studies were performed to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), and the cerebral metabolic rate of oxygen (CMRO2). RESULTS: The extent of necrotic brain damage 8 h after MCA occlusion was significantly (P < 0.05) greater in the transient model than in the permanent model. Cortical damage was greater in the transient model. The MCA occlusion decreased CBF and CMRO2 in deep MCA territory and increased OEF in the cortex. In the permanent model, these changes continued throughout the experiment. In the transient model, the reperfusion induced postischemic hyperperfusion in the cortex, which showed necrotic damage at the end of the experiment. In this area, OEF and CMRO2 were decreased by reperfusion. CONCLUSION: The results suggest that reperfusion may strongly contribute to cortical damage. PET studies revealed that reperfusion decreased OEF and CMRO2 in the hyperperfused cortex. These changes may indicate reperfusion injury.

Animals↗

PubMed1999

Isoflurane anesthesia enhances the inhibitory effects of cocaine and GBR12909 on dopamine transporter: PET studies in combination with microdialysis in the monkey brain.

The effects of the dopamine transporter (DAT) inhibitors cocaine and GBR12909 on DAT and dopamine D(2) receptors were evaluated in the brains under awake and isoflurane-anesthetized monkeys using high-resolution positron emission tomography (PET) in combination with microdialysis. The striatal DAT availability and dopamine D(2) receptor binding were assayed with [11C]beta-CFT (WIN35,428) and [11C]raclopride, respectively. Cocaine or GBR12909 at a dose of 2 mg/kg was administered intravenously 30 min prior to the injection of labeled compounds. In the awake state, the in vivo binding of [11C]beta-CFT to DAT was significantly decreased by administration of cocaine or GBR12909 at a dose of 2 mg/kg. In contrast, [11C]raclopride binding to dopamine D(2) receptors was decreased only by GBR12909. Under isoflurane anesthesia, dopamine concentration in the striatal extracellular fluid (ECF), as measured by microdialysis, was markedly increased by cocaine or GBR12909 compared to the awake state. Isoflurane anesthesia more markedly enhanced the binding of [11C]beta-CFT in the saline-injected animals, and the degrees of reduction by cocaine and GBR12909 were more marked than those observed in the awake state. Under isoflurane anesthesia, the binding of [11C]raclopride was reduced not only by GBR12909 but also by cocaine which did not affect the binding in the awake state. Taken together, these observations indicated that isoflurane anesthesia enhanced not only the direct inhibitory effects of cocaine and GBR12909 on DAT, but also their indirect effects on dopamine D(2) receptors.

Anesthesia, Inhalation↗

PubMed1999

The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes.

6Ckine is an unusual chemokine capable of attracting naive T lymphocytes in vitro. It has been recently reported that lack of 6Ckine expression in lymphoid organs is a prominent characteristic of mice homozygous for the paucity of lymph node T cell (plt) mutation. These mice show reduced numbers of T cells in lymph nodes, Peyer's patches, and the white pulp of the spleen. The genetic reason for the lack of 6Ckine expression in the plt mouse, however, has remained unknown. Here we demonstrate that mouse 6Ckine is encoded by two genes, one of which is expressed in lymphoid organs and is deleted in plt mice. A second 6Ckine gene is intact and expressed in the plt mouse.

Animals↗

PubMed1999

Is synaptic dopamine concentration the exclusive factor which alters the in vivo binding of [11C]raclopride?: PET studies combined with microdialysis in conscious monkeys.

The effects of dopamine release manipulated by drugs on the in vivo binding of [11C]raclopride in the striatum were evaluated in conscious monkeys combined with microdialysis. The in vivo binding of [11C]raclopride was evaluated by high resolution positron emission tomography (PET), and the dopamine concentrations in the striatal extracellular fluid (ECF) were measured by microdialysis in the same animals. The systemic administration of the direct dopamine enhancers, GBR12909 (a dopamine transporter (DAT) blocker, at 0.5, 2 and 5 mg/kg) or methamphetamine (a dopamine releaser, at 0.1, 0.3 and 1 mg/kg) dose-dependently increased the dopamine concentration in the striatal ECF, and decreased in vivo [11C]raclopride binding in the striatum. The administration of the indirect dopamine modulators benztropine (a muscarinic cholinergic antagonist, at 0.1, 0.3 and 1 mg/kg) or ketanserine (a 5-HT2 antagonist, at 0.3, 1 and 3 mg/kg) also increased dopamine level in the striatal ECF, and decreased [11C]raclopride binding in a dose-dependent manner. However, the plots of percentage change in dopamine concentration in striatal EFC against that in [11C] raclopride binding indicated different relationships between the effects of direct dopamine enhancers (GBR12909 and methamphetamine) and indirect dopamine modulators (benztropine and ketanserine). These results suggested that the alternation of [11C]raclopride binding in vivo as measured by PET was differently affected by different neuronal manipulations, and not simply by the synaptic concentration of dopamine.

Animals↗

PubMed1999

Cultured murine parenchymal liver cells induce differentiation of bone marrow cells to macrophage-like cells which present antigen to Th1 clones but inhibit their proliferation by nitric oxide and prostaglandins.

Suppressor cells were developed from nylon wool nonadherent CD4(-)8(-)TCRbeta(-) bone marrow cells cocultured with parenchymal liver cells for 2.5 days. The major suppressor cell population consisted of nylon wool/plastic dish-adherent, phagocytic Mac-1(+) CD3(-)4(-)8(-) cells (Ad cells), with 34% of the Ad cells being F4/80(+). These Ad cells suppressed the antigen-specific proliferation of Th1 clones in an MHC-nonrestricted manner. They showed a dose-dependent increase in suppressive activity, with both NO and PGE(2) levels in the culture supernatant rising with Ad cell concentration. OVA-pulsed Ad cells (OVA-Ad cells) were found to stimulate IFN-gamma production, resulting in an elevation of the NO and PGE(2) levels in wells containing OVA-specific Th1 clones. No DNA synthesis by these clones was detected in the absence of N(G)-monomethyl-l-arginine and indomethacin, yet the proliferation of the clone was induced in the presence of these chemicals. As proliferation is inhibited by NO and PGE(2) the Ad cells give the impression that they have no antigen-presenting function. This function is MHC-class-II-restricted. If cells such as Ad cells did actually exist in the hepatic sinusoid, they could by their nature play a major role in inducing the early emerging unresponsiveness of T cells in the liver which we reported in a previous paper.

Animals↗

PubMed1999

FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, restores the regional cerebral blood flow response abolished by scopolamine but not by HA-966: a positron emission tomography study with unanesthetized rhesus monkeys.

The interactions of FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, with cholinergic and glutamatergic neuronal systems were evaluated with respect to its effects on the regional cerebral blood flow (rCBF) response to vibrotactile stimulation in unanesthetized rhesus monkeys with [15O]H2O and high resolution positron emission tomography (PET). Under a saline condition, the vibrotactile stimulation given on the right forepaw induced a significant increase in the rCBF response in the contralateral somatosensory cortex of the monkey brain. Systemic administration of scopolamine (50 microg/kg, i.v.), a muscarinic cholinergic receptor antagonist, completely abolished the rCBF response to the stimulation, and the abolishment lasted, at least, up to 4 h after scopolamine injection. The scopolamine-induced abolishment of rCBF response was restored by the administration of FK960 at relatively wide dosing range from 1 to 1000 microg/kg (i.v. ), and the recovery by FK960 on the rCBF response lasted for 1 h following the administration of FK960 at doses of 100 and 1000 microg/kg. On the other hand, the rCBF response abolished by 1000 microg/kg of (+)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), an antagonist of the glycine modulatory site on the N-methyl-d-aspartate (NMDA) receptors, was not restored by FK960 (1000 microg/kg, i.v.). These findings suggest that FK960 reverses the abolished rCBF response to somatosensory stimulation via enhancement of cholinergic neurotransmission but not via the glutamatergic one.

Animals↗