Biomedical subjects

Hiroyuki Kamei

Publications and source records attributed to Hiroyuki Kamei.

13 recordsLinked to original sources

PubMed2006

The rewards of nicotine: regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1.

Nicotine, a primary component of tobacco, is one of the most abused drugs worldwide. Approximately four million people die each year because of diseases associated with tobacco smoking. Mesolimbic dopaminergic neurons mediate the rewarding effects of abused drugs, including nicotine. Here we show that the tissue plasminogen activator (tPA)-plasmin system regulates nicotine-induced reward and dopamine release by activating protease activated receptor-1 (PAR1). In vivo microdialysis revealed that microinjection of either tPA or plasmin into the nucleus accumbens (NAc) significantly potentiated whereas plasminogen activator inhibitor-1 reduced the nicotine-induced dopamine release in the NAc in a dose-dependent manner. Nicotine-induced dopamine release was markedly diminished in tPA-deficient (tPA-/-) mice, and the defect of dopamine release in tPA-/- mice was restored by microinjection of either exogenous tPA or plasmin into the NAc. Nicotine increased tPA protein levels and promoted the release of tPA into the extracellular space in the NAc. Immunohistochemistry revealed that PAR1 immunoreactivity was localized to the nerve terminals positive for tyrosine hydroxylase in the NAc. Furthermore, we demonstrated that plasmin activated PAR1 and that nicotine-induced place preference and dopamine release were diminished in PAR1-deficient (PAR1-/-) mice. Targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches to the treatment of nicotine dependence.

Acetylcholine↗

PubMed2006

Neural circuits containing pallidotegmental GABAergic neurons are involved in the prepulse inhibition of the startle reflex in mice.

BACKGROUND: Prepulse inhibition (PPI) of the startle response is a measure of the inhibitory function and time-linked information processing by which a weak sensory stimulus (the prepulse) inhibits the startle response caused by a sudden intense stimulus. We attempted to clarify the neuronal circuits underlying the control of PPI of the startle reflex in mice. METHODS: c-Fos immunohistochemistry was used to detect neurons activated by startle pulse and/or prepulse trials. Behavioural pharmacology and tracing studies were also conducted. RESULTS: The lateral globus pallidus (LGP) was activated by prepulses. Activation of the caudal pontine reticular nucleus (PnC) evoked by the startle pulses was inhibited under PPI conditions. Double-immunostaining revealed that c-Fos-positive cells in the LGP following prepulse trials were GABAergic neurons. Bilateral microinjections of lidocaine into the LGP resulted in an impairment of PPI. Fluoro-gold infusion into the PnC and the pedunculopontine tegmental nucleus (PPTg) retrogradely labeled neurons in the PPTg and LGP, respectively. Microinjections of phaclofen into the PPTg significantly impaired PPI. CONCLUSIONS: These results suggest that GABAergic neurons in the LGP which project to the PPTg play a crucial role through the activation of GABAB receptors in the regulation of PPI of the startle reflex in mice.

Acoustic Stimulation↗

PubMed2006

Involvement of hippocampal extracellular signal-regulated kinase 1/2 in spatial working memory in rats.

The role of the phosphorylation of hippocampal extracellular signal-regulated kinase 1/2 in spatial working memory in rats was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Phosphorylated extracellular signal-regulated kinase 1/2 levels were significantly and transiently increased in the hippocampus by 60 min, and then returned to the control levels 120 min after the training phase. Bilateral microinjections of the PD98059, an inhibitor of the extracellular signal-regulated kinase 1/2 kinase MEK, into the hippocampus impaired performance in the test phase of the delayed spatial win-shift task at 5-min delay. These results suggest that extracellular signal-regulated kinase 1/2 activation in the hippocampus plays a crucial role in spatial working memory.

Animals↗

PubMed2006

Involvement of tissue plasminogen activator-plasmin system in depolarization-evoked dopamine release in the nucleus accumbens of mice.

Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin. In the present study, we investigated the role of the tPA-plasmin system in depolarization-evoked dopamine (DA) and acetylcholine (ACh) release in the nucleus accumbens (NAc) and hippocampus, respectively, of mice, by using in vivo microdialysis. Microinjection of either tPA or plasmin significantly potentiated 40 mM KCl-induced DA release without affecting basal DA levels. In contrast, plasminogen activator inhibitor-1 dose-dependently reduced 60 mM KCl-induced DA release. The 60 mM KCl-evoked DA release in the NAc was markedly diminished in tPA-deficient (tPA-/-) mice compared with wild-type mice, although basal DA levels did not differ between the two groups. Microinjections of either exogenous tPA (100 ng) or plasmin (100 ng) into the NAc of tPA-/-mice restored 60 mM KCl-induced DA release, as observed in wild-type mice. In contrast, there was no difference in either basal or 60 mM KCl-induced ACh release in the hippocampus between wild-type and tPA-/-mice. Our findings suggest that the tPA-plasmin system is involved in the regulation of depolarization-evoked DA release in the NAc.

Acetylcholine↗

PubMed2005

Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice.

BACKGROUND: Recent clinical studies have suggested that chronic use of methamphetamine (METH) induces long-term cognitive deficits. To clarify the mechanism of METH-induced cognitive impairment, we investigated the effect of METH on cognitive function in mice. METHODS: Mice were repeatedly administered METH for 7 days, and their cognitive function was assessed using a novel-object recognition task. Therapeutic effects of clozapine and haloperidol on METH-induced cognitive impairment were investigated. Western blotting and specific inhibitors were employed to determine the role of extracellular signal-regulated kinase 1/2 (ERK1/2). RESULTS: Repeated METH treatment induced an impairment of recognition of novel objects and behavioral sensitization. These effects persisted for at least 28 days after the drug withdrawal. Clozapine, but not haloperidol, reduced METH-induced cognitive impairment. Hyperphosphorylation of ERK1/2 was found in the prefrontal cortex of mice exposed to the novel objects, but was abolished in mice treated with METH. Inhibition of ERK1/2 by the microinjection of PD98059 into the prefrontal cortex resulted in cognitive impairment. CONCLUSIONS: These results suggest that repeated METH treatment induces cognitive impairment, which is associated with the dysfunction of the ERK1/2 pathway in the prefrontal cortex.

Animals↗

PubMed2005

Effects of memantine and donepezil on amyloid beta-induced memory impairment in a delayed-matching to position task in rats.

We investigated the effects of memantine and donepezil on amyloid beta (Abeta)-induced memory impairment in rats, which was assessed by a delayed-matching to position (DMPT) paradigm in three-lever operant chambers. Aggregated Abeta1-40 was microinjected bilaterally (1 nmol/side) into both CA1 and CA3 subfields of the hippocampus in rats that had previously performed the DMTP task. Memantine (20 mg/(kg day), s.c.) was continuously infused by an osmotic minipump for 4 weeks from 3 days before the microinjection of Abeta. Donepezil (2.5 mg/kg, p.o.) was administered 60 min before the DMTP test session. Bilateral microinjections of Abeta1-40 into the hippocampus resulted in a delayed, but persistent impairment of DMTP performance, which appeared more than 50 days after the injection. Memantine prevented the development of Abeta-induced memory impairment, while donepezil symptomatically alleviated the deficits. Because of a ceiling effect, the combination of donepezil with memantine failed to produce any additive or synergic effects. These results support the clinical data showing that memantine and donepezil are effective for the treatment of Alzheimer's disease. Moreover, it is suggested that memantine is effective for preventing Abeta-induced short-term memory impairment.

Amyloid beta-Peptides↗

PubMed2005

Modification by the tissue plasminogen activator-plasmin system of morphine-induced dopamine release and hyperlocomotion, but not anti-nociceptive effect in mice.

The extracellular serine protease tissue plasminogen activator (tPA) that converts plasminogen into plasmin is abundantly expressed throughout the central nervous system. We have recently demonstrated that the tPA-plasmin system participates in the rewarding and locomotor-stimulating effects of morphine by acutely regulating morphine-induced dopamine release in the nucleus accumbens (NAc). In the present study, we examined the effects of microinjections of plasminogen activator inhibitor-1 (PAI-1), tPA or plasmin into the NAc on morphine-induced dopamine release, hyperlocomotion and anti-nociceptive effects in ICR mice. A single morphine treatment resulted in an increase in protein levels of PAI-1 in the NAc. Microinjection of PAI-1 into the NAc dose-dependently reduced morphine-induced dopamine release and hyperlocomotion. In contrast, microinjection of tPA into the NAc significantly potentiated morphine-induced dopamine release and hyperlocomotion without affecting basal levels. Furthermore, microinjection of plasmin enhanced morphine-induced dopamine release, but did not modify the hyperlocomotion induced by morphine. The intracerebroventricular injection of PAI-1, tPA and plasmin at high doses had no effect on the anti-nociceptive effects of morphine. These results suggest that the tPA-plasmin system is involved in the regulation of morphine-induced dopamine release and dopamine-dependent behaviors but not the anti-nociceptive effects of morphine.

Animals↗

PubMed2004

Enhanced antidepressant efficacy of sigma1 receptor agonists in rats after chronic intracerebroventricular infusion of beta-amyloid-(1-40) protein.

Treatment of depressive symptoms in patients suffering from neurodegenerative disorders remains a challenging issue, since few available antidepressants present an adequate efficacy during pathological aging. Previous reports suggested that selective sigma(1) receptor agonists might constitute putative candidates. We here examined the pharmacological efficacy of igmesine and (+)-SKF-10,047 and the sigma(1) receptor-related neuroactive steroid dehydroepiandrosterone sulfate, in rats infused intracerebroventricularly during 14 days with the beta-amyloid-(1-40) protein and then submitted to the conditioned fear stress test. Igmesine and (+)-SKF-10,047 significantly reduced the stress-induced motor suppression at 30 and 6 mg/kg, respectively, in beta-amyloid-(40-1)-treated control rats. Active doses were decreased, to 10 and 3 mg/kg, respectively, in beta-amyloid-(1-40)-treated animals. The dehydroepiandrosterone sulfate effect was also facilitated, both in dose (10 vs. 30 mg/kg) and intensity, in beta-amyloid-(1-40)-treated rats. Neurosteroid levels were measured in several brain structures after beta-amyloid infusion, in basal and stress conditions. Progesterone levels, both under basal and stress-induced conditions, were decreased in the hippocampus and cortex of beta-amyloid-(1-40)-treated rats. The levels in pregnenolone, dehydroepiandrosterone and their sulfate esters appeared less affected by the beta-amyloid infusion. The sigma(1) receptor agonist efficacy is known to be inversely correlated to brain progesterone levels, synthesized mainly by neurons that are mainly affected by the beta-amyloid toxicity. The present study suggests that sigma(1) receptor agonists, due to their enhanced efficacy in a nontransgenic animal model, may alleviate Alzheimer's disease-associated depressive symptoms.

Alzheimer Disease↗

PubMed2003

Comparative study of acute effects of single doses of fexofenadine, olopatadine, d-chlorpheniramine and placebo on psychomotor function in healthy volunteers.

Since most classical (first-generation) antihistamines have undesirable sedative effects on the central nervous system (CNS), newer (second-generation) antihistamines have been developed to relieve the sedative effects and to improve the patient's quality of life. However, the psychomotor profiles of second-generation antihistamines are not fully elucidated. In this randomized, double-blind, crossover study, the acute effects of single doses of second-generation antihistamines, fexofenadine (120 mg) and olopatadine (10 mg), on cognitive and psychomotor performance were investigated in comparison with those of placebo and d-chlorpheniramine (4 mg), a first-generation antihistamine, using objective and subjective assessments, in 11 healthy Japanese volunteers. In a battery of psychomotor tests, d-chlorpheniramine impaired tracking ability in the compensatory tracking task and caused a reduction in behavioural activity as continuously measured by wrist actigraphy. Olopatadine, like d-chlorpheniramine, reduced the behavioural activity, while fexofenadine had no effect in any of the tests. No significant changes in the subjects' self-ratings of drowsiness were found with the three antihistamines. These results suggest that d-chlorpheniramine and olopatadine, but not fexofenadine, produce sedative effects on psychomotor performance, and that the CNS profile of fexofenadine is different from that of olopatadine.

Adult↗

PubMed2003

[Objective evaluation of clinical pharmacy lectures and experience in a master program using visual analog scale method].

We conducted an investigation to determine whether the visual analogue scale (VAS) method could be utilized in evaluating the lectures and pharmacy experience of the Division of Pharmacy and Health Sciences, Graduate School of Natural Science and Technology, Kanazawa University. Graduate students who had finished the 1-year pharmacy experience at the Kanazawa University Hospital were asked to make a self-evaluation of the understanding/attainment of lectures and experience in the course. Since the experience was carried out as a one-student-to-one-pharmacist system, the preceptors (pharmacists) were also asked to evaluate their corresponding students. When evaluating the necessity of the lectures, students tended to feel that the medical science- or pharmacotherapy-related subjects were important and those of social sciences were less important. These results suggest the need to review the contents of the lectures to enhance the interests of the students in the latter. By comparing the extent of understanding of each lecture before and after pharmacy experience, it was found that students had a better understanding of the lectures through their experience. In most results from the answers in pharmacy experience, students also scored themselves higher than their preceptors. Therefore comparisons of evaluation may provide more objective results in pharmacy experience. It was demonstrated that utilization of the VAS method and comparing the data are very useful in evaluating not only students' understanding/attainment but also the importance and usefulness of lectures and pharmacy experience in an objective way.

Adult↗

PubMed2003

[Effects of sigma receptor ligands on psychiatric disorders].

It has recently been suggested that sigma receptors are involved in psychiatric disorders. Sigma 1 receptor antagonists are effective in animal models of positive symptoms, cognitive deficit and disruption of prepulse inhibition in schizophrenia. They also inhibit the development and expression of the conditioned place preference induced by cocaine. On the other hand, sigma 1 receptor agonists reduce the immobility time in the forced swimming and tail suspension tests. Furthermore, sigma 1 receptor agonists attenuate the conditioned fear stress (CFS) response (which is not attenuated by typical anxiolytics or antidepressants) in rodents. The attenuating effects are mediated through sigma 1 receptors, which are closely related to the mesolimbic dopaminergic systems. Sigma 1 receptor agonists also have anti-amnesic effects in various experimental models. Neurosteroids such as dehydroepiandrosterone sulfate and pregnenolone sulfate attenuate the CFS response and have anti-amnesic effects, the effects being mediated via sigma 1 receptors. These findings suggest that sigma receptors are novel potential targets for the treatment of psychiatric disorders such as schizophrenia, drug abuse, depression and dementia.

Animals↗

PubMed2002

Learning and memory in two different reward tasks in a radial arm maze in rats.

In an eight-arm radial maze, working and reference memory can be assessed simultaneously in the fixed position of reward task (FPRT) in which half of the arms are baited and their positions are fixed throughout the training trails. We characterized performance of rats in the variable position of reward task (VPRT), in which four out of eight arms were baited, but the positions were varied in every training trial. In the VPRT, the rats learned to choose all arms without any discrimination between baited and non-baited arms and the memory retention was time-dependent. The performance of rats in the FPRT was impaired by altering the spatial organization of the extramaze cues while it was not affected in the VPRT. The number of Fos-positive cells transiently increased in the cerebral cortex and hippocampus of both groups of animals during the training. Finally, bilateral lesions of the dorsal hippocampus resulted in an impairment of working memory in the FPRT and the performance of the rats in the VPRT. These results suggest that different strategies are used between the FPRT and VPRT but the hippocampus plays an important role in performance of rats trained for the VPRT as well as FPRT.

Animals↗

PubMed2002

[Anti-dementia drugs for Alzheimer disease in present and future].

Alzheimer disease(AD) is characterized as neurodegenerative disease showing impairment of cognitive function, death of neuronal cells, numerous numbers of senile plaques and tangle of neurofilaments. There are two different hypotheses that neurotoxicity of aggregated amyloid beta protein(A beta) and hyperphosphorylation of tau protein are the causes of AD. The dysfunction of cholinergic neuronal system is observed in the early stage of AD. Therefore, the strategy to increase of acetylcholine (ACh) level in brain by using ACh esterase inhibitor is mainstream in the present. We have tacrine, donepezil, rivastigmine and galantamine. Tacrine, the first drug for AD, is replaced by other drugs, because of its hepatic toxicity. Galantamine binds allosteric sites of nicotine receptor and stimulates it in addition to its inhibitory effect on ACh esterase. Metamantine was approved in EU in 2002. It is non-competitive inhibitor of NMDA receptors, and dopamine releaser, which has neuroprotective effect. All of the above drugs improve cognitive function of patients, and they could delay hospitalization for 7 months or more. In the present anti-inflammatory drugs, anti-oxidative drugs and estrogen are under investigation. As anti-A beta therapy, inhibitors of beta -and gamma-secretase, A beta aggregation inhibitors, A beta degradation stimulators and A beta vaccination are possible strategies. The inhibitors of tau protein phosphorylation and activators of phosphates could be that of anti-tau protein phosphorylation. Additionally, it is expected to have the strategies such as neuroregeneration by neurotorophic factors and immunopyline ligands, and supply of neuronal cells by gene therapy and human ES cells.

Acetylcholine↗