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D Nakahara

Publications and source records attributed to D Nakahara.

At least 19 recordsLinked to original sources
PubMed2001

Intracranial self-stimulation induces Fos expression in GABAergic neurons in the rat mesopontine tegmentum.

The cholinergic neurons which originate in the mesopontine tegmentum and innervate the midbrain ventral tegmental area have been proposed to play a key role in intracranial self-stimulation reward. This mesopontine area also contains GABA neurons. Detailed information is still lacking, however, about the relationship of cholinergic and GABAergic neurons in this region to self-stimulation reward. Therefore, using double immunostaining for Fos as a marker of neuronal activity and choline acetyltransferase as a marker of cholinergic neurons, or for Fos and GABA, we investigated whether self-stimulation of the medial forebrain bundle induces Fos expression within cholinergic and GABAergic neurons in two regions of the mesopontine tegmentum, i.e., pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus. Self-stimulation of the medial forebrain bundle for 1 h induced a large increase in the number of cells expressing Fos in both the pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus, when compared to control brains. However, the self-stimulation-induced expression of Fos was restricted mostly to GABA-, but not choline acetyltransferase-, immunostained cells. We also examined, using microdialysis, whether self-stimulation increases acetylcholine efflux in the ventral tegmental area, a terminal region of the mesopontine tegmentum cholinergic pathway. One hour of self-stimulation significantly increased acetylcholine efflux from this terminal area. These results indicate that intracranial self-stimulation of the medial forebrain bundle may increase acetylcholine release without affecting expression of Fos in cholinergic neurons, while the same stimulation may induce Fos expression in GABAergic neurons of the mesopontine tegmentum. GABAergic as well as cholinergic neurons in this area appear to be activated by self-stimulation reward in the medial forebrain bundle.

Acetylcholine↗
PubMed2001

Immunohistochemical characterisation of Fos-positive cells in brainstem monoaminergic nuclei following intracranial self-stimulation of the medial forebrain bundle in the rat.

Fos immunostaining was used as a marker of neuronal activity following intracranial self-stimulation (ICSS) of the medial forebrain bundle (MFB) in the rat, and was combined with immunostaining for tyrosine hydroxylase (TH), serotonin (5-HT), gamma-aminobutyric acid (GABA), or NR1 (one of the glutamate N-methyl- D-aspartate receptor subunits) for purposes of neurochemical identification. ICSS induced a significant but different degree of increase in the number of Fos-immunopositive (Fos+) cells in the six brainstem monoaminergic nuclei examined, which included the ventral tegmental area (VTA), substantia nigra pars compacta (SNc), dorsal raphe nucleus (DR), median raphe nucleus (MR), locus coeruleus (LC), and A7 noradrenaline cells. Densely labelled Fos+ cells were observed in the LC following ICSS, and many of these Fos+ cells were colocalized with TH. Similarly, many of Fos+ cells in the A7 and DR/MR were colocalized with TH and 5-HT, respectively. By contrast, a smaller number of Fos+ cells was detected in the VTA and SNc following the ICSS, and in these regions the majority of Fos+ cells were not colocalized with TH. Although results among regions quantitatively differed, the ICSS induced a significant increase in the number of double-labelled cells (GABA+/Fos+ or NR1+/Fos+) in all of the VTA, DR, and LC, in which the ICSS produced an ipsilaterally weighted increase in Fos-like immunoreactivity. These results suggest that ICSS of the MFB induces differential Fos expression within monoaminergic and GABAergic neurons in brainstem monoaminergic nuclei under modulation by glutamatergic afferents.

Animals↗
PubMed2000

Intracranial self-stimulation increases differentially in vivo hydroxylation of tyrosine but similarly in vivo hydroxylation of tryptophan in rat medial prefrontal cortex, nucleus accumbens and striatum.

We have examined using microdialysis the effect of intracranial self-stimulation (ICSS) on the in vivo hydroxylation rate of tyrosine and tryptophan in the medial prefrontal cortex (mPFC), nucleus accumbens (NAC) and striatum (STR). A decarboxylase inhibitor NSD-1015 was included in the perfusate, which enabled the simultaneous measurement of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) as an index of the in vivo hydroxylation level of tyrosine and tryptophan. When rats were exposed to 1 h of ICSS at the medial forebrain bundle (MFB), their extracellular levels of DOPA significantly increased in the mPFC, NAC and STR, but with a different magnitude and time course. The same stimulation produced a delayed increase in extracellular 5-HTP, compared to DOPA, in these brain regions. The profile of 5-HTP response demonstrated no apparent difference among the regions. These findings indicate that ICSS of the MFB can increase differentially the in vivo hydroxylation of tyrosine but similarly the in vivo hydroxylation of tryptophan in the mPFC, NAC and STR.

5-Hydroxytryptophan↗
PubMed2000

Modest neuropsychological deficits caused by reduced noradrenaline metabolism in mice heterozygous for a mutated tyrosine hydroxylase gene.

Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme for the biosynthesis of catecholamines that are considered to be involved in a variety of neuropsychiatric functions. Here, we report behavioral and neuropsychological deficits in mice carrying a single mutated allele of the TH gene in which TH activity in tissues is reduced to approximately 40% of the wild-type activity. In the mice heterozygous for the TH mutation, noradrenaline accumulation in brain regions was moderately decreased to 73-80% of the wild-type value. Measurement of extracellular noradrenaline level in the frontal cortex by the microdialysis technique showed a reduction in high K(+)-evoked noradrenaline release in the mutants. The mutant mice displayed impairment in the water-finding task associated with latent learning performance. They also exhibited mild impairment in long-term memory formation in three distinct forms of associative learning, including active avoidance, cued fear conditioning, and conditioned taste aversion. These deficits were restored by the drug-induced stimulation of noradrenergic activity. In contrast, the spatial learning and hippocampal long-term potentiation were normal in the mutants. These results provide genetic evidence that the central noradrenaline system plays an important role in memory formation, particularly in the long-term memory of conditioned learning.

Animals↗
PubMed2000

Lack of glucocorticoids attenuates the self-stimulation-induced increase in the in vivo synthesis rate of dopamine but not serotonin in the rat nucleus accumbens.

Our previous study demonstrated that intracranial self-stimulation of the medial forebrain bundle can increase the in vivo synthesis turnover rate of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of adrenal-intact rats. The present study examined using microdialysis whether such increases in DA and 5-HT syntheses are influenced by adrenal hormones, which are also activated following intracranial self-stimulation. A decarboxylase inhibitor, NSD-1015, was perfused through reversed microdialysis which enabled the simultaneous measurement of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) as an index of the in vivo turnover rate of DA and 5-HT syntheses. Adrenalectomy (ADX) attenuated significantly the self-stimulation-induced increase in dialysate levels of DOPA but not 5-HTP. Corticosterone (Cort) replacement reversed the attenuation in DOPA levels in adrenalectomized rats. The finding indicates that activation of DA synthesis in vivo in the nucleus accumbens during intracranial self-stimulation is dependent on, whereas that of 5-HT synthesis is independent of glucocorticoid modulation.

5-Hydroxytryptophan↗
PubMed1999

Differential effect of immobilization stress on in vivo synthesis rate of monoamines in medial prefrontal cortex and nucleus accumbens of conscious rats.

We have used microdialysis to measure the in vivo hydroxylation level of tyrosine and tryptophan in the medial prefrontal cortex and nucleus accumbens of conscious rats that were subjected to immobilization. The brain was perfused with an inhibitor of aromatic L-amino acid decarboxylase, 3-hydroxybenzylhydrazine, and the amount of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) accumulating in the dialysate was measured as an index of the in vivo hydroxylation rate of tyrosine and tryptophan. One hour of immobilization caused a significant increase in extracellular DOPAin the medial prefrontal cortex but not nucleus accumbens. The same manipulation produced a significant and more prolonged elevation in extracellular 5-HTP in the nucleus accumbens as well as medial prefrontal cortex. The observed profile of stress-induced 5-HTP response was comparable in two brain regions. The results suggest that in vivo catecholamine synthesis is heterogenous, whereas in vivo serotonin synthesis is homogenous, with respect to responsiveness to stress in the medial prefrontal cortex and nucleus accumbens.

5-Hydroxytryptophan↗
PubMed1999

Regional differences in desensitization of c-Fos expression following repeated self-stimulation of the medial forebrain bundle in the rat.

The acute self-stimulation of the medial forebrain bundle was reported to induce the expression of c-Fos, the protein product of c-fos, an immediate early gene, in the central nervous system. In the present study, we examined regional changes in c-Fos expression in several reward-related areas of rat brain in response to short- and long-term exposure to self-stimulation of the medial forebrain bundle. Short-term one-hour stimulation of the medial forebrain bundle for one day after training, which evoked steady self-stimulation behavior, significantly increased the number of c-Fos-positive neurons bilaterally in all of 15 brain structures assayed, as compared to the non-stimulation control. Among them, structures showing a larger number of the stained neurons on the stimulated side were the anterior olfactory nucleus, amygdala, medial caudate-putamen complex, lateral septum, bed nucleus of the stria terminals, ventral pallidum, substantia innominata, lateral preoptic area, medial preoptic area, lateral hypothalamus rostral to the stimulating electrodes, and substantia nigra. Long-term stimulation of the medial forebrain bundle once daily for five successive days, which maintained consistently stable self-stimulation behavior, also increased the number of c-Fos-positive neurons in the aforementioned structures, as compared to the control. However, the long-term rewarding stimulation diminished the increased number of labeled neurons, as compared to the short-term rewarding stimulation. Seven areas, medial caudate-putamen complex, ventral pallidum, substantia innominata, lateral preoptic area, medial preoptic area, rostral lateral hypothalamus and substantia nigra, showed asymmetrical, ipsilateral predominance after the short- and long-term stimulation. However, the stained neuron count in those areas after the long-term stimulation was reduced to less than 50% of that found after the short-term stimulation with the exception of lateral preoptic area and rostral lateral hypothalamus. The results suggest that the development of desensitization of c-Fos response may differ among the reward-relevant brain regions as a consequence of repeated self-stimulation. They also indicate that a larger portion of neurons in the lateral preoptic area and rostral lateral hypothalamus may be implicated in both short- and long-term self-stimulations of the medial forebrain bundle.

Animals↗
PubMed1998

Characterization of beta-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study.

In vivo microdialysis was used to investigate the effect of beta-phenylethylamine on extracellular levels of monoamines and their metabolites in the nucleus accumbens of conscious rats. At all doses tested (1, 10 and 100 microM), infusion of beta-phenylethylamine through the microdialysis probe significantly increased extracellular levels of dopamine in the nucleus accumbens. These increases were dose-related. The increase in dopamine levels induced by 100 microM beta-phenylethylamine was not affected by co-perfusion of 4 microM tetrodotoxin. The ability of 100 microM beta-phenylethylamine to increase the extracellular level of dopamine was comparable to that of the same dose of methamphetamine. On the other hand, beta-phenylethylamine had a much less potent enhancing effect on 5-hydroxytryptamine (5-HT) than dopamine levels. Only the highest dose (100 microM) caused a statistically significant effect on 5-HT levels. Over the dose range tested (1, 10 and 100 microM), beta-phenylethylamine had no effect on extracellular metabolite levels of dopamine and 5-HT. The results suggest that beta-phenylethylamine increases the efflux of monoamines, preferentially dopamine, without affecting monoamine metabolism, in the nucleus accumbens.

Animals↗
PubMed1998

Generation of reactive oxygen species accounts for cytotoxicity of an endogenous dopaminergic neurotoxin, (R)-N-methylsalsolinol, to differentiated dopaminergic SH-SY5Y cells.

The mechanism of the cytotoxicity of endogenous dopamine-derived (R)-1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)-N-methylsalsolinol] to differentiated human dopaminergic neuroblastoma SH-SY5Y cells was studied using a reduction-oxidation indicator, Alamar Blue. N-Methylsalsolinol and its oxidation product, 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, were found to inhibit oxidative phosphorylation, as shown by the Redox capacity. Antioxidants, such as reduced glutathione, catalase, Tris and n-propyl gallate, reduced the cytotoxicity of N-methylsalsolinol, suggesting that hydroxyl radical was the major reactive oxygen species for the cytotoxicity. Deprenyl also protected the cells from the decrease of the Redox capavity by N-methylsalsolinol. However, antioxidants did not protect the cells from the cytotoxicity of the catechol isoquinolinium ion. The results suggest that oxidative stress induced by hydroxyl radical may be involved in the cell death of dopaminergic neurons by N-methylsalsolinol.

Cell Differentiation↗
PubMed1997

Cytotoxicity of endogenous isoquinolines to human dopaminergic neuroblastoma SH-SY5Y cells.

Endogenous isoquinolines with and without catechol structure have been proposed to be neurotoxins specific for dopamine neurons. In this paper they were examined for the cytotoxicity of human dopaminergic neuroblastoma SH-SY5Y cells. The cytotoxicity was quantitatively determined using Alamar Blue assay, by which the reduction-oxidation potency in the living cells can be measured spectrometrically. 1,2-Dimethyl-6,7-dihydroxyisoquinolinium ion [1,2-DMDHIQ+], an oxidation product of a parkinsonism-inducing isoquinoline, 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahroisoquinoline [N-methyl-(R)salsolinol, NM(R)Sal] was found to be the most potent toxin among isoquinolines examined. In general, catechol isoquinolines were more toxic than isoquinolines without catechol structure. With and without catechol structure, the oxidized isoquinolinium ion having methyl groups at C-1 and N-2 positions proved to be more cytotoxic than the simple isoquinolines. The involvement of 1,2-DMDHIQ+ to the neurotoxicity of NM(R)Sal was suggested and discussed.

Cell Survival↗
PubMed1996

Dopamine-derived endogenous 1(R),2(N)-dimethyl-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline, N-methyl-(R)-salsolinol, induced parkinsonism in rat: biochemical, pathological and behavioral studies.

Dopamine-derived 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol, Sal) and related compounds were examined for their selective neurotoxicity to dopamine neurons by injection into the rat striatum. Among salsolinol analogs examined, only N-methyl-(R)- salsolinol (NM(R)Sal) induced behavioral changes very similar to those in Parkinson's disease: hypokinesia, stiff tail, limb twitching at rest and postural abnormality. Biochemical analysis showed that after NM(R)Sal injection, NM(R)Sal itself and its oxidation product, 1-2-dimethyl-6,7-dihydroxyisoquinolinium ion (DMDHIQ+) accumulated in the striatum, and also in the substantia nigra definite amount of DMDHIQ+ was detected. Dopamine and noradrenaline were reduced in the striatum and more markedly in the substantia nigra, whereas serotonin and its metabolite were not affected. Morphological analysis revealed selective reduction of tyrosine hydroxylase (TH)-containing neurons in the substantia nigra after continuous NM(R)Sal administration in the striatum. These results demonstrate the selective cytotoxicity of NM(R)Sal to the dopamine neurons in the substantia nigra, and the possible involvement of this 6,7-dihydroxy-isoquinoline in the pathogenesis of Parkinson's disease is discussed.

Animals↗
PubMed1996

Effects of moclobemide on forced-swimming stress and brain monoamine levels in mice.

Moclobemide [Ro 11-1163, p-chloro-N-(2-morpholinoethyl)benzamide, AURORIX] is known as an antidepressant and a reversible inhibitor of type A monoamine oxidase. In the present study, a forced swimming test was applied to mice to evaluate behavioral and neurochemical effects of this drug. During forced swimming posture of immobility, a typical behavioral change, was observed, and biochemical analysis of the brain revealed significant changes in the monoamine levels. The norepinephrine concentration was reduced, while that of its product was increased, indicating increase in norepinephrine turnover. The stress increased the levels of dopamine, serotonin, and their metabolites. Moclobemide significantly improved the immobility elicited by the test, and it could prevent the changes in the turnover of norepinephrine, dopamine, and serotonin induced by the stress. These results suggest that moclobemide may improve the behavioral changes induced by the forced swimming through its effects on monoamine metabolism.

Animals↗
PubMed1995

N-methyl-4-phenylpyridinium and an endogenously formed analog, N-methylated beta-carbolinium, inhibit striatal tyrosine hydroxylation in freely moving rats.

The effects of N-methyl-4-phenylpyridinium (MPP+) and its endogenous analog, 2,9-di-methyl-norharmanium (2,9-Me2NH+), on in vivo tyrosine hydroxylation were evaluated in freely moving rats. MPP+ gradually but almost completely reduced tyrosine hydroxylation, even at a dose as low as 0.05 mM. This effect was considered to be caused by the inhibition of tyrosine hydroxylase (TH) activation. On the contrary, 1 mM 2,9-Me2NH+ rapidly reduced 3,4-dihydroxyphenylalanine production to 10% of the basal level only during its perfusion, indicating direct inhibition of TH activity. The present study revealed that MPP+ and 2,9-Me2NH+ were taken up into dopaminergic neurons and then inhibited in vivo dopamine synthesis prior to cell death possibly in different manners.

1-Methyl-4-phenylpyridinium↗
PubMed1995

Toluene induces behavioral activation without affecting striatal dopamine metabolism in the rat: behavioral and microdialysis studies.

We examined the effects of toluene on the release of dopamine (DA) and its metabolites in rat striatum using microdialysis. Intraperitoneal injection of 800 mg/kg toluene significantly increased motor activity in rats, as did methamphetamine (MAP) (1 mg/kg). However, 800 mg/kg toluene did not affect the extracellular levels of DA, 3,4-dihydroxyphenylacetic acid, homovanillic acid, or 5-hydroxyindoleacetic acid. This is in contrast to MAP, which significantly increased extracellular DA and decreased the extracellular levels of its metabolites. These results suggest that toluene-induced behavioral augmentation may not be associated with alterations in DA or serotonin neurochemistry such as are associated with MAP-induced behavioral augmentation.

Animals↗
PubMed1994

Peripherally administered (6R)-tetrahydrobiopterin increases in vivo tyrosine hydroxylase activity in the striatum measured by microdialysis both in normal mice and in transgenic mice carrying human tyrosine hydroxylase.

The intraperitoneal administration of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4), the natural cofactor of tyrosine hydroxylase (TH), increased the accumulation of L-3,4-dihydroxyphenylalanine (DOPA) measured using microdialysis under the inhibition of aromatic L-amino acid decarboxylase by NSD-1015 (in vivo TH activity) in the striatum both of transgenic mice carrying human TH gene and of non-transgenic mice, to a similar extent by about 4-fold. The results indicate that the peripherally administered 6R-BH4 activates in vivo TH activity in the nigrostriatal dopamine neurons in both non-transgenic and transgenic mice.

Animals↗
PubMed1994

Characterization of the in vivo action of (R)-salsolinol, an endogenous metabolite of alcohol, on serotonin and dopamine metabolism: a microdialysis study.

Using a microdialysis-HPLC technique in conscious rats, we examined the action of (R)-1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-salsolinol (R-Sal), a possible endogenous metabolite of alcohol, on serotonin (5-HT) and dopamine (DA) metabolism in four regions of the brain: the striatum, the substantia nigra, the hippocampus and the hypothalamus. Following 1 mM R-Sal perfusion, the dialysate level of 5-HT in the striatum markedly increased from non-detectable levels to 4259.2 +/- 617.5 nM, while DA increased from 3.4 +/- 0.9 nM to 206.0 +/- 56.5 nM. This increase was one order of magnitude larger in 5-HT than in DA. Conversely, the output of 5-hydroxyindoleacetic acid decreased markedly to non-detectable levels, while 3,4-dihydroxyphenylacetic acid and homovanillic acid outputs decreased below 40% of basal levels. These effects were dose-related to R-Sal (1 microM to 1 mM) and were confirmed also in 3 other brain regions. The R-Sal-induced responses in the striatum were observed even after pretreatment of 2 microM tetrodotoxin, a blocker of nerve-firing activity, via the dialysis membrane. The repetitive perfusion with 1 mM R-Sal into the striatum induced the reproducible response of 5-HT and DA. Furthermore, the potencies of 1 mM R-Sal to increase the output of 5-HT and DA were approximately 783.0-fold and 2.6-fold stronger, respectively, than those of the same dose of methamphetamine. The results suggest that R-Sal acts to stimulate a release of monoamines, 5-HT preferentially, with inhibition of monoamine oxidase and catechol-O-methyltransferase activities.

3,4-Dihydroxyphenylacetic Acid↗