Ameliorative role of aspirin in paraquat‐induced lung toxicity via mitochondrial mechanisms

Paraquat (PQ) has accounted for numerous suicide attempts in developing countries. Aspirin (ASA) as an adjuvant treatment in PQ poisoning has an ameliorative role. And, it's uncoupling of mitochondrial oxidative phosphorylation role has been well established. The current study aimed at examining the aspirin mechanism on lung mitochondria of rats exposed to PQ. Male rats were randomly allocated in five groups: Control group, PQ group (50 mg/kg; orally, only on the first day), and PQ + ASA (100, 200, and 400 mg/kg; i.p.) groups for 3 weeks. Mitochondrial indices and respiratory chain‐complex activities were determined. PQ induced lung interstitial fibrosis; however, ASA (400 mg/kg) led to decrease in this abnormal alteration. In comparison with PQ group, complex II and IV activity, and adenosine triphosphate content in ASA groups had significantly increased; however, reactive oxygen species production, mitochondrial membrane permeabilization, and mitochondrial swelling were significantly reduced. In conclusion, aspirin can alleviate lung injury induced by PQ poisoning by improving mitochondrial dynamics.     

Maneb and paraquat-induced modulation of toxicant responsive genes in the rat liver: comparison with polymorphonuclear leukocytes

Experimental studies have shown that toxicant responsive genes, cytochrome P450s (CYPs) and glutathione S-transferases (GSTs) play a critical role in pesticide-induced toxicity. CYPs play pro-oxidant role and GSTs offer protection in maneb (MB) and paraquat (PQ)-induced brain and lung toxicities. The present study aimed to investigate the effect of repeated exposures of MB and/or PQ on lipid peroxidation (LPO), glutathione content (GSH) and toxicant responsive genes, i.e., CYP1A1, 1A2, 2E1, GSTA4-4, GSTA1-1 and GSTA3-3 in the liver and to correlate the same with polymorphonuclear leukocytes (PMNs). A significant augmentation in LPO and reduction in GSH content was observed in a time of exposure dependent manner in the liver and PMNs of MB and/or PQ treated animals. The expression and catalytic activity of CYP2E1 and GSTA4-4 were significantly increased following MB and/or PQ exposure both in the liver and PMNs. Although the expression of GSTA3-3 was increased, the expression of GSTA1-1 was unaltered after MB and/or PQ treatment in both the liver and PMNs. MB augmented the expression and catalytic activity of CYP1A1 in the liver, however, CYP1A2 was unaffected. PQ, on the other hand, significantly increased hepatic CYP1A2 expression and catalytic activity. MB and/or PQ did not produce any significant changes in CYP1A1 and CYP1A2 in PMNs. The results of the study thus demonstrate that MB and PQ differentially regulate hepatic CYP1A1 and CYP1A2 while LPO, GSH, CYP2E1, GSTA4-4 and GSTA3-3 are modulated in the similar fashions both in the liver and PMNs.     

Evidence that Extracellular Concentrations of Dopamine Are Regulated by Noradrenergic Neurons in the Frontal Cortex of Rats

Abstract: Experiments were performed to confirm that noradrenergic terminals regulate extracellular concentrations of dopamine (DA) in the frontal cortex of rats. The effects of 20 mg/kg 1-[2-[bis(4-fluorphenyl)methoxy]-ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), a selective inhibitor of DA uptake, and 2.5 mg/kg desipramine (DMI) on the extracellular concentrations of DA in the frontal cortex and striatum were studied in rats given 6-hydroxydopamine (6 µg/µl) bilaterally into the locus coeruleus to destroy noradrenergic terminals. GBR 12909 increased dialysate DA similarly in the striatum of vehicle and 6-hydroxydopamine-treated rats, whereas in the frontal cortex it raised DA concentrations only in lesioned animals. DMI raised extracellular DA concentrations in the frontal cortex but not in the striatum of controls. The effect of DMI on cortical DA was abolished by the 6-hydroxydopamine lesion. GBR 12909, at a subcutaneous dose of 20 mg/kg, further increased cortical dialysate DA in rats given DMI intraperitoneally at 20 mg/kg or through the probe at 10⁻⁵ mol/L. The data support the hypothesis of an important regulation of the extracellular concentrations of DA in the frontal cortex by noradrenergic terminals.     

Reserpine pretreatment prevents increases in extracellular striatal dopamine following L-DOPA administration in rats with nigrostriatal denervation

The influence of L-DOPA and reserpine on extracellular dopamine (DA) levels in the striatum of intact and dopaminergic denervated rats was studied using the brain microdialysis technique. In intact rats, reserpine (5 mg/kg s.c.) reduced extracellular DA levels to 4% of basal values. L-DOPA (50 mg/kg i.p.) had no effect on extracellular DA levels in reserpine-pretreated rats. In rats with 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic system, basal levels of extracellular DA were low but markedly increased by L-DOPA (50 mg/kg i.p.). In 6-hydroxydopamine-lesioned rats, pretreatment with reserpine (5 mg/kg s.c.) diminished L-DOPA (50 mg/kg i.p.)-induced increases in extracellular DA levels to 16% of those obtained in denervated animals not pretreated with reserpine (p<0.01). These results suggest that in the intact striatum, extracellular DA stems mainly from vesicular storage sites and that in the striatum with dopaminergic denervation, a large part of the L-DOPA-derived extracellular DA is also derived from a vesicular pool that is released by an exocytosis mechanism.     

Serotonin Agonists Reduce Dopamine Synthesis in the Striatum Only when the Impulse Flow of Nigro-Striatal Neurons Is Intact

The effects of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) and m-chlorophenylpiperazine (CPP), two 5-hydroxytryptamine (5-HT, serotonin) agonists, on the accumulation of 3,4-dihydroxyphenylalanine (DOPA] were studied in the striatum of rats treated with gamma-butyrolactone (GBL). Unlike 2 mg/kg i.p. apomorphine, neither 5 mg/kg i.p. 5-MeO-DMT nor 2.5 mg/kg i.p. CPP significantly reduced the GBL-induced increase in DOPA accumulation in the striatum. 5-MeO-DMT and CPP significantly reduced DOPA accumulation in animals that had received the aromatic amino acid decarboxylase inhibitor Ro 4-4602 but not GBL. 5-HT (10 micrograms in 0.5 microliter) injected in the substantia nigra, pars compacta, like GBL, significantly increased Ro 4-4602-induced accumulation of DOPA in the striatum. The data indicate that 5-HT agonists can reduce 3,4-dihydroxyphenylethylamine (DA, dopamine) synthesis in the striatum of rats only when the impulse flow of DA neurons is intact. An indirect effect through mechanisms controlling DA synthesis in the striatum, for instance cholinergic and GABA-ergic neurons, is suggested.     

Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): implications to manganese-induced parkinsonism

The long-term consequences of chronic manganese (Mn) exposure on neurological health is a topic of great concern to occupationally-exposed workers and in populations exposed to moderate levels of Mn. We have performed a comprehensive assessment of Mn effects on dopamine (DA) synapse markers using positron emission tomography (PET) in the non-human primate brain. Young male Cynomolgus macaques were given weekly i.v. injections of 3.3-5.0 mg Mn/kg (n = 4), 5.0-6.7 mg Mn/kg (n = 5), or 8.3-10.0 mg Mn/kg (n = 3) for 7-59 weeks and received PET studies of various DA synapse markers before (baseline) and at one or two time points during the course of Mn exposure. We report that amphetamine-induced DA release measured by PET is markedly impaired in the striatum of Mn-exposed animals. The effect of Mn on DA release was present in the absence of changes in markers of dopamine terminal integrity determined in post-mortem brain tissue from the same animals. These findings provide compelling evidence that the effects of Mn on DA synapses in the striatum are mediated by inhibition of DA neurotransmission and are responsible for the motor deficits documented in these animals.     

Prolonged Alterations in Canine Striatal Dopamine Metabolism Following Subtoxic Doses of l-Methyl-4-Phenyl- 1,2,3,6-Tetrahydropyridine (MPTP) and 4''-Amino-MPTP Are Linked to the Persistence of Pyridinium Metabolites

Single toxic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).HCl (2.5 mg/kg i.v.) and 4'-amino-MPTP.2HCl (22.5 mg/kg) induce loss of striatal dopamine (DA) and tyrosine hydroxylase (TH) activity and of nigral DA neurons in the dog. To examine the subacute neurochemical changes induced by low doses of MPTP and 4'-amino-MPTP, dose-response studies of these compounds were carried out in the dog, using 6- and 3-week survival times for these two compounds, respectively. Low single doses of MPTP (1.0, 0.5, and 0.1 mg/kg i.v.) and 4'-amino-MPTP (15, 7.5, and 3.75 mg/kg i.v.) did not cause depletion of canine striatal DA or TH or a loss of nigral neurons. However, levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were decreased in a dose-related fashion, with significant loss of DOPAC being evident 6 weeks after the lowest administered dose of MPTP and 3 weeks after 4'-amino-MPTP. This selective loss of DA metabolites following nontoxic doses of MPTP and 4'-amino-MPTP led to a shift in the ratio of DA to DOPAC or HVA, which was characteristic for each compound. The measurement of striatal 1-methyl-4-phenylpyridinium (MPP+) and 4'-amino-MPP+ levels revealed that high concentrations (up to 150 microM) persist in the striatum for weeks following administration of a single nontoxic dose of MPTP or 4'-amino-MPTP. A causal relationship between the striatal concentration of MPP+ or 4'-amino-MPP+ and the change in DA metabolism as reflected in the DA/DOPAC ratio is suggested by a significant correlation between these measures. It is suggested that presynaptic sequestration and retention of MPP+ and 4'-amino-MPP+ by striatal DA terminals result in the inhibition of the monoamine oxidase contained within these terminals.     

Altered central monoamine response tod-amphetamine in rats chronically exposed to inorganic lead

Investigations of the mechanisms involved in the neurotoxicity resulting from chronic inorganic lead (Pb) exposure have centered on CNS biogenic amine function on the basis of behavioral and neurochemical findings. The following study examined the time course of the response of dopamine (DA) and 5-hydroxytryptamine (5-HT) neurons to d-amphetamine (AMPH) in rats chronically exposed to Pb from birth in order to further examine neurochemical mechanisms implicated by previous work. Offspring were exposed to 0.2% Pb acetate via the lactating dam and then weaned to the same drinking solution. At 120–140 days animals were injected with 1.0 mg/kg s.c. of the drug or with saline and sacrificed after various intervals. DA content in nucleus accumbens and corpus striatum in Pb-exposed animals was significantly higher than corresponding levels in controls at 20 minutes post-drug and remained significantly higher than baseline values at 80 minutes after the drug when DA concentrations in controls had returned to normal. These data suggest enhanced AMPH-induced DA synthesis in exposed rats. 5-Hydroxyindoleacetic acid (5-HIAA) content was significantly increased in three brain regions in exposed rats given AMPH compared to values in saline-injected exposed animals, indicating a compensation in these areas for the decreases in 5-HIAA values produced by Pb exposure alone. The results of this study reinforce the hypothesis that DA and 5-HT neurons are sensitive to relatively low levels of Pb exposure.     

Chronic treatment with high doses of haloperidol fails to decrease the time course for the development of depolarization inactivation of midbrain dopamine neurons

Using extracellular single unit recording techniques, we investigated the effects produced by chronic treatment with high doses of haloperidol (CHAL, 5 mg/kg/day, s.c.) on midbrain dopamine (DA) neuronal activity. This regimen of HAL treatment produced a time-dependent reduction in the number of spontaneously active DA neurons. Additionally, this dose regimen induced an irregular firing pattern in many of the remaining active DA neurons in both the ventral tegmental area (A10) and substantia nigra pars compacta (A9) regions. These effects were comparable to those obtained previously in rats treated chronically with lower doses of HAL (0.5 mg/kg/day, s.c.). However, there was a greater decrease in the number of spontaneously active DA cells detected in rats treated with high doses of HAL for three weeks compared to those receiving the low doses. On the other hand, higher doses of apomorphine (200 micrograms/kg, i.v.) were required to reverse both the reduction of DA activity and irregular discharge pattern in rats treated chronically with high doses of HAL. In conclusion, the results of the present study substantiate the view that CHAL-induced depolarization inactivation (DI) of DA neurons is a time-dependent process and chronic treatment with high doses of HAL did not shorten the time course required for the development of DI on the majority of midbrain DA neurons.     

甘草酸二铵对百草枯中毒致急性肺损伤大鼠TLR-4表达的影响

目的探讨甘草酸二铵(DG)对百草枯(PQ)中毒致急性肺损伤(ALI)大鼠的保护作用及其机制。方法选择健康SD大鼠50只,随机分为百草枯组(PQ组)、甘草酸二铵组(DG组)和正常对照组(NS组),PQ组和DG组予百草枯100mg/kg灌胃1次,DG组于灌胃后立即腹腔注射DG 50mg/kg,每日1次,对照组与PQ组注射等剂量的生理盐水。观察至48h处死大鼠,取肺组织检测肺湿干重比;肺组织HE染色评价肺组织损伤情况;采用RT-PCR法检测肺组织TLR-4mRNA和NF-κB mRNA的表达情况。另选择健康SD大鼠50只,分组及各组处置方法同上,观察其7天内死亡率。结果 PQ组与DG组肺湿干比、肺组织TLR-4mRNA和NF-κB mRNA表达较NS组明显升高(P0.01);DG组各指标明显低于PQ组(P0.01)。HE染色结果,NS组肺部结构正常,PQ组、DG组可见肺组织水肿、出血及炎性细胞浸润等肺损伤表现,DG组病变轻于PQ组。群体死亡率比较,PQ组7天死亡率为90%,DG组为40%,NS组无死亡。结论甘草酸二铵可减轻百草枯中毒致急性肺损伤大鼠肺部炎症,其机制可能与降低TLR-4、NF-κB的表达有关。     

Enhanced lipid peroxidation is not necessary for induction of metallothionein-I by oxidative stress

A study has been made of factors which may influence the induction of metallothionein-I (MT-I) synthesis by the superoxide radical generating agent, paraquat (PQ). Hepatic concentrations of zinc (Zn) and MT-I increased in rats injected with PQ (40 mg/kg, s.c.) or fasting, but were greater in the former. Renal concentration of MT-I increased in fasted rats but not in PQ-treated rats. The data suggest that the increase in MT-I concentrations in PQ-treated rats is not caused by reduction in food intake. Administration of PQ increased hepatic concentrations of Zn, MT-I and thiobarbituric acid-reactive substances (TBA-RS), indicating the occurrence of lipid peroxidation. Treatment of rats with vitamin E (400 mg/kg, s.c.) on 4 successive days before injection of PQ prevented only the enhancement of lipid peroxidation. The data indicate that the induction of MT synthesis by PQ is not correlated with enhancement of lipid peroxidation. Similar results were obtained in the liver of rats subjected to the radical-generating conditions, such as fasting and exposure to carbon tetrachloride. Free radicals may induce MT synthesis by direct or indirect mechanisms.     

Locomotion induced by non-contingent intracranial stimulation: comparison to psychomotor stimulant

Non-contingent experimenter-applied stimulation (nEAS) to the ventral mesencephalon, unlike contingent intracranial self-stimulation (ICSS), elicits high rates of general locomotion. This locomotion may be due to the nature of the presentation of stimulation, in that nEAS is non-contingent, while ICSS depends on a specific and focused response (e.g., bar pressing). Psychomotor stimulants also elicit high amounts of general locomotion, with the locomotion attributed to increased dopamine release. Interestingly, dopamine release decreases or is absent with repeated ICSS, but not nEAS. This suggests that the locomotion elicited by nEAS may be the result of DA release similar to that observed with psychomotor stimulants. To determine the relationship between locomotion induced by nEAS and psychomotor stimulants, locomotion elicited by nEAS was directly compared to that produced by cocaine, a psychomotor stimulant and indirect DA agonist. Six groups of rats were examined: (1) DA+ group: rats were implanted with a stimulating electrode in the ventral mesencephalon and activation of DA neurons was verified during surgery by monitoring DA release in the striatum; (2) DA- group: rats were also implanted with stimulating electrodes, but the location in the ventral mesencephalon did not elicit DA release; (3) 10-mg/kg cocaine group: rats were exposed to a low dose (10 mg/kg) of cocaine; (4) 40-mg/kg cocaine group: rats were exposed to a high dose (40 mg/kg) of cocaine; (5) saline group: rats were injected with saline; and (6) naive group: rats received no treatment. The topography of behavior was assessed in all rats during four periods: a pre-treatment baseline, treatment, early post-treatment, and a late post-treatment end point. The results suggest that locomotion elicited by nEAS was stereotypic, dependent upon DA release and similar, but not identical, to psychomotor stimulant-induced locomotion.     

Mephedrone in Adolescent Rats: Residual Memory Impairment and Acute but Not Lasting 5-HT Depletion

Mephedrone (4-methylmethcathinone, MMC) is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days) injections of MMC (30 mg/kg) or the comparator drug methamphetamine (METH, 2.5 mg/kg). Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA) levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT) levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([¹²⁵I]CLINDE ligand used as a marker for translocator protein (TSPO) expression) with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days) and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg) dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted.     

P-glycoprotein induction: an antidotal pathway for paraquat-induced lung toxicity

The widespread use of the nonselective contact herbicide paraquat (PQ) has been the cause of thousands of deaths from both accidental and voluntary ingestion. The main target organ for PQ toxicity is the lung. No antidote or effective treatment to decrease PQ accumulation in the lung or to disrupt its toxicity has yet been developed. The present study describes a procedure that leads to a remarkable decrease in PQ accumulation in the lung, together with an increase in its fecal excretion and a subsequent decrease in several biochemical and histopathological biomarkers of toxicity. The administration of dexamethasone (100 mg/kg ip) to Wistar rats, 2 h after PQ intoxication (25 mg/kg ip), decreased the lung PQ accumulation to about 40% of the group exposed to only PQ and led to an improvement in tissue healing in just 24 h as a result of the induction of de novo synthesis of P-glycoprotein (P-gp). The involvement of P-gp in these effects was confirmed by Western blot analysis and by the use of a competitive inhibitor of this transporter, verapamil (10 mg/kg ip), which, given 1 h before dexamethasone, blocked its protective effects, causing instead an increase in lung PQ concentration and an aggravation of toxicity. In conclusion, the induction of P-gp, leading to a decrease in lung levels of PQ and the consequent prevention of toxicity, seems to be a new and promising treatment for PQ poisonings that should be further clinically tested.     

Early differential gene expression of rat lung after exposure to paraquat

Paraquat (PQ), a quaternary nitrogen herbicide, is highly toxic to humans and animals. Acute poisoning and death due to PQ exposure have been reported over the past few decades. Excessive production of oxygen free radicals has been proposed to play an important role in the pulmonary pathology. The aim of the present work was to evaluate the implications for genes that are regulated by oxidative stress at the early stage of PQ exposure in rat lungs. We performed differential display RT-PCR (DD-PCR) on total RNA extracted from rat lungs after injection of 20mg per kg body weight. The experimental DD-PCR conditions, primer length and annealing temperature, were adjusted to improve reproducibility, and 19 differentiated clones were isolated. Sequence analysis followed by conventional RT-PCR and real-time RT-PCR analyses were used to confirm the results. Four clones were finally determined to be significantly affected. These genes were mRNAs for plasma phospholipid transfer protein (PLTP), CL1BA protein, (latrophilin: LPH), and alphaII-spectrin as well as one unknown gene. We demonstrated the distribution of mRNA expression of one gene, LPH, in lung tissues. The present study suggests that 20mg per kg intraperitoneal PQ affects the expression of numerous genes in the lung at 3 h, the onset of pulmonary injury, and that the four genes specified may be major contributors to serious lung injury due to PQ exposure.     

Enhancement of benzene clastogenicity by praziquantel in mice

Praziquantel (PQ) is a commonly used drug to treat patients with schistosomiasis. Previous studies using cells in vitro have shown that PQ can enhance the mutagenic activities of known mutagens. We have conducted a cytogenetic - urine metabolite study to determine the in vivo clastogenic and co-clastogenic potential of PQ with a ubiquitous environmental contaminant, benzene (BZ). 16 groups of adult male ICR mice (5 animals per group) were used. They were negative control, solvent controls (cremophore E1 3%, olive oil and combined), positive control (BZ 440 mg/kg b.w.) and 11 exposed groups. To test for clastogenicity of PQ, mice were treated orally with 100, 400, 800 and 1200 mg/kg b.w. PQ and sacrificed 30 h later for determination of micronuclei (MN) frequency in bone-marrow polychromatic erythrocytes (PCE). None of these PQ does induced an increase of MN frequency. On the other hand, BZ induced, as expected, a high frequency of MN (46.4 +/- 6.34/1000 PCE). The enhancement effect of PQ was tested in 7 groups of mice using 3 different protocols. Mice were treated with 440 mg/kg b.w. BZ and 1 h later with 0, 100, 200, 400, 800 and 1200 mg/kg b.w. PZ. In another group, 800 mg/kg PQ was administered at 3 h after BZ exposure. In the last group, PQ (800 mg/kg) was administered at 1 h prior to BZ exposure. Results from the first combined exposure group showed a significant PQ dose-dependent increase in the frequency of MN in PCE (p less than 0.05). The increase with the two high doses of praziquantel is significantly higher (p less than 0.05) than the MN frequencies in the benzene control and the expected value based on the additive effects of the two agents. Studies with other combined treatment groups showed that the induction of MN was highest when PQ was administered at 1 h before BZ exposure. Moreover, the presence of BZ metabolites (muconic acid, phenol, catechol and hydroquinone) in urine was studied in 6 of the combined treatment groups. This metabolite study revealed that PQ enhanced the metabolism of BZ towards the pathway to form muconaldehyde which is converted to muconic acid in urine. In conclusion, our study showed that PQ is not a clastogen but can enhance the clastogenic activity of BZ in vivo by shifting the metabolic pathways of BZ towards formation of muconaldehyde which may be responsible for the enhancement effect.     

Effects of chronic, systemic treatment with the dopamine receptor agonist R-apomorphine in partially lesioned rat model of Parkinson's disease: an electrophysiological study of substantia nigra dopamine neurons

Previous studies have suggested that R-apomorphine (R-APO), a non-selective dopamine (DA) receptor agonist, has neuroprotective effects in the experimental models of Parkinson's disease (PD). In this study, we investigated the effects of chronic, systemic treatment with R-APO in the firing activity of substantia nigra pars compacta (SNc) DA neurons in 6-hydroxydopamine (6-OHDA) partially lesioned rats. In the 6-OHDA-lesioned rats treated with vehicle, injection of 6-OHDA (20.1 microg) into the striatum produced a partial lesion causing 41% loss of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the SNc. In the partially lesioned rats, chronic, systemic treatment of R-APO (10 mg/kg/day, s.c., 11 days) attenuated loss of TH-ir neurons in the SNc. The partial lesion of the nigrostriatal pathway and R-APO treatment did not change the firing rate and firing pattern of DA neurons in the SNc of rats. In contrast, the R-APO treatment increased the number of spontaneously active DA neurons of the SNc in the partially lesioned rats, while the lesion decreased the number of spontaneously active DA neurons. In addition, the chronic R-APO treatment decreased the responsiveness of the DA neurons to intravenously administrated R-APO in the partially lesioned rats. These results indicate that chronic, systemic R-APO treatment has the neuroprotective effect, and reverses the decrease in the number of spontaneously active DA neurons in the SNc whereas the treatment induces a reduction in the sensitivity of DA receptors in the SNc to R-APO stimulation in this model.