Occurrence of heat shock response in deafferented neurons in the substantia nigra of rats

The substantia nigra is innervated by massive inhibitory GABAergic projections from the striatum and globus pallidus, deafferentation of which is supposed to lead to anterograde trans-synaptic degeneration of the nigral neurons. An immunohistochemical method was used to examine the induction of 72,000 mol. wt heat shock protein in the substantia nigra following cerebral hemitransection or transient middle cerebral artery occlusion. At three and four days post-transection, strong immunoreactivity for 72,000 mol. wt heat shock protein was found in the ipsilateral substantia nigra pars reticulata. Light microscopic observation revealed a number of pars reticulata neurons showing strong immunoreactivity for 72,000 mol. wt heat shock protein in their perikarya and proximal processes. In addition, Golgi-like stained neurons with dystrophic features were occasionally observed in the ipsilateral substantia nigra pars reticulata. The immunoreactivity for 72,000 mol. wt heat shock protein in the ipsilateral pars reticulata gradually declined and almost disappeared by 15 days after transection. No apparent induction of 72,000 mol. wt heat shock protein was found in the substantia nigra pars compacta throughout the time period examined. Massive striatal ischemic injury produced by transient middle cerebral artery occlusion also induced expression of 72,000 mol. wt heat shock protein in the pars reticulata neurons three and four days postoperatively. These findings suggest that deafferentation of the striatal or striatopallidal inputs per se is a harmful stress for the substantia nigra pars reticulata neurons, inducing 72,000 mol. wt heat shock protein synthesis. The present data may contribute to our understanding of the molecular basis of the pathomechanism of the transneuronal regression of substantia nigra pars reticulata neurons, which may occur after removal of inhibitory GABAergic inputs.     

Postsynaptic nicotinic receptors on dopaminergic neurons in the substantia nigra pars compacta of the rat

Previous studies have shown that application of nicotinic agonists in the substantia nigra pars compacta increases the firing rate of dopaminergic neurons. We have used intracellular recordings to show that the response of these neurons to nicotine is postsynaptic, since it persists in the presence of low-calcium buffer containing tetrodotoxin. Burst firing in the presence of nicotine was not observed. The presence of postsynaptic nicotinic receptors was confirmed by immunohistochemical localization of the alpha4 nicotinic receptor subunit on dendrites in the substantia nigra pars compacta. The majority of tyrosine hydroxylase-immunopositive neurons in the substantia nigra pars compacta were also immunopositive for the alpha4 subunit. Immunohistochemical localization of the alpha4 and beta2 subunits in adjacent brain sections produced similar patterns of staining. Electron micrographs clearly indicated the presence of alpha4 subunit at postsynaptic densities. The predominant role of nicotinic receptors in the central nervous system has been suggested to be the presynaptic modulation of neurotransmitter release [McGehee D. S. and Role L. W. (1995) A. Rev. Physiol. 57, 521-546]. Although several postsynaptic nicotinic responses have also been reported in the literature, it is unclear as to whether the postsynaptic nicotinic receptors mediating responses to exogenously applied agonists are involved in synaptic transmission. From our electrophysiological and immunohistochemical results, we conclude that alpha4-containing nicotinic receptors are found at synapses on dopaminergic neurons. These synapses are similar to the cholinergic synapses described at these neurons, suggesting that nicotinic receptors are important in modulating the excitability of dopaminergic neurons by direct synaptic transmission.     

Rapid tolerance and crosstolerance to motor impairment effects of benzodiazepines, barbiturates, and ethanol

Susceptibility to develop Parkinson's disease has been linked to abnormalities of P450 enzyme function. Multiple P450 enzymes are expressed in brain but the relationship of these to Parkinson's disease is unknown. We have investigated the expression of P450 enzymes in the rat substantia nigra and their co-localization in tyrosine hydroxylase-positive neurons and astrocytes. Immunohistochemistry was performed using anti-peptide antisera against the following P450 enzymes: CYP1A1, CYP1A2, CYP2B1/2, CYP2C12, CYP2C13/2C6, CYP2D1, CYP2D4, CYP2E1, CYP3A1, CYP3A2 and NADPH-P450 oxidoreductase. Immunoreactivity in nigral cells was found only for CYP2E1 and CYP2C13/2C6. CYP2E1 immunoreactivity was localized to many midbrain nuclei including the substantia nigra pars compacta but not the substantia nigra pars reticulata while immunoreactivity to CYP2C13/2C6 was found in the substantia nigra pars compacta, substantia nigra pars reticulata and many other midbrain nuclei. Sections of rat midbrain double labelled for either CYP2E1 or CYP2C13/2C6 and tyrosine hydroxylase or glial fibrillary acidic protein were examined for co-localization by confocal laser scanning microscopy. CYP2E1 and CYP2C13/2C6 immunoreactivity was found in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta but not in glial cells. CYP2C13/2C6, but not CYP2E1, was also found in non-glial, non-tyrosine hydroxylase-expressing cells in the substantia nigra pars reticulata. Isoniazid induction increased CYP2E1 fluorescence signal intensity from nigral dopaminergic neurons. At least two P450 enzymes are found in nigral dopamine containing cells and one, namely CYP2E1, is selectively localized to this cell population. CYP2E1 is a potent generator of free radicals which may contribute to nigral pathology in Parkinson's disease. The expression of CYP2E1 in dopaminergic neurons in substantia nigra raises the possibility of a causal association with Parkinson's disease.     

Regulated expression of 5''-deleted mouse GLUT4 minigenes in transgenic mice: effects of exercise training and high-fat diet

Striatal lesions are known to cause the anterograde transneuronal degeneration of the substantia nigra pars reticulata (SNr) neurons in consequence to loss of GABAergic inhibitory striatonigral efferents. The present study was undertaken to examine whether long-term intraventricular administration of the GABA agonist muscimol could promote reformation of the striatonigral pathway arising from transplants by rescuing host SNr neurons from transneuronal death in rats with striatal ischemic lesions. Compared to nongrafted rats with striatal lesions, (i) a prominent axonal projection from the transplants to the ipsilateral substantia nigra, (ii) a significant increase in number of survived neurons in the ipsilateral SNr, and (iii) a significant reduction in number of apomorphine-induced turning behaviors were found in grafted animals with muscimol infusion, but not in those without muscimol administration. These findings suggest that preservation of the host target neurons for grafted cells may increase an efficacy of cerebral implants in establishment of the host-graft fiber connections, possibly, leading to functional restoration.     

Angiotensin II receptor binding associated with nigrostriatal dopaminergic neurons in human basal ganglia

In the human brain, receptor binding sites for angiotensin are found in the striatum and in the substantia nigra pars compacta overlying dopamine-containing cell bodies. In contrast, angiotensin-converting enzyme occurs in the substantia nigra pars reticulata and is enriched in the striosomes of the striatum. In this study, using quantitative in vitro autoradiography, we demonstrate decreased angiotensin receptor binding in the substantia nigra and striatum of postmortem brains from patients with Parkinson's disease. In the same brains the density of binding to angiotensin-converting enzyme shows no consistent change. We propose, from these results, that angiotensin receptors in the striatum are located presynaptically on dopaminergic terminals projecting from the substantia nigra. In contrast, the results support previous studies in rats demonstrating that angiotensin-converting enzyme is associated with striatal neurons projecting to the substantia nigra pars reticulata. These findings raise the possibility that newly emerging drugs that interact with the angiotensin system, particularly converting enzyme inhibitors and new nonpeptide angiotensin receptor blockers, may modulate the brain dopamine system.     

Regional distribution of monoamine vesicular uptake sites in the mesencephalon of control subjects and patients with Parkinson's disease: a postmortem study using tritiated tetrabenazine

The distribution of the vesicular monoamine transporter was investigated post mortem in the human ventral mesencephalon of control subjects (n = 7) and patients with Parkinson's disease (n = 4) using tritiated dihydrotetrabenzine binding and autoradiography. Tritiated dihydrotetrabenazine binding was characterized by a single class of sites with a Kd of 7 nM and a Bmax of 180 fmol/mg of protein in the substantia nigra. Tritiated dihydrotetrabenazine binding sites were heterogeneously distributed in the mesencephalon of control subjects: the density of tritiated dihydrotetrabenazine binding sites was high in the substantia nigra pars compacta, locus coeruleus and nucleus raphe dorsalis, moderate in the ventral tegmental area and low in the substantia nigra pars reticulata and catecholaminergic cell group A8. Within the substantia nigra, a zone with maximal density of tritiated dihydrotetrabenazine binding, two times higher than the mean estimate for the whole substantia nigra pars compacta, was detected in the medial part of the structure. The anatomical organization of the human ventral mesencephalon was analyzed on adjacent sections stained for acetylcholinesterase histochemistry and tyrosine hydroxylase immunohistochemistry. Tritiated dihydrotetrabenazine binding displayed the same characteristic regional pattern of distribution as that observed with tyrosine hydroxylase immunohistochemistry except in the nucleus raphe dorsalis, where no tyrosine hydroxylase immunoreactivity was detected. In parkinsonian brains, the level of tritiated dihydrotetrabenazine binding was dramatically decreased in all regions of the ventral mesencephalon analyzed except in the substantia nigra pars reticulata. In the substantia nigra pars compacta, the reduction was by 55% for the whole structure and by 65% in its medial zone, where binding site density was maximal. In most nigral subsectors analyzed, the decrease in density of tritiated dihydrotetrabenazine binding sites reached the level expected given the loss of tyrosine hydroxylase-positive cells observed. By contrast, the ratio of [3H]dihydrotetrabenazine binding to the number of tyrosine hydroxylase positive neurons was significantly increased in the zone of high [3H]dihydrotetrabenazine binding sites. This relative sparing of tritiated dihydrotetrabenazine binding sites may be due either to the contribution of other monoaminergic neurons such as serotoninergic neurons or more likely to hyperactivity of the still surviving dopaminergic neurons.     

Hyperpolarization induces a rise in intracellular sodium concentration in dopamine cells of the substantia nigra pars compacta

We investigated the effect of changes in membrane-voltage on intracellular sodium concentration ([Na+]i) of dopamine-sensitive neurons of the substantia nigra pars compacta in a slice preparation of rat mesencephalon. Whole-cell patch-clamp techniques were combined with microfluorometric measurements of [Na+]i using the Na+-sensitive probe, sodium-binding benzofuran isophthalate (SBFI). Hyperpolarization of spontaneously active dopamine neurons (recorded in current-clamp mode) caused the cessation of action potential firing accompanied by an elevation in [Na+]i. In dopamine neurons voltage-clamped at a holding potential of -60 mV elevations of [Na+]i were induced by long-lasting (45-60 s) voltage jumps to more negative membrane potentials (-90 to -120 mV) but not by corresponding voltage jumps to -30 mV. These hyperpolarization-induced elevations of [Na+]i were depressed during inhibition of I(h), a hyperpolarization-activated inward current, by Cs+. Hyperpolarization-induced elevations in [Na+]i might occur also in other cell types which express a powerful I(h) and might signal lack of postsynaptic activity.     

Expression of metabotropic glutamate receptor 1 isoforms in the substantia nigra pars compacta of the rat

Metabotropic glutamate receptors, which are linked via G-proteins to second messenger systems, have been implicated in the physiological regulation of dopaminergic neurons of the substantia nigra pars compacta as well as in neurodegeneration. Of the eight known metabotropic glutamate receptors, metabotropic glutamate receptor 1 is the most abundant subtype in the substantia nigra pars compacta. Metabotropic glutamate receptor 1 is alternatively spliced at the carboxy terminal region to yield five variants: 1a, 1b, 1c, 1d and a form recently identified in human brain, 1g. We used an antibody recognizing metabotropic glutamate receptor 1, and another recognizing the splice form la only, to study the localization of these receptors in dopaminergic neurons identified by the presence of tyrosine hydroxylase. Metabotropic glutamate receptor immunoreactivity was present within the somata, axons, and dendrites of substantia nigra pars compacta neurons. The 1a splice form specific antibody, however, did not label these cells, suggesting that they express a metabotropic glutamate receptor 1 splice form different from 1a. In situ hybridization with splice form-specific oligonucleotide probes was used to determine which of the other known metabotropic glutamate receptor 1 splice forms might be present in the substantia nigra pars compacta. Each probe produced a very distinct labelling pattern in the rat brain with the exception of the 1g specific probe which produced only background signal. Substantia nigra pars compacta neurons were most intensely labelled by the metabotropic glutamate receptor 1d splice form specific probe. Metabotropic glutamate receptor 1a was expressed weakly whereas there was no detectable 1b, c, or g signal in the substantia nigra pars compacta. These data demonstrate that metabotropic glutamate receptor 1 protein is present within the perikarya and processes of dopaminergic neurons in the substantia nigra pars compacta. The majority of this protein is not the 1a splice form, which is abundant in other brain regions, and may be the 1d isoform. Since splicing alters the carboxy terminus of the receptor, it is likely to affect the interaction of the receptor with intracellular signalling systems.     

Effects of YM872 on atrophy of substantia nigra reticulata after focal ischemia in rats

Middle cerebral artery (MCA) occlusion causes atrophy in the ipsilateral substantia nigra reticulata (SNR). The effects of glutamate AMPA receptor antagonism on SNR atrophy, which is supposed to inhibit excitatory inputs from the subthalamic nucleus to the SNR, was investigated in rats with permanent MCA occlusions. Histological examination revealed marked atrophy two weeks after MCA occlusion in the saline-treated control group. However, constant i.v. infusion of YM872, a selective AMPA receptor antagonist, for 2 weeks significantly reduced SNR atrophy; neurological deficits also decreased. These results suggest that the AMPA receptor may be involved in the pathogenesis of SNR atrophy during the subacute phase of focal cerebral ischemia.     

Striatal dopamine-glutamate interactions reflected in substantia nigra reticulata firing

To gain insight into the role of striatal dopamine in basal ganglia functioning, dopaminergic drugs alone and in combination with the glutamate receptor agonist kainic acid were infused in the lateral striatum via a microdialysis probe, while single-unit recordings of substantia nigra reticulata neurons were made in chloral hydrate-anaesthetized rats. Striatal infusion of dopaminergic drugs did not significantly affect the firing rate of substantia nigra reticulata neurons, which was related to the low activity of striatal cells under basal conditions, illustrated by the lack of effect of striatal infusion of TTX on substantia nigra reticulata activity. Under glutamate-stimulated conditions, striatal infusion of d-amphetamine potentiated the inhibition of substantia nigra reticulata neurons induced by striatal kainic acid. Thus, under stimulated but not basal conditions, the modulatory role of dopamine in the striatum could be demonstrated. Dopamine potentiated the inhibitory effect of striatal kainic acid on the firing rate of the basal ganglia output neurons.     

NMDA-NR1 receptor subunit mRNA expression in rat brain after 6-OH-dopamine induced lesions: a non-isotopic in situ hybridization study

Antisense digoxigenin-labeled deoxyoligonucleotides probes and non-isotopic in situ hybridization (HIS) techniques have been used to explore the NMDA-NR1 receptor subunit mRNA distribution in different brain areas of rats which had their dopaminergic nigrostriatal pathway previously lesioned with intracerebral administration of 6-OH-dopamine (6-OH-DA). Intense and significant hybridization signals for NR1 mRNA were found in dentate gyrus and regions CA1-CA2-CA3 of the hippocampus, in layers II-III and V-VI of the cerebral cortex, and in the cerebellum of sham-treated rats. Basal ganglia structures such as the striatum exhibited few NR1 mRNA hybridization signals as compared to the hippocampus and cerebral cortex. In contrast, both zona compacta and reticulata of substantia nigra (SN) showed a reduced number of cells with nevertheless intense NR1 mRNA HIS signals. The NR1 mRNA distribution in the brain was affected in a brain regional selective manner by 6-OH-DA induced lesions of DA neuronal systems. A striking increase in NR1 mRNA HIS signals was observed in both striata after unilateral lesioning with 6-OH-DA. Instead, in SN compacta but not in reticulata, a moderate but significant bilateral reduction of NR1 mRNA was observed after unilateral 6-OH-DA injection. No significant changes in NR1 mRNA were detected in cerebral cortex and other brain regions after 6-OH-DA treatment. These studies, and others reported in the literature, support the view that extensive lesions of nigrostriatal DA-containing neurons in the brain may trigger compensatory or adaptative responses in basal ganglia structures such as striatum and substantia nigra which involve glutamateric neurons and the genic expression of NMDA receptors.     

High-performance liquid chromatographic analysis of the new antitumour drug N-benzoylstaurosporine (CGP 41 251) and four potential metabolites in micro-volumes of plasma

Molecular events underlying the mechanism by which brain injury elicits delayed transneuronal degeneration of neurons remote from the site of initial injury are not well understood. In rats, acute injury of the caudate nucleus (CN) and globus pallidus (GP) by local injection of excitotoxic ibotenic acid (IA) or by transient forebrain ischemia resulted in delayed cell death of neurons in the substantia nigra reticulata (SNr). To elucidate the involvement of glutamate receptor mediated hyperactivity of neurons produced by loss of inhibitory inputs in this delayed degeneration of SNr neurons, the region-specific expression of an immediate early gene, c-fos, and the effect of glutamate receptor antagonists on the c-fos expression were examined by using immunocytochemical and in situ hybridization analysis. Following unilateral IA-injection into the CN and GP, a robust expression of c-fos mRNA and Fos protein was induced specifically in neurons of both subthalamic nucleus (STN) and SNr deafferented by the IA-lesions 36 h after IA-injection. The delayed expression of Fos-protein in SNr neurons lasted for 48 h longer than that in STN neurons. Following unilateral IA-injection confined to the CN, an intense but short-term expression of Fos-protein was exhibited only in neurons of the deafferented SNr. c-fos mRNA and Fos protein were not expressed in neurons of the substantia nigra compacta at any time points examined. The induction of c-fos mRNA and Fos protein in neurons of the STN and SNr following IA-lesions of the CN and GP was reduced markedly by non-NMDA receptor antagonist (GYKI52466), but not by NMDA receptor antagonist (MK-801). The region-specific c-fos expression implies that deprivation of inhibitory afferents (disinhibition) due to destruction of presynaptic neurons can induce increased activity of postsynaptic neurons. The effect of GYKI52466 on the c-fos gene expression in neurons of the deafferented STN and SNr suggests that activation of non-NMDA receptors may be involved in a pathophysiological cascade for the transneuronal degeneration of SNr neurons.     

d-Ala2]deltorphin I-like immunoreactivity in the adult rat brain: immunohistochemical localization

Using a specific antiserum recently raised against [D-Ala2]deltorphin I (DADTI: Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2), a highly selective ligand for delta-opioid receptors, we have previously demonstrated the occurrence of positive immunostaining in several structures of mouse brain. We describe here the neuroanatomical distribution patterns of DADTI-immunoreactive neuronal bodies, axons, and tanycytes in rat brain. Positive neuronal somata were localized mainly in the ventral mesencephalon, including the ventral tegmental area and the pars compacta of the substantia nigra. A minor population of positive somata was found in the pars reticulata and pars lateralis of the substantia nigra, raphe nuclei, supramammillary nucleus, and retrorubral reticular nucleus. All these regions, except for the supramammillary nucleus, contain dopamine cell bodies. Intensely stained positive nerve fibers could be traced along the medial forebrain bundle. Dense positive terminals were seen in the neostriatum, nucleus accumbens shell, olfactory tubercle, septal areas, cingulate, and medial prefrontal cortex. Double-immunostaining study revealed that, in the substantia nigra, almost all (97.8%) DADTI-positive neurons colocalized with tyrosine hydroxylase (TH), and the doubly stained cells occupied about one-third (29.1%) of the total population of TH-positive neurons. Only a few DADTI/TH-positive cells also stained for 28-kDa calbindin D, although many neurons double-stained for 28-kDa calbindin D and TH. In contrast, the supramammillary nucleus contained a number of DADTI-positive cells, which nearly always stained positively for 28-kDa calbindin D but did not stain for TH. The association of DADTI-like immunoreactivity with certain dopaminergic pathways seems of particular interest. A small population of DADTI-immunostained tanycytes was present in the ventral part of the third ventricle wall.     

Insulin-induced hypoglycemia does not impair the surge of luteinizing hormone secretion in the proestrous rat

Dopamine (DA) neurons in the ventral tegmental area and substantia nigra pars compacta were induced to fire in bursts with application of N-methyl-D-aspartate (NMDA, 20 microM) and apamin (100 nM) while recording intracellularly in the rat brain slice. L-Arginine (300 microM), a substrate for nitric oxide (NO) production, increased both the number of spikes per burst and the magnitude of interburst hyperpolarizations. Nitric oxide synthase inhibitors N-nitro-L-arginine methyl ester (L-NAME, 100 microM), N-nitro-L-arginine, and 7-nitroindazole inhibited NMDA-induced burst firing by reducing the number of spikes per burst. Moreover, L-arginine (100 microM) reversed the inhibition of burst firing produced by L-NAME. These findings suggest that NO facilitates NMDA-induced burst firing in DA neurons.     

Ventricular dilation over several weeks following induction of excitotoxic (systemic lithium/pilocarpine) lesions: potential role of damage to the substantia nigra reticulata

Time-dependent atrophy of cerebral space and enlargement of the lateral ventricles were noted in healthy rats 1 to 100 days after the induction of seizures by a single systemic injection of lithium and pilocarpine. The rate of atrophy was most strongly correlated (0.90) with the log (base 10) of the time in days. Most of the degeneration had occurred within about 20 to 30 days after the seizure-induced brain trauma. Concomitant reduction in the area of the substantia nigra reticulata was the most powerful predictor of ventricular enlargement at the level of the caudate-putamen.     

Rescuing neurons from trans-synaptic degeneration after brain damage: Helpful, harmful, or neutral in recovery of function?

Two experiments supported the hypothesis that muscimol (MC) spared substantia nigra pars reticulata (SNR) neurons by replacing gamma-aminobutyric acid (GABA) at the postsynaptic receptor. Exp 1 investigated behavioral impairments in 12 male rats who were given intraventricular infusions of MC or saline following unilateral axon-sparing damage to striatal cells. Exp 2 examined whether the detrimental effect on recovery caused by MC in Exp 1 was related to a protective effect on neurons in the SNR or to an effect of enhanced GABAergic activity in 16 rats assigned to diazepam (a GABA agonist) or vehicle groups. Behavioral impairments were assessed with tests of behaviors that included circling and forelimb adduction. (French abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Allergen immunotherapy inhibits airway eosinophilia and hyperresponsiveness associated with decreased IL-4 production by lymphocytes in a murine model of allergic asthma

Microelectrode recording methods for stereotactic localization of the subthalamic nucleus (STN) and surrounding structures are described. These methods accurately define targets for chronic deep brain stimulation in the treatment of Parkinson's disease. Mean firing rates and a burst index were determined for all recorded neurons, and responses to active and passive limb and orofacial movements were tested. STN neurons had a mean firing rate of 37+/-17 Hz (n = 248) and an irregular firing pattern (median burst index, 3.3). Movement-related activity and tremor cells were identified in the STN. Ventral to the STN, substantia nigra pars reticulata neurons had a mean rate of 71+/-23 Hz (n = 56) and a more regular firing pattern (median burst index, 1.7). Short trains (1-2 seconds) of electrical microstimulation of STN could produce tremor arrest but were not found to be useful for localization. Compared with data from normal monkeys our findings suggest that STN neuronal activity is elevated in Parkinson's disease.     

CD4+ T lymphocytes contribute to protective immunity induced in sheep and goats by Haemonchus contortus gut antigens

"Freezing" is a sudden, unforeseen state of immobility occurring independently of L-Dopa dosage timing and often presents in connection with walking, speech and hand movements. The immobility results from deficits in initiating or simultaneously and sequentially executing movements, in correcting inappropriate movements or planning movements. However, since the progression of motor activity is strongly dependent upon external stimuli, the patient can overcome the freezing phenomena with the aid of certain stimuli or subjective strategies. No consistent relationships have been found with respect to age, length of illness, L-dopa dosis or L-dopa treatment. Neurotransmitter models to explain the freezing phenomena are: a noradrenalin deficiency in locus coeruleus or alternately a dopamine deficiency in substantia nigra, pars compacta, which can possibly be coupled with a GABA deficiency in substantia nigra, pars reticulata. In addition to optimal drug therapy, patients require physiotherapeutical and ergotherapeutical assistance to develop subjectively effective strategies in counteracting freezing during everyday activities.     

Fertility results after ovarian transposition for pelvic malignancies treated by external irradiation or brachytherapy

The spontaneous recovery of nigrostriatal dopaminergic neurons was quantitatively analyzed with tyrosine hydroxylase (TH)-immunocytochemistry in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 young mice. A substantial reduction of striatal dopamine (DA) level was observed until 24 days following MPTP treatment. The TH-immunoreactive (IR) fibers and number of TH-positive cell bodies were also markedly reduced at 3 days after the toxin treatment. Thereafter, TH-IR fiber densities showed to progressively recover through the examining period. The number of TH-positive cell bodies in substantia nigra pars compacta were not changed during the recovery period. These results indicate that MPTP-treated mice have a potential for spontaneous regenerative sprouting in nigrostriatal dopaminergic system.