Hideyuki Nakane

CRF receptor antagonist attenuates stress-induced noradrenaline release in the medial prefrontal cortex of rats

Noradrenaline release in rat medial prefrontal cortex (PFC) was measured using a brain microdialysis technique. Immobilization stress increased noradrenaline release to a maximum level of 248.7 +/- 12.8% of the basal release, which was significantly attenuated by preinjection of alpha-helical CRF9-41 (50 micrograms/rat) into the lateral cerebroventricle. Intracerebroventricular injection of CRF also increased noradrenaline release in the medial PFC. These results suggest that immobilization-stress facilitates noradrenaline release in the medial PFC through activation of the CRF system in the brain.

Serotonergic activity in the rat striatum after intrastriatal transplantation of fetal nigra as measured by microdialysis.

In vivo microdialysis was used to examine the effects of dopaminergic transplants on extracellular concentrations of dopamine (DA), serotonin (5-HT), and their precursors and major metabolites in the denervated rat striatum. Dialysis perfusates were collected from intact 6-hydroxydopamine (6-OHDA) lesion plus sham grafted, and lesion plus fetal substantia nigra (SN) grafted striata. The SN transplants ameliorated the reduction of striatal DA and dihydroxyphenylacetic acid (DOPAC) levels in rats with unilateral 6-OHDA lesions of the mesostriatal pathway. The transplants also increased extracellular levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the denervated striatum. In response to NSD-1015 (an inhibitor of aromatic L-amino acid decarboxylase, AADC), 5-hydroxytryptophan (5-HTP) levels were substantially elevated in the SN grafted striata as compared with those in the sham grafted controls, which continued even after subsequent administration of L-3,4-dihydroxyphenylalanine (L-DOPA, 100 mg/kg i.p.). Immunohistochemical analysis showed hyperinnervation of 5-HT fibers in the grafted striatum, which was consistent with the results of microdialysis experiments. These results indicated that implantation of SN grafts into the 6-OHDA-lesioned striatum of rats induces hyperactivity of 5-HT synthesis, release and metabolism.

Peripherally administered tetrahydrobiopterin increases in vivo tryptophan hydroxylase activity in the striatum after transplantation of fetal ventral mesencephalon in six hydroxydopamine lesioned rats

The intraperitoneal administration of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4), a natural cofactor for tyrosine hydroxylase and tryptophan hydroxylase (TRH), dose-dependently increased the extracellular concentration of 6R-BH4 itself in rat striatum. The concentration was investigated by in vivo microdialysis and measured simultaneously with 5-hydroxytryptophan (5-HTP), a precursor of serotonin, by high performance liquid chromatography with electrochemical detection. The 6R-BH4 (50 mg/kg, i.p.) administration increased the accumulation of 5-HTP as an index of in vivo TRH activity under the inhibition of aromatic L-amino acid decarboxylase by NSD-1015 in the striatum of both normal control and 6-hydroxydopamine lesioned rats with intrastriatal transplants of fetal ventral mesencephalon (VM). The results suggest that TRH in the striatum of both control and VM-grafted rats is activated by 6R-BH4 penetrating into the brain from the blood.

Methamphetamine-induced Fos expression in the substantia nigra pars reticulata in rats with a unilateral 6-OHDA lesion of the nigrostriatal fibers

In rats with a unilateral 6-hydroxydopamine (6-OHDA)-induced lesion in the nigrostriatal fibers, methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI), which was inhibited by pretreatment with N-methyl-D-aspartate antagonist MK-801 (1 mg/kg, i.p.), not only in the medial striatum contralateral to the lesion but also in the substantia nigra pars reticulata (SNr) ipsilateral to the lesion. Thus, hemispheric asymmetries in FLI were induced by methamphetamine in the medial striatum and the SNr in the 6-OHDA model of turning which may be related to the altered function of glutamatergic transmission.

Different response between production of free radicals induced by central and peripheral administration of interleukin-1β in conscious rats

We examined whether central or peripheral administration of interleukin-1beta (IL-1beta) might change levels of nitric oxide (NO) and hydroxyl radical (*OH) in the medial prefrontal cortex (mPFC). Extracellular levels of NO metabolites (NOx(-)) and 2,3-dihydroxybenzoic acid (2,3-DHBA), as a marker of *OH production, were determined with an in vivo microdialysis technique in conscious rats. In the mPFC, central administration of IL-1beta into the mPFC resulted in dose-dependent increases in levels of both NOx(-) and 2,3-DHBA. In contrast, peripheral administration of IL-1beta significantly increased NOx(-) levels but not 2,3-DHBA levels. Perfusion of Mn(III) tetrakis (4-benzoic acid) porphyrin chloride, a superoxide (O(2)(-)) dismutase mimic, into the mPFC reduced the increases in levels of 2,3-DHBA induced by centrally administered IL-1beta, but enhanced the increases in levels of NOx(-) induced by centrally administered IL-1beta. The present results show a different response in free radical productions in the mPFC between central and peripheral administration of IL-1beta. This finding should be useful for our understanding of the response of NO and free radicals such as *OH and O(2)(-) in the mPFC after central and peripheral administration of IL-1beta.