Biomedical subjects

Akemichi Baba

Publications and source records attributed to Akemichi Baba.

At least 19 recordsLinked to original sources

PubMed2006

Modification of cocaine-induced behavioral and neurochemical effects by serotonin1A receptor agonist/antagonist in mice.

Administration of cocaine causes a locomotor stimulant effect and increases extracellular levels of serotonin (5-HT) and dopamine (DA) in the brains of rodents. Previous studies show that 5-HT1A receptor agonist and antagonist modify the cocaine-induced behavioral and neurochemical effects in the rats. However, the role of the 5-HT system on the effects of cocaine has not been studied in the prefrontal cortex. The present study examined in ddY-strain male mice the effects of the 5-HT1A receptor agonist osemozotan and the receptor antagonist WAY100635 on cocaine-induced locomotor stimulant effect and increases in extracellular levels of 5-HT and DA in the prefrontal cortex. The cocaine-induced locomotor stimulant effect was attenuated by osemozotan and enhanced by WAY100635. The cocaine-induced increase in extracellular levels of 5-HT was attenuated by osemozotan, and enhanced by WAY100635. The cocaine-induced increase in extracellular levels of DA was enhanced by osemozotan, but not affected by WAY100635. These results suggest that the prefrontal 5-HT system plays a pivotal role in the locomotor stimulant effect of cocaine in mice.

Animals↗

PubMed2006

Lack of enhanced effect of antipsychotics combined with fluvoxamine on acetylcholine release in rat prefrontal cortex.

We have shown that coadministration of sulpiride and fluvoxamine preferentially increases the release of dopamine in the prefrontal cortex. To study the possible role of the cortical cholinergic system in this effect, we combined several other antipsychotic drugs with fluvoxamine and examined the effects on acetylcholine release in rat prefrontal cortex. Risperidone and clozapine significantly increased the release of acetylcholine but sulpiride did not, and fluvoxamine did not enhance the effects of the antipsychotics. These results further support the previous suggestion that the cortical dopamine system plays an important role in the effects of antipsychotic drugs administered in combination with fluvoxamine.

Acetylcholine↗

PubMed2006

Effects of osemozotan, ritanserin and azasetron on cocaine-induced behavioral sensitization in mice.

Repeated intermittent administration of psychostimulants causes behavioral sensitization in rodents. Previous studies using serotonin (5-HT) receptor ligands show that the 5-HT system is involved in cocaine-induced behavioral sensitization in rats, but the role of the 5-HT system has not been studied in mice. The present study examined the effects of the 5-HT(1A) receptor agonist osemozotan, the 5-HT(2) receptor antagonist ritanserin and the 5-HT(3) receptor antagonist azasetron on cocaine-induced behavioral sensitization in male ddY mice. Repeated administration of cocaine for 7 days enhanced cocaine-induced locomotor activity, and this sensitization was observed even after withdrawal for 7-14 days. Cocaine-induced behavioral sensitization after a 7-day withdrawal was significantly reduced with the coadministration of osemozotan, ritanserin or azasetron with cocaine repeatedly for 7 days. A single injection of osemozotan or ritanserin before cocaine challenge also reduced repeated cocaine-induced behavioral sensitization. However, none of these ligands inhibited cocaine-induced behavioral sensitization, when each drug was administered for 7 days after repeated cocaine administration. These results suggest that the central 5-HT system plays a role in the development and expression, but not maintenance, of behavioral sensitization in cocaine-treated mice.

Animals↗

PubMed2006

Topics on the Na+/Ca2+ exchanger: responses of Na+/Ca2+ exchanger to interferon-gamma and nitric oxide in cultured microglia.

The Na(+)/Ca(2+) exchanger (NCX) plays a role in regulation of intracellular Ca(2+) levels, but little is known about the functional role of NCX in microglia. To clarify the role of NCX in microglia, we studied the responses of NCX to pathological conditions such as interferon-gamma or nitric oxide (NO) exposure. Treatment with interferon-gamma caused a biphasic increase in NCX activity. The delayed increase in NCX activity was accompanied by increases in the mRNA and protein levels. Pharmacological studies show that protein kinase C and tyrosine kinase are involved in the transient and delayed increases in NCX activity, and the extracellular signal-regulated protein kinase is involved in the delayed increase in NCX activity. On the other hand, NO causes apoptotic cell death in cultured microglia. We observed, using the specific NCX inhibitor SEA0400, that NO activates NCX activity and NCX is involved in NO-induced depletion of Ca(2+) in the endoplasmic reticulum (ER), leading to ER stress. These results suggest that NCX is involved in the regulation of Ca(2+) levels in the ER. The responses of NCX to interferon-gamma and NO implies that NCX plays a key role in microglial function.

Animals↗

PubMed2006

Expression of prokineticin receptors in mouse cultured astrocytes and involvement in cell proliferation.

Effects of prokineticins (PKs), a novel family of bioactive peptides with a mitogenic action to endothelial cells of the endocrine gland and testis, on astrocytic functions were examined. Mouse cultured astrocytes expressed PK-R1 type PK receptors, while there was little expression of the PK-R2 type. PKs caused increases in astrocytic cytosolic Ca2+ levels and BrdU incorporation. Increases in Ca2+ levels by PK-2 were diminished by U73122 (a phospholipase C inhibitor). PK-induced BrdU incorporation was inhibited by U73122, GF109203 (a protein kinase C inhibitor) and PD98059 (a MEK/ERK inhibitor). These results indicate that PK receptors are expressed in astrocytes and regulate astrocytic proliferation.

Animals↗

PubMed2006

Attenuation by the 5-HT1A receptor agonist osemozotan of the behavioral effects of single and repeated methamphetamine in mice.

This study examined the effects of the selective 5-HT1A receptor agonist osemozotan on repeated methamphetamine (METH)-induced behavioral sensitization and single METH-induced locomotor stimulant effect in mice, and then the neurochemical mechanisms using in vivo microdialysis. Repeated administration of METH for 7 days enhanced METH challenge-induced locomotor activity, and this sensitization was observed even after its withdrawal for 7-14 days. Administration of osemozotan to METH-sensitized mice inhibited the maintenance of behavioral sensitization. This effect was blocked by a low dose of WAY100635, a selective 5-HT1A receptor antagonist. A METH challenge increased the extracellular levels of dopamine (DA), 5-HT, and noradrenaline in the prefrontal cortex, but only the increase in 5-HT release was enhanced by repeated METH administration. This augmented response of 5-HT release was attenuated by osemozotan in a WAY100635-sensitive way. A single administration of osemozotan to drug naïve mice inhibited METH-induced locomotor stimulant effect and reduced METH-induced increase in prefrontal 5-HT, but not DA, release. These results suggest that prefrontal 5-HT release is involved at least partly in the effects of osemozotan on single and repeated METH-induced behavioral effects in mice, and imply that the 5-HT1A receptors may have a potential therapeutic value in the remission of schizophrenia.

Analysis of Variance↗

PubMed2006

Cardioprotection via activation of protein kinase C-delta depends on modulation of the reverse mode of the Na+/Ca2+ exchanger.

BACKGROUND: Pretreatment with the volatile anesthetic sevoflurane protects cardiomyocytes against subsequent ischemic episodes caused by a protein kinase C (PKC)-delta mediated preconditioning effect. Sevoflurane directly modulates cardiac Ca2+ handling, and because Ca2+ also serves as a mediator in other cardioprotective signaling pathways, possible involvement of the Na+/Ca2+ exchanger (NCX) in relation with PKC-delta in sevoflurane-induced cardioprotection was investigated. METHODS AND RESULTS: Isolated right ventricular rat trabeculae were subjected to simulated ischemia and reperfusion (SI/R), consisting of superfusion with hypoxic glucose-free buffer for 40 minutes after rigor development, followed by reperfusion with normoxic glucose containing buffer. Preconditioning with sevoflurane before SI/R improved isometric force development during contractile recovery at 60 minutes after the end of hypoxic superfusion (83+/-7% [sevo] versus 57+/-2% [SI/R];n=8; P<0.01). Inhibition of the reverse mode of the NCX by KB-R7943 (10 micromol/L) or SEA0400 (1 micromol/L) during preconditioning attenuated the protective effect of sevoflurane. KB-R7943 and SEA0400 did not have intrinsic effects on the contractile recovery. Furthermore, inhibition of the NCX in trabeculae exposed to sevoflurane reduced sevoflurane-induced PKC-delta translocation toward the sarcolemma, as demonstrated by digital imaging fluorescent microscopy. The degree of PKC-delta phosphorylation at serine643 as determined by western blot analysis was not affected by sevoflurane. CONCLUSIONS: Sevoflurane-induced cardioprotection depends on the NCX preceding PKC-delta translocation presumably via increased NCX-mediated Ca2+ influx. This may suggest that increased myocardial Ca2+ load triggers the cardioprotective signaling cascade elicited by volatile anesthetic agents similar to other modes of preconditioning.

Anesthetics, Inhalation↗

PubMed2006

Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum.

The administration of high doses of methamphetamine causes the degeneration of striatal dopaminergic fibers in the brains of rodents, and oxidative stress appears to be one of the main factors of neurotoxicity. This study examined whether edaravone, a radical scavenger, protects against methamphetamine-induced neurotoxicity in mice. Methamphetamine treatment (4 mg/kg, s.c. x 4 with 2 h intervals) showed striatal dopaminergic degeneration as observed by decreases in dopamine levels and tyrosine hydroxylase immunoreactivity in the striatum. The neurotoxicity was reduced by edaravone (3 mg/kg, i.p.), when it was administered four times 30 min before methamphetamine at 2 h intervals and additionally four times after methamphetamine at 12 h intervals. An immunohistochemical study showed that methamphetamine increased 3-nitrotyrosine immunoreactivity, an in vivo marker of peroxynitrite production, and activated microglia and astrocytes in the striatum. Edaravone blocked the increase in 3-nitrotyrosine immunoreactivity and the activation of astrocytes, but it did not affect the activation of microglia. Edaravone did not affect methamphetamine-induced hyperthermia and striatal dopamine release. These results suggest that edaravone protects against methamphetamine-induced neurotoxicity in the striatum by blocking peroxynitrite production. This study also suggests that methamphetamine activates microglia in a radical-independent mechanism.

Animals↗

PubMed2006

Psychostimulant-induced attenuation of hyperactivity and prepulse inhibition deficits in Adcyap1-deficient mice.

Psychostimulants, including amphetamine, act as antihyperkinetic agents in humans with hyperkinetic disorder such as attention-deficit hyperactivity disorder and are known to be effective in enhancing attention-related processes; however, the underlying mechanisms have not been adequately addressed. Mice lacking the Adcyap1 gene encoding the neuropeptide pituitary adenylate cyclase-activating polypeptide (Adcyap1(-/-)) display psychomotor abnormalities, including increased novelty-seeking behavior and hyperactivity. In this study, Adcyap1(-/-) mice showed sensory-motor gating deficits, measured as deficits in prepulse inhibition (PPI), and showed normal PPI in response to amphetamine. Amphetamine also significantly decreased hyperlocomotion in Adcyap1(-/-) mice, and this paradoxical antihyperkinetic effect depended on serotonin 1A (5-HT(1A)) receptor signaling. c-Fos-positive neurons were increased in the prefrontal cortex in amphetamine-treated Adcyap1(-/-) mice, suggesting increased inhibitory control by prefrontal neurons. Additionally, amphetamine produced an antihyperkinetic effect in wild-type mice that received the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin. These results indicate that Adcyap1(-/-) mice act as a model of hyperlocomotion and PPI deficits and suggest that 5-HT(1A)-mediated pathways are important determinants of the psychostimulant-elicited, rate-dependent effects that are in a negative function of the baseline rate of activity.

Acoustic Stimulation↗

PubMed2006

Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been reported to decrease ischemic neuronal damage and increase IL-6 secretion in rats. However, the mechanisms underlying neuroprotection are still to be fully elucidated. The present study was designed to investigate the role played by PACAP and IL-6 in mediating neuroprotection after ischemia in a null mouse. Infarct volume, neurological deficits, and cytochrome c in cytoplasm were higher in PACAP(+/-) and PACAP(-/-) mice than in PACAP(+/+) animals after focal ischemia, although the severity of response was ameliorated by the injection of PACAP38. A decrease in mitochondrial bcl-2 was also accentuated in PACAP(+/-) and PACAP(-/-) mice, but the decrease could be prevented by PACAP38 injection. PACAP receptor 1 (PAC1R) immunoreactivity was colocalized with IL-6 immunoreactivity in neurons, although the intensity of IL-6 immunoreactivity in PACAP(+/-) mice was less than that in PACAP(+/+) animals. IL-6 levels increased in response to PACAP38 injection, an effect that was canceled by cotreatment with the PAC1R antagonist. However, unlike in wild-type controls, PACAP38 treatment did not reduce the infarction in IL-6 null mice. To clarify the signaling pathway associated with the activity of PACAP and IL-6, phosphorylated STAT (signal transducer and activator of transcription) 3, ERK (extracellular signal-regulated kinase), and AKT levels were examined in PACAP(+/-) and IL-6 null mice after ischemia. Lower levels of pSTAT3 and pERK were observed in the PACAP(+/-) mice, whereas a reduction in pSTAT3 was recorded in the IL-6 null mice. These results suggest that PACAP prevents neuronal cell death after ischemia via a signaling mechanism involving IL-6.

Animals↗

PubMed2006

Role of serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice.

This study examined the roles of presynaptic and postsynaptic serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice. The effect of fluvoxamine was attenuated by the serotonin type 1A receptor antagonist WAY100635 at 1 mg/kg, while it was enhanced by the antagonist at 0.1 mg/kg. Fluvoxamine (30 mg/kg) and WAY100635 (0.1 and 1 mg/kg) did not affect spontaneous locomotor activity. These results suggest that the effect of fluvoxamine is mediated by postsynaptic serotonin type 1A receptors and it is enhanced by an inhibition of presynaptic serotonin type 1A receptors.

Animals↗

PubMed2006

New insights into the central PACAPergic system from the phenotypes in PACAP- and PACAP receptor-knockout mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a structurally highly conserved neuropeptide and displays pleiotropic activity, including functioning as a neurotransmitter, neuromodulator, and neurotrophic factor. A series of recent experiments, including genetic manipulation of PACAP and its receptors, has led to better understanding of both normal and pathological processes in which PACAP has been proposed to play a role, and sheds light on previously uncharacterized functions of endogenous PACAP. The aim of this article is to briefly review the recent advances in understanding the role of PACAP in the central nervous system from PACAP- and PACAP receptor-deficient mice, particularly with respect to behavioral and neurological features, including psychomotor behavior, feeding, stress responses, memory performance, ethanol sensitivity, chronic pain, and circadian rhythms. This article also discusses their potential involvement in human diseases.

Animals↗

PubMed2006

Inhibition of self-renewal and induction of neural differentiation by PACAP in neural progenitor cells.

Several lines of evidence have suggested roles for pituitary adenylate cyclase-activating polypeptide (PACAP) in the developing nervous system. Previously, we showed that mRNA for PACAP, vasoactive intestinal peptide (VIP), and their three receptor subtypes, is differentially expressed in embryonic stem (ES) cells, ES cell-derived, neural stem cell-enriched cultures, and differentiated neurons, by using the five steps of the in vitro neuronal culture model of ES cell differentiation. Here, we examined the effects of PACAP on self-renewal and cell lineage determination of neural progenitor/stem cells. PACAP inhibited the basic fibroblast growth factor-induced proliferation (self-renewal), as assessed by neurosphere formation. PACAP increased microtubule-associated protein 2-positive neurons without affecting the number of cells positive for the neural stem cell marker nestin, astrocyte marker glial fibrillary acidic protein, and oligodendrocyte marker CNPase. These results suggest that PACAP inhibits self-renewal but, instead, induces early neuronal differentiation of neural progenitor cells.

Animals↗

PubMed2006

Lack of trimethyltin (TMT)-induced elevation of plasma corticosterone in PACAP-deficient mice.

Accumulating evidence implicates pituitary adenylate cyclase-activating polypeptide (PACAP) in a number of stress responses. By using PACAP-deficient mice, PACAP has been shown to have an in vivo role in the regulation of the sympathoadrenal axis, but a role in regulating the hypothalamo-pituitary-adrenal (HPA) axis has not been fully addressed. To elucidate the role of endogenous PACAP in HPA axis regulation during pathological conditions, mice lacking the Adcyap1 gene encoding the neuropeptide PACAP (Adcyap1-/-) were injected with trimethyltin (TMT), a neurotoxin known to induce neuronal damage and several systemic responses including elevated plasma corticosterone levels. In wild-type controls, TMT induced transient decreases in water and food intake, with a concomitant decrease in body weight; however, no significant changes were observed in Adcyap1-/- mice. Basal corticosterone levels were not significantly different between the mutant and wild-type mice. TMT induced a marked elevation of plasma corticosterone above basal levels in wild-type mice but no significant increase was seen in Adcyap1-/- mice. The present article suggests that PACAP is involved in the corticosterone release in some pathological conditions but not in the basal state.

Animals↗

PubMed2006

Serotonergic inhibition of intense jumping behavior in mice lacking PACAP (Adcyap1-/-).

Genetic manipulation of pituitary adenylate cyclase-activating polypeptide (PACAP) in mice has uncovered its involvement in psychomotor function. We previously observed that mice lacking the Adcyap1 gene encoding the neuropeptide PACAP (Adcyap1-/-) displayed intense jumping behavior when placed in a novel environment such as an open field. Here, we show that Adcyap1-/- mice manifest jumping behavior as early as at least 6 weeks of age when compared with wild-type mice and that the selective serotonin (5-HT) reuptake inhibitor, fluoxetine, as well as the serotonin precursor, 5-hydroxytryptophan, suppress jumping behavior. Our previous study showed a slight decrease in 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in Adcyap1-/- mouse brain. Taken together, these results suggest that there is a developmental aspect to the jumping behavior seen in Adcyap1-/- mice, and that jumping behaviour may involve the serotonergic system.

5-Hydroxytryptophan↗

PubMed2005

Effect of zotepine on dopamine, serotonin and noradrenaline release in rat prefrontal cortex.

The present study examined the effect of zotepine, an atypical antipsychotic, on the in vivo release of monoamines in the prefrontal cortex of rats using microdialysis. Local perfusion of zotepine at 10 microM increased extracellular levels of serotonin (5-HT), as well as dopamine and noradrenaline, in the prefrontal cortex. However, systemic administration of zotepine did not affect 5-HT release, although it increased the dopamine and noradrenaline release. These results suggest that the prefrontal 5-HT system does not contribute to the antidepressant effect of zotepine. The difference in the effect of zotepine between local and systemic treatment is discussed.

Animals↗

PubMed2005

Roles of PACAP and PHI as inhibitory neurotransmitters in the circular muscle of mouse antrum.

Mediators of neurogenic responses of the gastric antrum were studied in wild-type and pituitary adenylate cyclase-activating polypeptide (PACAP) -knockout (KO) mice. Electrical field stimulation (EFS) to the circular muscle strips of the wild-type mouse antrum induced a triphasic response; rapid transient relaxation and contraction, and sustained relaxation that was prolonged for an extended period after the end of EFS. The transient relaxation and contraction were completely inhibited by L-nitroarginine and atropine, respectively. The sustained relaxation was significantly inhibited by a PACAP receptor antagonist, PACAP(6-38). The antral strips prepared from PACAP-KO mice unexpectedly exhibited a tri-phasic response. However, the sustained relaxation was decreased to about one-half of that observed in wild-type mice. PACAP(6-38) inhibited EFS-induced sustained relaxation (33.5% of control) in PACAP-KO mice. Anti-peptide histidine isoleucine (PHI) serum partially (the 30% inhibition) or significantly (the 60% inhibition) inhibited the sustained relaxations in the wild-type and PACAP-KO mice, respectively. The immunoreactivities to the anti-PACAP and anti-PHI serums were found in myenteric ganglia of the mouse antrum. These results suggest that nitric oxide and acetylcholine mediate the transient relaxation and contraction, respectively, and that PACAP and PHI separately mediate the sustained relaxation in the antrum of the mouse stomach.

Animals↗

PubMed2005

PACAP- and PHI-mediated sustained relaxation in circular muscle of gastric fundus: findings obtained in PACAP knockout mice.

Mediators of neurogenic responses of the gastric fundus were studied in wild type and pituitary adenylate cyclase activating peptide (PACAP) knockout mice. Electrical field stimulation (EFS) to the circular muscle strips of the wild type mouse fundus induced a tri-phasic response, rapid transient contraction and relaxation, and sustained relaxation that was prolonged for an extended period after the end of EFS. The transient relaxation and contraction were completely inhibited by N(G)-nitro-L-arginine and atropine, respectively. The sustained relaxation was completely inhibited by a PACAP receptors antagonist, PACAP(6-38). The strips prepared from PACAP knockout mice exhibited a large contraction without rapid relaxation and unexpectedly, a sustained relaxation. However, the sustained relaxation was decreased to about a half of that observed in wild type mice. Anti-peptide histidine isoleucine (PHI) serum abolished the sustained relaxation in the knockout mice. The serum partially inhibited the sustained relaxation in wild type mice and PACAP(6-38) abolished the relaxation that remained after the antiserum-treatment. PHI relaxed the strips prepared from wild type mice. The relaxation was completely inhibited by PACAP(6-38). It was concluded that PACAP and PHI separately mediate the sustained relaxation in the mouse gastric fundus, and that nitric oxide and ACh mediate transient relaxation and contraction, respectively.

Animals↗