Dehydroepiandrosterone (DHEA) such as 17beta-estradiol prevents MPTP-induced dopamine depletion in mice

Previous work from our laboratory has shown prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion in mice by 17beta-estradiol, progesterone, and raloxifene. Dehydroepiandrosterone (DHEA), a neurosteroid, was shown to have neuroprotective activities in various paradigms of neuronal death but its effect in vivo in mice on MPTP toxicity has not been reported. We investigated the effects of 17beta-estradiol (2 microg/day) and DHEA (3 mg/day) for 5 days before and after an acute treatment of four MPTP (10 mg/kg) injections in male C57Bl/6 mice. Striatal DA concentrations and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by HPLC. MPTP mice that received 17beta-estradiol or DHEA had striatal DA, DOPAC, and HVA concentrations comparable to intact animals and higher than striatal DA, DOPAC, and HVA levels in saline-MPTP-treated mice. MPTP treatment led to an increase of striatal DA turnover (assessed with the HVA/DA ratio); DHEA and 17beta-estradiol prevented this increase. 17beta-Estradiol did not affect striatal DA and metabolites concentrations in intact mice in this paradigm. Furthermore, in the substantia nigra DHEA and 17beta-estradiol prevented the MPTP-induced dopamine transporter and tyrosine hydroxylase mRNA decreases measured by in situ hybridization. Therefore, DHEA such as 17beta-estradiol is active in preventing the catecholamine-depleting effect of MPTP and our results suggest that this involves neuroprotection of DA neurons.     

Ethylenebisdithiocarbamate enhances MPTP-induced striatal dopamine depletion in mice

Diethyldithiocarbamate (DDC) has been shown to enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine depletion in mice. Surprisingly, although DDC is a prototypic member of a class of compounds called dithiocarbamates (DTCs) that are widely used in industry and agriculture, only one study has investigated the interaction of dithiocarbamates other than DDC with MPTP. The purpose of the present study was to investigate whether two other widely used dithiocarbamates, ethylenebisdithiocarbamate (EBDC) and methyldithiocarbamate (MDC), would also enhance MPTP toxicity. The dithiocarbamates were administered to mice intraperitoneally at various doses with or without MPTP. Doses were chosen based on the LD50 values for each compound. DDC was also tested (using a previously reported dose) for comparison. Striata were obtained one week later for dopamine measurements. Consistent with previous reports, DDC produced statistically significant enhancement in MPTP-induced striatal dopamine depletion. EBDC also produced significant exacerbation of MPTP-induced dopamine depletion. In contrast to DDC and EBDC, MDC failed to enhance the effects of MPTP, even when administered at doses of high lethality. Further studies of the dithiocarbamate class of compounds may help to elucidate the mechanism of DDC and EBDC enhancement of MPTP toxicity. Given the widespread use of these compounds in the environment such studies may also provide clues to the process of nigrostriatal cell degeneration in Parkinson's disease.     

Ovarian steroids and raloxifene prevent MPTP-induced dopamine depletion in mice

The activity of steroids was studied in 1-methyl-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned retired breeder C57BL/6 male mice as a model of Parkinson's disease. Steroids were injected daily for 5 days before MPTP (4 injections, 15 mg/kg i.p., at 2 h intervals) and hormonal treatment continued for 5 more days. Mice that received 17beta-estradiol or progesterone or raloxifene (a selective estrogen receptor modulator) and MPTP had striatal concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) similar to those in control animals, whereas mice that received MPTP alone or with 17alpha-estradiol (the isomer with weak estrogenic activity) had an extensive decrease of DA and its metabolites. These results suggest stereospecific prevention of MPTP-induced dopamine loss by 17beta-estradiol, which is also observed with progesterone and raloxifene.     

Systemic proteasomal inhibitor exposure enhances dopamine turnover and decreases dopamine levels but does not affect MPTP-induced striatal dopamine depletion in mice

The validation of an in vivo proteasomal inhibitor (PSI) model to translate ubiquitin-proteasomal-system dysfunction involved in the pathogenesis of Parkinson's disease (PD) into a commonly accepted animal model is ongoing. Here we first report the effects of systemic administration of the proteasomal inhibitor Z-lle-Glu(OtBu)-Ala-Leu-CHO (3 mg/kg, s.c., six times over 2 weeks) alone to extend the rat model to mice. Second we investigate the consequences of PSI pretreatment 42 weeks before an acute treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57bl/6 mice. HPLC postmortem neurochemistry showed a significant increase in dopamine turnover and decrease of striatal dopamine levels, only 14 weeks after PSI treatment, but no enhancement of dopamine turnover or differences in striatal dopamine levels when comparing MPTP with MPTP plus PSI treatment. Behavioral analysis (rotarod, open field activity) did not indicate that PSI affects this type of motor behavior. Systemic PSI administration in mice appears not to be a valid animal model under the experimental conditions used. Potential solutions are discussed.     

Melatonin fails to protect against long-term MPTP-induced dopamine depletion in mouse striatum

Several laboratories recently have reported that melatonin may possess neuroprotective properties. The present paper presents the results of our studies on the long term in vivo neuroprotective effects of melatonin in a well-defined neurotoxicity model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the C57BL/6 mouse. MPTP is bioactivated by brain monoamine oxidase B (MAO-B) to its neurotoxic pyridinium metabolite 1-methyl-4-phenylpyridinium (MPP(+)) which destroys dopaminergic nerve terminals leading to the depletion of neostriatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC). Our initial study compared striatal DA and DOPAC levels in MPTP-only-treated animals and animals treated with melatonin 30 min prior to and 3 times hourly post-MPTP. DA/DOPAC levels measured 7 days after MPTP were similar in both groups. A second study was designed to address the possibility that melatonin cleared from the brain prior to MPP(+). Animals, that had been administered the same regimen of melatonin as in the first study plus a fourth post-MPTP melatonin dose, were maintained on melatonin in drinking water until 5 days post-MPTP. Striatal DA/DOPAC levels of these melatonin-plus-MPTP treated animals also were the same as the MPTP-only-treated animals. In vitro studies confirmed that melatonin is not an inhibitor of MAO-B. These data demonstrate that melatonin does not have any significant protective effects against the long-term striatal DA and DOPAC depletion induced by MPTP in the C57BL/6 mouse.     

内源性MAO—B抑制因子—靛红预防MPTP对多巴胺神经递质的耗竭作用

研究内源性单胺氧化酶B抑制因子 靛红 (2 ,3 吲哚醌 ,isatin)对MPTP引起的小鼠纹状体DA含量降低的影响。用高效液相色谱配电化学检测器测定纹状体DA ,DOPAC和HVA水平。MPTP 30mg/kgip使纹状体DA ,DOPAC和HVA含量与各自对照组比较显著降低 (P <0 .0 1) ,预先靛红 (2 0 0mg/kg·d ,× 4d ,ig)几乎完全抑制了上述效应 ,并减少了MPTP对DA更新率的升高 ,说明靛红有预防MPTP对中枢DA能神经元的毒性。     

内源性MAO-B抑制因子-靛红预防MPTP对多巴胺神经递质的耗竭作用

研究内源性单胺氧化酶B抑制因子-靛红(2,3-吲哚醌,isatin)对MPTP引起的小鼠纹状体DA含量降低的影响.用高效液相色谱配电化学检测器测定纹状体DA,DOPAC和HVA水平.MPTP 30 mg/kg ip使纹状体DA,DOPAC和HVA含量与各自对照组比较显著降低(P＜0.01),预先靛红(200mg/kg@d,×4 d,ig)几乎完全抑制了上述效应,并减少了MPTP对DA更新率的升高,说明靛红有预防MPTP对中枢DA能神经元的毒性.     

Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter

MPTP has been shown to induce parkinsonism both in human and in nonhuman primates. The precise mechanism of dopaminergic cell death induced following MPTP treatment is still subject to intense debate. MPP+, which is the oxidation product of MPTP, is actively transported into presynaptic dopaminergic nerve terminals through the plasma membrane dopamine transporter (DAT). In this study, we used mice lacking the DAT by homologous recombination and demonstrated that the MPTP-induced dopaminergic cell loss is dependent on the presence of the DAT. For this we have used tyrosine hydroxylase immunoreactivity (TH-IR) labeling of dopamine cells of the substantia nigra compacta in wild-type, heterozygote, and homozygote mice that were given either saline or MPTP treatments (two ip injections of 30 mg/kg, 10 h apart). Our results show a significant loss of TH-IR in wild type (34.4%), less loss in heterozygotes (22.5%), and no loss in homozygote animals. Thus dopamine cell loss is related to levels of the DAT. These results shed light on the degenerative process of dopamine neurons and suggest that individual differences in developing Parkinson's disease in human may be related to differences of uptake through the DAT of a yet unidentified neurotoxin.     

Direct effect of 17 beta-estradiol on striatum: sex differences in dopamine release

The nigrostriatal dopamine (DA) system is sexually dimorphic. In female but not male rats, striatal DA activity is modulated by gonadal steroid hormones. Ovariectomy (OVX) decreases striatal DA release and turnover. Estrogen replacement restores the response to that of the intact female in estrus. In contrast, castration (CAST) of male rats has no effect on the stimulated release of DA from striatal tissue. This report addresses the question: Dose estrogen act directly on the striatum to induce changes in DA release? Physiological concentrations of 17b?-estradiol and other steroids or a nonsteroidal estrogen analog were applied directly to striatal tissue maintained in an in vitro superfusion system. The effect of hormonal treatments on the responsiveness of striatal DA terminals to stimulation was examined in tissue from OVX females and intact and CAST male rats. The results are summarized as follows: (1) Infusion of 17b?-estradiol (p < 0.01) and diethylstilbesterol (p < 0.05) increased amphetamine (AMPH)-stimulated striatal DA release from striatal tissue of OVX female rats compared with the effect of cholesterol. 17alpha-Estradiol also tended to potentiate the striatal DA response to AMPH, but this result was not statistically significant (p < 0.062). 17b?-Estradiol had no effect on AMPH-stimulated DA release from striatal tissue of intact male rats. (2) The KCl-stimulated release of DA from striatal tissue of OVX rats exposed in vitro to 100 pg/ml 17b?-estradiol (a physiological dose) was significantly greater (p < 0.05) than the response after exposure to vehicle. In contrast, 1,000 pg/ml 17b?-estradiol produced a decrease in KCl-induced striatal DA release (p < 0.05), whereas 17alpha-estradiol (100 pg/ml or 1,000 pg/ml) did not significantly influences the response to KCl. (3) The pulsatile administration of 17b?-estradiol stimulated DA release from strital tissue of OVX females (p < 0.05; compared with tissue from an OVX group that received vehicle or CAST male rats exposed to either 17b?-estradiol or vehicle). It is concluded that with tissue from OVX rats, physiological concentrations of estrogen can act directly on striatal tissue in vitro to stimulate DA release and to increase striatal DA responsiveness to stimulation, whereas prolonged exposure or high concentrations of 17b?-estradiol decreases striatal DA responsiveness. The striatum and/or the striatal DA system are sexually dimorphic in this regard.     

Suppressive effect of FK-506, a novel immunosuppressant, against MPTP-induced dopamine depletion in the striatum of young C57BL/6 mice

Systemic injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to damage the dopaminergic nigrostriatal system in C57BL/6 mice. We have investigated the effects of immunosuppressants, FK-506 and cyclosporin A (CsA), on MPTP-induced dopamine (DA) depletion in the striatum of young C57BL/6 mice. 10 days after MPTP treatment (25 mg/kg i.p. given daily, 5 days), DA in the striatum was depleted by 80%. However, pretreatment with FK-506, a novel immunosuppressant, significantly protected MPTP-induced DA depletion in the striatum, but FK-506 itself did not affect the DA content. CsA, another immunosuppressant, also protected MPTP-induced DA depletion. From these results can be seen that immunosuppressants seem to inhibit MPTP neurotoxicity toward nigrostriatal dopaminergic neurons of young C57BL/6 mice.     

Saccade responses to dopamine in human MPTP-induced parkinsonism

Depletion of dopamine content in the substantia nigra resulting from 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) toxicity produces parkinsonism. Management of 3 patients with MPTP-induced parkinsonism required drug holidays during which there was a state of dopamine depletion followed by dopamine replacement. We used this opportunity to study the effect of the selective loss of pars compacta dopaminergic cells on vertical and horizontal saccade (fast) eye movements. During the drug holidays, visually guided saccades were hypometric and had long latencies but retained a normal saccade velocity-amplitude relationship. Dopamine agonists or precursors improved the accuracy and reaction times of saccades in all directions, but not their velocity. Two of the three patients also had intermittent blepharospasm during dopamine depletion. During the episodes of blepharospasm, saccade responses became slow eye movements. MPTP causes a dopaminergic-responsive disorder of saccade initiation that is similar to idiopathic parkinsonism. The inhibition of voluntary eyelid opening during MPTP-induced blepharospasm further increases this impairment of fast eye movements and altered saccade velocity, presumably via the pars reticulata of the substantia nigra.     

17Alpha-estradiol and 17beta-estradiol treatments are effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice

Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17beta-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid beta (Abeta) levels and amyloid beta-protein precursor (AbetaPP) processing in vivo, Swedish mutant AbetaPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17beta- or 17alpha-estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Abeta levels; however, the levels of Abeta were decreased by 27% and 38% in mice treated with 17beta- and 17alpha- estradiol, respectively, with no change in AbetaPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAbetaPPalpha, the secreted form of AbetaPP. The ratio of Abeta/sAbetaPPalpha, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Abeta lowering effect of 17beta- and 17alpha-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17alpha-estradiol versus 17beta-estradiol may help to develop safe and effective therapeutics.     

Time course of MPTP-induced degeneration of the nigrostriatal dopamine system in C57 BL/6 mice

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a parkinsonism-inducing dopamine (DA) neurotoxin most effective in primates. MPTP also causes a degeneration of both perikarya and axon terminals of the nigrostriatal DA neurons in C57 BL/6 mice. The time courses of the changes in tyrosine hydroxylase immunoreactive objects, endogenous DA concentrations and specifically bound 3H-mazindol as markers of the integrity of DA neurons were studied in substantia nigra and striatum of adult C57 BL/6 mice, after systemic treatment with MPTP or intranigral injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). A rapid decrease in the three parameters studied was found in the substantia nigra during the first 2 days after MPTP-treatment while the MPTP-induced effects in the striatum were more protracted and maximal reduction was observed 7 days after MPTP. A basically similar pattern was found when studying the 6-OHDA-induced anterograde degeneration of the nigrostriatal system. These results indicate that in C57 BL/6 mice, MPTP primarily destroys the DAergic perikarya with a subsequent anterograde degeneration of the striatal axon terminals, although a limited rapid destruction of some striatal terminals cannot be excluded.     

Norepinephrine loss selectively enhances chronic nigrostriatal dopamine depletion in mice and rats

In this study we investigated whether a selective pattern of norepinephrine loss potentiates methamphetamine-induced striatal dopamine depletion in rats. We also evaluated whether chronic norepinephrine depletion reduces the threshold dose of methamphetamine necessary to induce long-lasting striatal dopamine loss in mice and in rats. Pre-treatment with the selective noradrenergic neurotoxin DSP-4 (50 mg/kg, i.p.) in mice and in rats significantly enhanced methamphetamine-induced striatal dopamine depletion. Administration of a low dose of methamphetamine (1 × 5 mg/kg and 3× 5 mg/kg, respectively, i.p., at 2-h interval) to C57B1/6N mice and Sprague-Dawley rats did not decrease striatal dopamine levels when injected alone but produced a significant decrease in striatal dopamine when given to rodents carrying a long-lasting norepinephrine depletion previously induced by DSP-4. Our results suggest that norepinephrine loss might both enhance neurotoxic damage and decrease the threshold for neurotoxicity to nigrostriatal dopaminergic neurons in different animal species.     

Opioid peptides alleviated while naloxone potentiated methamphetamine-induced striatal dopamine depletion in mice

Summary. Delta opioid peptide [d-Ala², d-Leu⁵] enkephalin (DADLE) can partially reverse long-term loss of striatal dopamine transporters induced by multiple doses of methamphetamine via an unknown mechanism. This study was designed to examine the modulating effects of three opioid ligands, DADLE, Leucine enkephalin (L-enk), and naloxone, on the long-lasting dopamine depletion produced by 4 cumulative doses of methamphetamine. Both DADLE (at a dose of 18 mg/kg) and L-enk (100 μg/kg × 2) effectively attenuated methamphetamine-induced dopamine depletion in the striatum while their protective effects were not blocked by coadministration of naloxone. In contrast, naloxone (10 mg/kg × 2) alone potentiated the long-lasting dopamine depletion produced by methamphetamine. Moreover, none of the treatments with DADLE (18 mg/kg), L-enk (100 μg/kg), or naloxone (10 mg/kg) alone affected body temperature. These results suggest that the opioid ligands may, directly or indirectly, modulate this methamphetamine-induced dopamine neurotoxicity in the nigrostriatal system via a temperature-independent mechanism. Received March 6, 2001; accepted June 10, 2001     

Methamphetamine-induced hyperthermia in mice: examination of dopamine depletion and heat-shock protein induction

Methamphetamine (METH) is a common drug of abuse and a clinical anoretic which is known to cause neurotoxicity in rodents as evidenced by a depletion of dopamine (DA) and by decreased numbers of DA uptake sites in the striatum. It is also known to cause hyperthermia which is believed to induce the production of the 72-kDa heat-shock protein (HSP-72). In the present study, we evaluated whether METH induced the production of HSP-72 in both the mouse hippocampus and striatum and also attempted to correlate this induction with monoamine depletion. Adult male C57BL/6N mice received METH (20 mg/kg, i.p.) in an ambient temperature of 27°C and body temperatures were monitored up to 240 min after treatment. Animals were sacrificed 12, 18, 24, 39, and 48 h after treatment. One striatum was examined for DA, DOPAC, and HVA levels using HPLC–EC and the contralateral striatum, along with the hippocampus, was prepared for immunoblotting. HPLC–EC analysis revealed a significant depletion of DA, DOPAC, and HVA at all time points. There was, however, a significant increase in DA at 48 vs. 39 h. A biphasic production of HSP-72, in both the hippocampus and striatum, was detected by immunoblot. HSP-72 production was strong at 12 h which corresponds to neuronal induction. However, at 18 h in the striatum and 24 h in the hippocampus, the induction appears to be reduced. A second phase of HSP-72 induction occurred at 39 h in both regions. In a second experiment, mice were dosed according to the same paradigm and were perfused at 18 h after treatment for immunohistochemical analysis. HSP-72 immunoreactivity was found in neurons of the CA1 and CA4 regions of the hippocampus; however, no detectable response was evident in the striatum. In conclusion, these data demonstrate that a single injection of METH can lead to hyperthermia which may then result in both the induction of HSP-72 and depletion of DA concentration.     

Apomorphine protects against MPTP-induced neurotoxicity in mice.

R-apomorphine is a potent radical scavenger and iron chelator. The neuroprotective property of R-apomorphine, a dopamine D1-D2 receptor agonist, has been studied in the MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Pretreatment with 5-10 mg/kg R-apomorphine administered subcutaneously in C57BL mice protects against MPTP (24 mg/kg administered intraperitoneally) induced loss of nigrostriatal dopamine neurons as indicated by striatal dopamine content, tyrosine hydroxylase content, and tyrosine hydroxylase activity. In vitro, R-apomorphine inhibited mice striatal MAO-A and MAO-B activities with IC50 values of 93 microM and 241 microM. It is suggested that the neuroprotective effect of R-apomorphine against MPTP neurotoxicity derives from its radical scavenging and MAO inhibitory actions and not from its agonistic activity because the mechanism of MPTP dopaminergic neurotoxicity involves the generation of oxygen radical species-induced oxidative stress.     

High-fat diet exacerbates MPTP-induced dopaminergic degeneration in mice

The identification of modifiable nutritional risk factors is highly relevant to the development of preventive strategies for neurodegenerative disorders including Parkinson's disease (PD). In this study, adult C57BL/6 mice were fed either a control (CD — 12% kcal) or a high-fat diet (HFD — 60% kcal) for 8 weeks prior to MPTP exposure, a toxin which recreates a number of pathological features of PD. HFD-fed mice significantly gained weight (+ 41%), developed insulin resistance and a systemic immune response characterized by an increase in circulating leukocytes and plasmatic cytokines/chemokines (interleukin-1α, MCP-1, MIP-1α). As expected, the MPTP treatment produced nigral dopaminergic degeneration as evidenced by the loss of striatal dopamine and the decreased number of nigral tyrosine hydroxylase (TH)- and dopamine transporter-expressing neurons (23% and 25%, respectively). However, exposure to HFD exacerbated the effects of MPTP on striatal TH (23%) and dopamine levels (32%), indicating that diet-induced obesity is associated with a reduced capacity of nigral dopaminergic terminals to cope with MPTP-induced neurotoxicity. Since high-fat consumption is commonplace in our modern society, dietary fat intake may represent an important modifiable risk factor for PD.     

Influence of noradrenaline denervation on MPTP-induced deficits in mice

Summary. C57/BL6 mice were administered either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 mg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 × 40 mg/kg, s.c., 24 hours between injections; the High dose groups), one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 × 20 mg/kg, s.c., 24 hours between injections; the Low dose groups), and one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered vehicle. Three weeks later, all six groups were tested in motor activity test chambers, followed by injections of L-Dopa (20 mg/kg, s.c.), and then tested over a further 360 min in the activity test chambers. It was found that pretreatment with the selective NA neurotoxin, DSP4, deteriorated markedly the dose-dependent motor activity deficits observed in the vehicle pretreated MPTP treated mice. These ‘ultra-deficits’ in the spontaneous motor behaviour of MPTP-treated mice were observed over all three parameters: locomotion, rearing and total activity, and were restricted to the 1^st and 2^nd 20-min periods. Administration of L-Dopa (20 mg/kg) following the 60-min testing of spontaneous behaviour restored the motor activity of Vehicle + MPTP treated mice (neither the Vehicle + MPTP-Low nor the Vehicle + MPTP-High groups differed from the Vehicle–Vehicle group, here) but failed to do so in the DSP4 pretreated mice. Here, a dose-dependent deficit of L-Dopa-induced motor activity (over all three parameters) was obtained thereby offering further evidence of an ‘ultra-deficit’ of function due to previous denervation of the NA terminals. The present findings support the notion that severe damage to the locus coeruleus noradrenergic system, through systemic DSP4, disrupts the facilitatory influence on the nigrostriatal DA system, and interferes with the ability of the nigrostriatal pathway to compensate for or recover from marked injury, MPTP treatment.