Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice

1-Methyl-4-phenyl-1,2,5,6- tetrahydropyri dine ( MPTP ) is known to cause an irreversible destruction of the dopaminergic nigrostriatal pathway and symptoms of parkinsonism in humans and in monkeys. However, MPTP has been reported to act only minimally or not at all in several other animal species. When MPTP (30 milligrams per kilogram of body weight) was administered parenterally to mice, a decrease in concentrations of neostriatal dopamine and its metabolites, a decrease in the capacity of neostriatal synaptosomal preparations to accumulate [3H]dopamine, and a disappearance of nerve cells in the zona compacta of the substantia nigra were observed. In contrast, MPTP administration had no effect on neostriatal concentrations of serotonin and its metabolites. MPTP administration thus results in biochemical and histological changes in mice similar to those reported in humans and monkeys and similar to those seen in Parkinson's disease in humans. The mouse should prove to be a useful small animal with which to study the mode of action of MPTP .     

Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis

Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.     

Reversal of experimental parkinsonism by lesions of the subthalamic nucleus

Although it is known that Parkinson's disease results from a loss of dopaminergic neurons in the substantia nigra, the resulting alterations in activity in the basal ganglia responsible for parkinsonian motor deficits are still poorly characterized. Recently, increased activity in the subthalamic nucleus has been implicated in the motor abnormalities. To test this hypothesis, the effects of lesions of the subthalamic nucleus were evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor. This result supports the postulated role of excessive activity in the subthalamic nucleus in Parkinson's disease.     

Memory disruption by electrical stimulation of substantia nigra, pars compacta

Electrical stimulation of the substantia nigra, pars compacta, of albino rats while they were learning a simple foot shock task of withdrawal and response suppression disrupted retention of that task 24 hours after original learning. Stimulation in the reticular zone of the substantia nigra was without effect on retention performance. Stimulation through electrodes in the medial lemniscus, red nucleus, or brainstem regions surrounding the substantia nigra, pars compacta, was also ineffective. Original learning performance, measured as time to criterion, was unimpaired by the stimulation. Posttrial stimulation in the substantia nigra, pars compacta, but not in adjacent structures, also disrupted retention performance.     

Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease

Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.     

Normalization of spiroperidol binding in the denervated rat striatum by homologous grafts of substantia nigra

Transplantation of embryonic substantia nigra into the adult rat brain decreases the motor asymmetry that is produced by dopamine receptor supersensitivity after a unilateral lesion of the substantia nigra. The authors report that this effect of transplantation is specific to grafts of substantia nigra. They also report that, in conjunction with the decrease in motor asymmetry, these grafts cause postsynaptic dopaminergic binding sites to return to normal density as measured by tritiated spiroperidol autoradiography. Thus, in animals with brain lesions, grafts of substantia nigra produce a long-term alteration in the functional status of host brain cell receptors that is associated with a reduction in the behavioral deficit.     

Dopamine modulation of the effects of gamma-aminobutyric acid on substantia nigra pars reticulata neurons

Studies were conducted to assess whether basal ganglia output neurons originating in the substantia nigra pars reticulata might be affected by dopamine released from dendrites of neighboring substantia nigra pars compacta neurons. Dopamine applied by iontophoresis increased the baseline firing rates of approximately half of the substantia nigra pars reticulata cells tested. The more significant finding, unrelated to the increase in firing, was the ability of dopamine to attenuate the inhibitory responses of these cells to iontophoretically applied gamma-aminobutyric acid. These findings suggest a role for dopamine as a neuromodulator and further suggest that it can act at sites beyond the striatum to modify transmission from the basal ganglia to motor nuclei.     

帕金森病模型大鼠脑内CDNF表达变化

为了探讨帕金森病(PD)发病过程中大脑多巴胺能神经营养因子(CDNF)表达的变化,以大鼠为模型,研究了帕金森病CDNF及相关基因的表达变化,从而为基因治疗帕金森病提供理论依据。实验采用单侧黑质内单点注射6-羟多巴胺的方法制备帕金森病大鼠模型;运用免疫组织化学、Western blot及Q-PCR方法检测CDNF和多巴胺合成限速酶—酪氨酸羟化酶(TH)在模型大鼠黑质中表达的变化。研究结果发现,PD模型大鼠脑黑质区CDNF和TH阳性细胞数明显减少;进一步研究表明,与正常大鼠相比,模型大鼠CDNF m RNA表达水平虽未见显著改变(P0.05),但CDNF及TH蛋白表达极显著降低(P0.01)。提示帕金森病的发病可能与黑质中CDNF和TH表达量降低,进而抑制多巴胺合成有关。     

Caudate unit responses to nigral stimuli: evidence for a possible nigro-neostriatal pathway

Electrical stimulation of the Substantia nigra evokes depressant and facilitatory responses from individually recorded caudate nucleus neurons. These effects resemble those elicited from caudate cells by microiontophoretic ejections of dopamine. Since histochemical evidence suggests that dopamine-containing fibers link the substantia nigra with the caudate, this pathway may mediate the changes in caudate spike rates produced by nigral stimuli.     

Haloperidol-induced plasticity of axon terminals in rat substantia nigra

An electron micrographic morphometric analysis of nerve endings in substantia nigra of rats repeatedly treated with haloperidol was performed. Although most parameters showed no difference, drug-treated animals exhibited a significant shift in the distribution of relative numbers of axon terminals, suggesting neuroleptic-induced axon-collateral sprouting.     

Tetrahydrobiopterin in striatum: localization in dopamine nerve terminals and role in catecholamine synthesis

The hydroxylase cofactor, tetrahydrobiopterin, and its biosynthetic system are localized in dopaminergic nerve terminals in the striatum. This conclusion is based on the nearly equivalent loss of tyrosine hydroxylase and tetrahydrobiopterin and its initial biosynthetic enzyme, guanosine triphosphate cyclohydrolase, after injection of 6-hydroxydopamine into the substantia nigra. The role of the hydroxylase cofactor in the regulation of dopamine synthesis is reassessed.     

Reversal by L-dopa of impaired learning due to destruction of the dopaminergic nigro-neostriatal projection

Rats receiving bilateral stereotaxic injections of 6-hydroxydopamine into the zona compacta of the substantia nigra failed to learn a one-way active avoidance response. Small doses of L-dopa (1.5 milligrams per kilogram of body weight) in combination with a peripheral decarboxylase inhibitor reversed this impairment. Animals with lesions which acquired the avoidance response during L-dopa administration retained this response when drug treatment was discontinued. These experiments suggest that the dopaminergic nigro-neostriatal projection serves a critical function in the acquisition of learned instrumental responses.     

Quantitative autoradiography of [3H]muscimol binding in rat brain

A simple quantitative autoradiographic technique for the study of neurotransmitter receptors that includes the use of a tritium-sensitive film permits saturation, kinetic, and competition studies of brain samples as small as 0.01 cubic millimeter. This technique was used to study [3H]muscimol binding in rat brain. Unilateral gamma-aminobutyric acid receptor supersensitivity was observed in the substantia nigra pars reticulata after production of localized lesions of the ipsilateral corpus striatum.     

Glucose, sulfonylureas, and neurotransmitter release: role of ATP-sensitive K+ channels

Sulfonylurea-sensitive adenosine triphosphate (ATP)-regulated potassium (KATP) channels are present in brain cells and play a role in neurosecretion at nerve terminals. KATP channels in substantia nigra, a brain region that shows high sulfonylurea binding, are inactivated by high glucose concentrations and by antidiabetic sulfonylureas and are activated by ATP depletion and anoxia. KATP channel inhibition leads to activation of gamma-aminobutyric acid (GABA) release, whereas KATP channel activation leads to inhibition of GABA release. These channels may be involved in the response of the brain to hyper- and hypoglycemia (in diabetes) and ischemia or anoxia.     

Electroconvulsive shock: progressive dopamine autoreceptor subsensitivity independent of repeated treatment

Repeated electroconvulsive shock, applied to rats, induces a subsensitivity of dopamine autoreceptors located in the substantia nigra as indexed by single-unit electrophysiological techniques. This reduced sensitivity is time-dependent, since effects similar to those seen with repeated treatment were also observed when single electroconvulsive shock was followed by an appropriate treatment-free interval. These data, coupled with identical results after the repeated administration of tricyclic antidepressants, raise the possibility that a reduction of dopamine autoreceptor sensitivity could underlie both electroconvulsive shock and pharmacological treatment of depression.     

Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons

Prolonged treatment with classical antipsychotic drugs decreased the number of spontaneously active dopamine neurons in both the substantia nigra (A9) and the ventral tegmental area (A10) of the rat brain. In contrast, treatment with atypical antipsychotic drugs selectively decreased the number of A10 dopamine neurons. Related drugs lacking antipsychotic efficacy failed to decrease dopamine activity. These findings suggest that the inability of atypical antipsychotic drugs to decrease A9 dopamine neuronal activity may be related to their lower potential for causing tardive dyskinesia and that the inactivation of A10 neurons may be involved in the delayed onset of therapeutic effects during treatment.     

Epidermal growth factor immunoreactive material in the central nervous system: location and development

Epidermal growth factor (EGF) is a potent mitogen with hormonal activity in the gastrointestinal tract. Material cross-reacting with EGF was detected in the central nervous system of the developing and adult albino rat by the indirect immunofluorescence technique. High concentrations of EGF-cross-reacting material were identified in forebrain and midbrain structures of pallidal areas of the brain. These include the globus pallidus, ventral pallidum, entopeduncular nucleus, substantia nigra pars reticulata, and the islands of Calleja . Thus, EGF may represent another gut-brain peptide with potential neurotransmitter-neuromodulator functions in pallidal structures of the extrapyramidal motor systems of the brain.     

Infection of the basal ganglia by a murine coronavirus

The coronavirus, mouse hepatitis virus strain A59 (MHV-A59), causes mild encephalitis and chronic demyelination. Immunohistochemical techniques showed that MHV-A59-infected C57BL/6 mice contained dense deposits of viral antigen in the subthalamic nucleus and substantia nigra, with fewer signs of infection in other regions of the brain. The animals showed extra- and intracellular vacuolation, neuronal loss, and gliosis in the subthalamic-nigral region. Such localization is unprecedented among known viral encephalitides of humans and other species. This infection by a member of a viral class capable of causing both encephalitis and persistent infection in several species may be related to postencephalitic parkinsonism.     

Distinct monoamine oxidase A and B populations in primate brain

Monoclonal antibodies specific for monoamine oxidase (MAO) A and MAO B, respectively, were used to localize these enzymes in primate brain. The reagents recognized different populations of neurons: those that recognized MAO A were located in cell groups containing catecholamines, including the substantia nigra, nucleus locus coeruleus, nucleus subcoeruleus, and the periventricular region of the hypothalamus, whereas those that recognized MAO B were observed in serotonin regions, including the nucleus raphe dorsalis and nucleus centralis superior. These data illustrate the physiological independence of MAO A and B and show that neurons may be specialized for their degradative as well as their synthetic functions.     

Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders

To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.