Striatal Dopaminergic Neurons Research Articles

Methamphetamine-induced neurotoxicity in BALB/c, DBA/2N and C57BL/6N mice

Repeated administration of methamphetamine (METH; 2 and 4 mg/kg, s.c. four times every 2 h) caused hyperthermia and a dose-dependent depletion of striatal dopamine levels 3 days after the METH-treatment in both BALB/cAnNCrj (BALB) and DBA/2NCrj (DBA) mice, but these responses were lower in C57BL/6NCrj (C57BL) mice. An acute decrease of striatal dopamine levels 30 min after the last injection of METH (4 mg/kg) was observed in both BALB and DBA mice, while an increase in dopamine was observed in C57BL mice. Striatal 3-methoxytyramine levels were drastically increased in both DBA and C57BL mice after this same treatment. Moreover, pretreatment with the superoxide dismutase inhibitor, diethyldithiocarbamate (200 mg/kg, i.p.) exacerbated the METH (4 mg/kg)-induced striatal dopamine-depletion in BALB mice. In addition, pretreatment with an inhibitor of poly(ADP-ribose) polymerase, benzamide (160 mg/kg, s.c.), significantly attenuated the METH (4 mg/kg)-induced striatal dopamine depletion in both BALB and DBA mice. These results suggest that both BALB and DBA mice possess a higher sensitivity to the METH-induced striatal dopaminergic neurotoxicity compared to C57BL mice. In addition, the striatal dopaminergic neurons of BALB mice may be more vulnerable to METH-induced oxidative stress as compared to that in C57BL mice.

Deficiency of selenium enhances the K +-induced release of dopamine in the striatum of mice

To determine whether a selenium (Se) deficiency in the brain leads to a functional change in dopaminergic transmission in the striatum, in vivo microdialysis was conducted in mice fed a low-Se diet. After 11–13 weeks of the diet regimen, the activity of glutathione peroxidase (GPx) in the Se-deficient brain was reduced to 60% of the control brain. A high K + perfusion (100 mM) increased the level of dopamine in the dialysate to 67±16 times the basal level; the increase was significantly greater than that observed in the control group (28±4 times). Such a between-group difference was not observed after 4–5 weeks of the Se− diet. These results indicated that prolonged Se deficiency altered the function of striatal dopaminergic neurons in mice. A possible contribution of enhanced oxidative stress due to the reduced GPx activity is discussed.

Estrogen decreases corpus striatal neurotoxicity in response to 6-hydroxydopamine

Ovariectomized rats treated or not with an estradiol pellet were subjected to an unilateral intrastriatal infusion of 6-hydroxydopamine (6-OHDA). Various parameters of nigrostriatal dopaminergic function as derived from measurements of dopamine and dihydroxyphenylacetic acid (DOPAC) concentrations were determined from the 6-OHDA lesioned and non-lesioned sides of the corpus striatum in these animals. Dopamine concentrations within the 6-OHDA lesioned striatum of estrogen-treated rats were significantly greater than non-estrogen-treated rats. There were no differences in striatal dopamine concentrations between estrogen- versus non-estrogen-treated rats on their non-lesioned side. In contrast to that of dopamine, no differences in DOPAC concentrations between estrogen and non-estrogen-treated rats were obtained within the 6-OHDA-lesioned side. The DOPAC concentrations on the non-lesioned side of the striatum were significantly greater in the non-estrogen-treated rats. These results demonstrate that estrogen significantly diminishes the depletion of striatal dopamine resulting from the neurotoxin 6-OHDA. The data obtained from the DOPAC determinations imply that this capacity of estrogen may be exerted through actions upon uptake processes of striatal dopaminergic neurons. Such findings suggest that estrogen may function as an important modulatory factor capable of attenuating degeneration within the corpus striatum, and in this way serve as a neuroprotectant of the nigrostriatal dopaminergic system.

Nitric oxide participates in the stimulatory and neurotoxic action of endothelin on rat striatal dopaminergic neurons.

1. Our method of real-time monitoring of dopamine release from rat striatal slices revealed that endothelin (ET)-3-induced dopamine release was inhibited by NG-methyl-L-arginine (L-NMMA; 1 mM), an inhibitor of nitric oxide (NO) synthase, while NG-methyl-D-arginine (D-NMMA; 1 mM), an inactive isomer of L-NMMA, had no effect. 2. The inhibition of L-NMMA (0.1 mM) became apparent when tissues were pretreated with tetrodotoxin (1 microM) for 30 min and subsequently exposed to ET-3 (4 microM). 3. L-NMMA (0.1 and 1 mM) dose dependently protected against ET-3-triggered hypoxic/hypoglycemic impairment of striatal responses to high K+. 4. Thus, NO may work as a promoter in mediation of the stimulatory and neurotoxic action of ET-3 on the striatal dopaminergic system, presumably by interacting with interneurons in the striatum.

Effect of chloral hydrate on in vivo KCl-induced striatal dopamine release in the rat.

The release of striatal dopamine (DA) and its metabolites in response to locally-induced K+ depolarization was investigated in vivo in chloral hydrate-anesthetized and freely moving rats. KCl at concentrations of 30, 50, and 100 mM induced significant dose-dependent increases in extracellular DA overflow in both chloral hydrate-anesthetized and freely moving rats (P < 0.05). Extracellular levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were decreased. The DA overflow in response to 30 mM KCl stimulation in anesthetized rats was significantly greater than that in freely moving rats (P < 0.05). In addition, chloral hydrate anesthesia resulted in a significant decrease in extracellular levels of DOPAC and significant increases in extracellular levels of HVA and 5-HIAA in comparison with freely moving rats (P < 0.05). Furthermore, the basal level of extracellular HVA in chloral hydrate-anesthetized rats was significantly higher than that in freely moving rats. These results suggest that chloral hydrate anesthesia could have significant effects on the pharmacological response of the striatal dopaminergic neurons.

Effect of perinatal methadone (M) on striatal cholinergic and dopaminergic neurons.

Effect of perinatal methadone (M) on striatal cholinergic and dopaminergic neurons.

Effect of perinatak methadone (M) on striatal cholinergic and dopaminergic neurons

Effect of perinatak methadone (M) on striatal cholinergic and dopaminergic neurons

Comparison of cytotoxicity of a quaternary pyridinium metabolite of haloperidol (HP+) with neurotoxinN-methyl-4-phenylpyridinium (MMP+) towards cultured dopaminergic neuroblastoma cells

Haloperidol has recently been found to be metabolized to its pyridinium ion (HP+). This conversion of haloperidol to HP+ appears to be similar to the activation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to N-methyl-4-phenyl pyridinium ion (MPP+). MPP+ is responsible for the damage of striatal dopaminergic neurons induced by MPTP in humans and animals. It seemed sensible to investigate whether or not HP+ might be toxic towards dopaminergic neurons and perhaps associated with some of the residual moto-function side effects of haloperidol. We therefore investigated the neurotoxicity of HP+ toward cultured human dopamine neuroblastoma cells (SH-SY5Y) and compared it with that of MPP+. HP+ reduced the viability as measured by MTT and [3H]thymidine incorporation methods in SH-SY5Y cells. Cell membrane integrity is reduced by the treatment of HP+ as measured by intracellular LDH levels. The toxicity was concentration and time dependent. Interestingly, HP+ appeared to be more toxic than MPP+ towards the SH-SY5Y cells in early phase in cultures. The toxicity of MPP+ appear to be progressive and subsequently become more than HP+ with prolonged cultivation. In contrary to MPP+, the toxic effect of HP+ towards a dopamine transporter transfected SK-N-MC cell line is not different from its wild type. This indicates that dopamine uptake system is probably not involved in the cytotoxicity caused by HP+.

Influence of growth factors on neuronal differentiation

With so many neutrophins and receptors now known, how is our picture of neurotrophism changing? Recent studies on knockout mice have confirmed our expectations of neurotrophin action in neuronal development. A notable exception is the activation of TrkB, on motor neurons, by an unknown ligand. It is also clear that some neurotrophins have diverse activities and influence early developmental stages. There are interesting new data concerning the role of p75, the low affinity neurotrophin receptor, as a modulator of neurotrophin activity. Even more exciting are new studies on glia-derived neurotrophic factor (GDNF) which demonstrate that this growth factor acts as a potential protector of motor neurons and striatal dopaminergic neurons.

Methamphetamine-induced neurotoxicity: roles for glutamate and dopamine efflux.

The neurotoxic effects of methamphetamine (METH) on striatal dopaminergic neurons have been hypothesized to be mediated by excess dopamine (DA) release. In addition, N-methyl-D-aspartate (NMDA) receptor antagonists block METH-induced DA depletions. This suggests that glutamate also mediates the toxic effects of METH. The purpose of this study is to demonstrate that DA and glutamate efflux contribute to METH-induced neurotoxicity. In vivo microdialysis in rats was used to measure extracellular concentrations of striatal DA and glutamate following 3 injections of METH (10 mg/kg, i.p.), each injection given 2 hours apart. One week following the dialysis experiment, rats were sacrificed and the ventral lateral striata were assayed for DA content. Glutamate concentrations in the dialysate increased by over 4-fold after the third METH injection. In these same animals, striatal DA tissue content was significantly depleted. In separate groups of rats, pretreatment with haloperidol (2 mg/kg at the first METH injection) significantly increased METH-induced DA efflux. The haloperidol pretreatment attenuated the extracellular increase in glutamate produced by METH and blocked subsequent neurotoxicity to DA neurons. In contrast, pretreatment with the DA uptake blocker, GBR-12909 (10 mg/kg, 30 min before each METH injection) significantly attenuated the increased DA release produced by METH but did not change glutamate efflux. However, pretreatment with GBR-12909 did protect against the tissue content depletion of DA in the striatum. Based on these findings, it appears that increased DA and glutamate release in the striatum are important and possibly interact in the development of METH-induced neurotoxicity.

Levodopa and dopamine agonists in the treatment of Parkinson's disease: advantages and disadvantages.

Recent studies have suggested that free radicals play a key role in the progression of Parkinson's disease (PD). Although levodopa is the most effective therapeutic agent in the treatment of PD and has improved the quality of life and increased life expectancy, its beneficial effects are not permanent. Long-term treatment with levodopa produces a variety of side effects in patients with PD. We have previously reported that levodopa may accelerate the progression of PD in certain patients. To determine whether neuronal damage can be caused by levodopa overdoses, we estimated the effects of levodopa on free radical formation. Electron spin resonance spectrometry showed that levodopa oxidation produced levodopa radicals. Furthermore, chronic administration of levodopa increased thiobarbituric acid-reacting substances (TBARS) in various brain regions of 6-hydroxydopamine (6-OHDA; i.c.v.)-pretreated mice, although levodopa administration in control mice had no effect on TBARS. These results indicate that high dose levodopa accelerates neuronal degeneration in some parkinsonian brains. We then evaluated the protective effects of bromocriptine on striatal dopaminergic neurons, with determination of dopamine (DA) and its metabolites as markers. Pretreatment of bromocriptine completely protected mice against the decreases in striatal DA and its metabolites induced by intracerebroventricular injection of 6-OHDA, while levodopa/carbidopa had no protective effects. Furthermore, in an in vitro system that generated .OH from FeSO4-H2O2, bromocriptine dose-dependently scavenged .OH. These findings clearly indicate that bromocriptine has neuroprotective effects against neurotoxins such as 6-OHDA, probably due in part to its free redical scavenging activity.(ABSTRACT TRUNCATED AT 250 WORDS)

P-130 - ETB receptor/nitric oxide system mediates stimulatory and neurotoxic action of endothelin on rat striatal dopaminergic neurons.

P-130 - ETB receptor/nitric oxide system mediates stimulatory and neurotoxic action of endothelin on rat striatal dopaminergic neurons.

Modifications of striatal D2 dopaminergic postsynaptic sensitivity during development of morphine tolerance-dependence in mice

Alterations in the activity of striatal dopaminergic neurons have been implicated in the development of morphine tolerance-dependence in rodents. To further explore this possibility, we examined the activity of these neurons in mice exposed to morphine during 4 days (addiction group) and subsequently treated with naloxone (withdrawal group). The efficiency of opiate treatment was assessed behaviorally. Striatal dopaminergic activity was evaluated by measuring: a) the ratio between the amounts of L-3,4-dihydroxyphenylacetic acid (DOPAC), the main intraneuronal metabolite of dopamine (DA), and the neurotransmitter itself, as an index of presynaptic activity; and b) the number and affinity of D1 and D2 dopaminergic receptors, as well as the amount of their coupled second messenger, cyclic adenosine monophosphate (cAMP), as postsynaptic parameters. Spontaneous motor activity was decreased in chronically morphine-exposed mice. In these animals, the number of striatal D2 receptors also decreased, with no changes in their affinity, whereas the number and affinity of D1 receptors remained uncharged. This hyposensitivity of D2 receptors was paralleled by an increase in the amount of cAMP with a good statistical correlation between both parameters. Treatment with naloxone of morphine-exposed mice resulted in the typical jumping behavior indicative of opiate withdrawal. The differences in D2 receptors between placebo- and morphine-exposed mice disappeared after naloxone-induced opiate withdrawal, although this effect was due more to the inhibitory effect of naloxone on the density of these receptors in placebo-exposed mice rather than to a stimulatory effect in morphine-addicted mice. The morphine-induced increase in cAMP content also disappeared after naloxone treatment. No significant changes occured in the presynaptic activity in both states, as reflected by the absence of changes in the DOPAC/DA ratio. However, DA storage decreased after the induction of opiate withdrawal, which could be related to a repeated DA utilization during the naloxone-induced jumping behavior in morphine-addicted mice. In summary, our results provide neurochemical evidence of changes in striatal dopaminergic neurotransmission concomitant to the typical motor alterations produced during morohine tolerance-dependence. These changes were mainly produced at the postsynaptic level, by decreasing the number of D2 receptors and increasing the cAMP production, during the morphine addiction. These differences disappeared after the naloxone-induced morphine withdrawal, likely by an inhibitory effect of naloxone on D2 receptors in placebo-exposed mice. Moreover, a presynaptic effect could be suspected during the opiate withdrawal in view of the decrease in DA content observed in naloxone-treated morphine-exposed mice.

Pharmacological modulation of development and plasticity in nigro striatal dopaminergic neurons

Parkinson’s disease is the second most common neurodegenerative disorder, characterized by the manifestation of motor symptoms, which are mainly attributed to the degeneration of dopamine neurons in the pars compacta of substantia nigra. Based on advancements in the understanding of the pathophysiology of the disease, especially in animal models, the subthalamic nucleus has been pointed as a major target for deep brain stimulation in the treatment of motor symptoms, first developed in non-human primate and then successfully transfered to parkinsonian patients. Nevertheless, despite the focus on motor deficits, Parkinson’s disease is also characterized by the manifestation of non-motor symptoms, which can be due to the additional degeneration of norepinephrine, serotonin and cholinergic systems. The pathophysiology of the non-motor symptoms is under studied and consequently not well treated. Furthermore, data from the literature about the impact of subthalamic deep brain stimulation on non-motor disorders are controversial and still under debate. Similarly, the risk of mood disorders post–deep brain stimulation surgery remains also controversial. Here, we review the clinical and experimental data of this neurosurgical approach on motor and non-motor behaviors and provide evidence for its interaction with the monoaminergic systems.

Inbred rat strain comparisons indicate different sites of action for cocaine and amphetamine locomotor stimulant effects

Cocaine and amphetamine produce several behavioral effects, most notably locomotor stimulation. Biochemically, evidence suggests specific involvement of dopaminergic systems, although not necessarily identical sites, in mediating cocaine- and amphetamine-induced locomotor stimulation. This study examined the effects of cocaine or amphetamine on locomotor activity in rats from the ACI, F344, LEW and NBR inbred strains. Dose-dependent increases in locomotor activity were found for both drugs in all strains. However, large potency and efficacy differences were found. Further, significant strain by drug interactions were found, in that the strain rank order for stimulant response to the two drugs was not identical. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D1 and D2 receptors in striatal tissue from these same strains of rats. No differences in these receptor binding parameters were found. These findings support the conclusion that these two drugs produce their locomotor stimulant effects through different sites of action, and that genetic differences in response to these drugs at the behavioral level do not appear to be mediated significantly by differences in structure or number of striatal dopaminergic sites. The further use of genetic methods, however, may aid in determining the specific sites of action of these widely used stimulant drugs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced damage of striatal dopaminergic fibers attenuates subsequent astrocyte response to MPTP

Acute administration of the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the C57BL/6 mouse caused a rapid decrease in the amount of striatal tyrosine hydroxylase (TH), a marker of the nigrostriatal dopaminergic pathway, followed by a large increase in the astrocyte protein, glial fibrillary acidic protein (GFAP). The astrocyte (GFAP) response declined to baseline three weeks after administration of MPTP. Administration of a second dosage of MPTP at this time evoked a second GFAP response. The magnitude of the second response, however, was decreased in comparison to the response seen after only a single exposure to MPTP. Increasing the initial dosage of MPTP resulted in greater reductions of the second GFAP response. These data indicate that MPTP-induced damage or loss of striatal dopaminergic neurons reduces the signal available for initiating astrogliosis and thereby reduces the astrocyte response to a second exposure to MPTP.

Behavioral sensitization to beta-phenylethylamine (PEA): enduring modifications of specific dopaminergic neuron systems in the rat

Repeated daily administration of an endogenous trace amine, beta-phenylethylamine (PEA), produces behavioral sensitization such that the intensity of PEA-induced stereotyped behaviors in rats increases gradually during the treatment, and a challenge injection with PEA reinstates the enhanced stereotypy even long after withdrawal. In the present study, we examined the neurochemical changes in the central dopaminergic neurons systems in the rat for 7 drug-free days after repeated treatment with PEA (50 mg/kg, IP day for 14 or 28 days). During withdrawal, a decrease in steady-state levels of tissue dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC), was found in the mesolimbic DA nerve terminal areas of the rat brain receiving repeated PEA treatment. Fifteen minutes after challenge administration of PEA at varying doses from 6.3 to 75 mg/kg, the rats with repeated PEA treatment required smaller doses of PEA challenge than the rats with acute PEA treatment in order to obtain a significant decrease in striatal DOPAC content compared to the saline control in each treatment group. These results imply that the behavioral sensitization to PEA is accompanied by enduring modifications of the specific dopaminergic neuron systems in the rat brain. This suggestion was strongly supported by the results of the study using in vivo intracerebral dialysis, which indicated that 25 mg/kg PEA challenge elicited a remarkable increase in the extracellular DA concentrations in striatal perfusates collected from the PEA-pretreated rats, in accordance with the intensity of stereotyped behaviors. These findings argue that the hyper-responsiveness to PEA of the striatal dopaminergic neuron systems persists long after withdrawal from repeated treatment with PEA.

Time-course of the effects of ovarian steroids on the activity of limbic and striatal dopaminergic neurons in female rat brain

This paper studies the time-course of the effects of pharmacological administrations of ovarian steroids on the functional state of dopaminergic terminals in the striatum and the limbic forebrain, using the ratio between the contents of dopamine (DA) and its metabolite, L-3,4 dihydroxyphenylacetic acid (DOPAC), as an index of nerve activity. Estradiol produced an increase in the dopaminergic activity of both limbic and striatal neurons, reflected in the high DOPAC/DA ratio observed in both areas. This estrogenic effect was only observed at 4 hours, disappearing in the subsequent times studied. The effect was antagonized by progesterone in both tissues, since a single injection of this steroid to estrogen-pretreated rats restored to control values the estradiol-induced increase, suggesting the existence of negative interactions between both steroids. Furthermore, treatment with progesterone produced also a late decrease of the DOPAC/DA ratio in the striatum, which was observed only in the animals nonpretreated with estrogens.

Cocaine produces locomotor stimulation in SS but not LS mice: Relationship to dopaminergic function

Cocaine produces several behavioral effects, most notably locomotor stimulation. While low doses of cocaine have been shown to decrease locomotor activity, moderate to high doses in the range of 5-50 mg/kg usually produce a marked increase in locomotor activity in rodents. This study examined the effects of a range of cocaine doses, 1-75 mg/kg, on locomotor activity in LS/Ibg (LS) and SS/Ibg (SS) mice. At the lowest doses, activity was depressed in both lines, but to a greater extent in LS mice. As the dose of cocaine was increased, activity returned to baseline, and at the highest doses, increases in locomotor activity were found, but only in SS mice. In LS mice, cocaine was ineffective in increasing locomotor activity at any of the doses tested. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D1 and D2 receptors in striatal tissue obtained from these two selected lines. No differences in these receptor binding parameters were found. However, because of their anomalous locomotor response to cocaine, LS mice may prove to be a valuable tool in increasing our understanding of those sites which mediate specific effects of cocaine.

MIF-Induced Augmentation of Melatonin Functions: Possible Relevance to Mechanisms of Action of MIF-1 in Movement Disorders

MIF-1, a synthetic tripeptide with MSH-release inhibitory properties, has been reported to improve symptoms of Parkinson's disease, attenuate levodopa-related dyskinesias and diminish the dyskinetic movements of Tardive dyskinesia. More recently, MIF-1 has been reported partially to protect against the nigro-striatal dopamine depleting effects of MPTP in mice, raising the possibility that it may exert protective effects against the development of Parkinson's disease. There is evidence to suggest that MIF-1 increases nigro-striatal dopaminergic activity, but its ability to improve symptoms in patients with Parkinson's disease, levodopa-related dyskinesias and Tardive dyskinesia cannot be explained solely on the basis of the drug's effect on striatal dopaminergic neurons. MIF-1 has been reported to potentiate the melanocyte-lightening effect of melatonin in rats and its effects in patients with Parkinson's disease and Tardive dyskinesia are associated with marked mood elevation. It is, therefore, possible that the effects of MIF-1 in movement disorders are associated with increased melatonin secretion. Thus, hypothalamic MIF may modulate nigro-striatal dopaminergic functions in part via pineal melatonin. Such an interaction represents a novel mechanism by which hypothalamic peptides act to modulate the expression of movement disorders.