Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization

doi:10.1016/0006-8993(80)90871-9

Brain Research

Volume 195, Issue 1, 11 August 1980, Pages 123-137

https://doi.org/10.1016/0006-8993(80)90871-9 Get rights and content

Abstract

Various doses of 6-hydroxydopamine injected into the rat substantia nigra produced partial, dose-dependent lesions of the dopaminergic nigrostriatal tract. The resulting reduction in striatal dopamine concentrations and tyrosine hydroxylase activities tended to be proportional, allowing these measurements to serve as indices for lesion severity in any particular animal. Lesions destroying two-thirds or more of the nigrostriatal neurons accelerated dopamine's synthesis in, and release from, surviving neurons, as indicated by increased striatal levels of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid. Formation of these metabolites was also enhanced in dendrites of dopaminergic neurons in the substantia nigra.

Supersensitivity of striatal postsynaptic receptors, as judged by induction of rotational behavior after apomorphine orl-DOPA administration, occurred when 90% or more of the nigrostriatal neurons had been destroyed. In contrast, rotational behavior could be induced by amphetamine in animals with only 50% of these neurons destroyed.

Reference (40)

BernheimerH. et al.
Brain dopamine and the syndromes of Parkinson and Huntington: clinical, morphological and neurochemical correlations
J. neurol. Sci.
(1973)
CreeseI. et al.
Nigrostriatal lesions enhance striatal [³H]apomorphine and [³H]-spiroperidol binding
Europ. J. Pharmacol.
(1979)
GibsonC.J. et al.
Physiological control of brain catecholsynthesis by brain tyrosine concentration
Biochem. Pharmacol.
(1977)
GuyenetP.G. et al.
Effects of dopaminergic receptor agonists and antagonists on the activity of the neostriatal cholinergic system
Brain Research
(1975)
HeftiF.
A simple, sensitive method for measuring 3,4-dihydroxyphenylacetic acid and homovanillic acid in rat brain tissue using high-performance liquid chromatography with electrochemical detection
Life Sci.
(1979)
JonesB.E. et al.
Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study
Brain Research
(1977)
LowryO.H. et al.
Protein measurement with the Folin phenol reagent
J. biol. Chem.
(1951)
McGeerE.G. et al.
Temporal changes in amine synthesizing enzymes of rat extra-pyramidal structures after hemitransections or 6-OHDA administration
Brain Research
(1973)
PalkovitsM. et al.
Norepinephrine and dopamine content of hypothalamic nuclei of the rat
Brain Research
(1974)
RacagniG. et al.
Functional interaction between rat substantia nigra and striatum: GABA and dopamine interaction
Brain Research
(1977)

RinneU.K. et al.

Effect ofl-DOPA on brain monoamines and their metabolites in Parkinson's disease

Life Sci.

(1971)

SaavedraJ.M. et al.

Biochemical changes accompaningg unilateral 6-hydroxydopamine lesions in the rat substantia nigra

Brain Research

(1978)

SoteloC. et al.

Injection of 6-hydroxydopamine in the substantia nigra of the rat: I. Morphological study

Brain Research

(1973)

UngerstedtU.

6-Hydroxydopamine induces degeneration of central monoamine neurons

Europ. J. Pharmacol.

(1968)

WaymireJ.C. et al.

Assay of tyrosine hydroxylase by coupled decar☐ylation of dopa formed formed 1-¹⁴C-tyrosine

Analyt. Biochem.

(1971)

AghajanianG.K. et al.

Dopamine ‘autoreceptors’: pharmacological characterization by microiontophoretic single cell recording studies

Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak.

(1977)

AgidY. et al.

Hyperactivity of remaining dopaminergic neurons after partial destruction of the nigrostriatal dopaminergic system in the rat

Nature New Biol.

(1973)

ButcherL.L.

Degenerative processes after punctate intracerebral administration of 6-hydroxydopamine

J. neural. Transm.

(1975)

CarlssonA. et al.

Simultaneous measurement of tyrosine and tryptophane hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decar☐ylase

Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak.

(1972)

CheramyA. et al.

Effects of peripheral and local administration of picrotoxin on the release of newly synthesized³H-dopamine in the caudate nucleus of the cat

Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak.

(1977)

Cited by (448)

Morphological changes in perisynaptic astrocytes induced by dopamine neuronal degeneration in the striatum of rats
2024, Heliyon
The typical functionality of astrocytes was previously shown to be disrupted by Parkinson's disease (PD), which actively regulates synaptic neurotransmission. However, the morphological changes in astrocytes wrapping glutamatergic synapses in the striatum after dopamine (DA) neuronal degeneration is unclear.
We utilized a range of methodologies, encompassing the 6-hydroxydopamine (6OHDA)-induced PD model, as well as techniques such as immunohistochemistry, Western blotting, immunofluorescence and immunoelectron microscopy (IEM) to delve into the consequences of DA neuronal degeneration on the morphological attributes of perisynaptic astrocytes.
Our findings demonstrated a notable rise in glial fibrillary acidic protein (GFAP) + astrocyte density and an upregulation in GFAP protein expression within the striatum due to DA neuronal degeneration, coincided with the enlargement, elongation, and thickening of astrocyte protuberances. However, the expression levels of glutamate transporter 1 (GLT1) and glutamine synthetase (GS), which are related to glutamate–glutamine cycle, were significantly reduced. Double immunofluorescence and IEM results indicated that different proportions of vesicular glutamate transporter 1 (VGlut1)+ and vesicular glutamate transporter 2 (VGlut2) + terminals were wrapped by astrocytes. Additionally, DA neuronal degeneration increased the percentage and area of VGlut1+ and VGlut2+ terminals wrapped by GFAP + astrocytes in the striatum. Furthermore, we noted that DA neuronal degeneration increased the percentage of VGlut1+ and VGlut2+ axo-spinous synapses wrapped by astrocytes but had no effect on axo-dendritic synapses.
Hence, perisynaptic astrocytes wrapping striatal glutamatergic synapses exhibit substantial morphological and functional alterations following DA neuronal degeneration making them a potential target for therapeutic interventions in PD.
Longitudinal characterization of cognitive and motor deficits in an excitotoxic lesion model of striatal dysfunction in non-human primates
2019, Neurobiology of Disease
As research progresses in the understanding of the molecular and cellular mechanisms underlying neurodegenerative diseases like Huntington's disease (HD) and expands towards preclinical work for the development of new therapies, highly relevant animal models are increasingly needed to test new hypotheses and to validate new therapeutic approaches. In this light, we characterized an excitotoxic lesion model of striatal dysfunction in non-human primates (NHPs) using cognitive and motor behaviour assessment as well as functional imaging and post-mortem anatomical analyses.
NHPs received intra-striatal stereotaxic injections of quinolinic acid bilaterally in the caudate nucleus and unilaterally in the left sensorimotor putamen. Post-operative MRI scans showed atrophy of the caudate nucleus and a large ventricular enlargement in all 6 NHPs that correlated with post-mortem measurements. Behavioral analysis showed deficits in 2 analogues of the Wisconsin card sorting test (perseverative behavior) and in an executive task, while no deficits were observed in a visual recognition or an episodic memory task at 6 months following surgery. Spontaneous locomotor activity was decreased after lesion and the incidence of apomorphine-induced dyskinesias was significantly increased at 3 and 6 months following lesion. Positron emission tomography scans obtained at end-point showed a major deficit in glucose metabolism and D2 receptor density limited to the lesioned striatum of all NHPs compared to controls. Post-mortem analyses revealed a significant loss of medium-sized spiny neurons in the striatum, a loss of neurons and fibers in the globus pallidus, a unilateral decrease in dopaminergic neurons of the substantia nigra and a loss of neurons in the motor and dorsolateral prefrontal cortex.
Overall, we show that this robust NHP model presents specific behavioral (learning, execution and retention of cognitive tests) and metabolic functional deficits that, to the best of our knowledge, are currently not mimicked in any available large animal model of striatal dysfunction. Moreover, we used non-invasive, translational techniques like behavior and imaging to quantify such deficits and found that they correlate to a significant cell loss in the striatum and its main input and output structures. This model can thus significantly contribute to the pre-clinical longitudinal evaluation of the ability of new therapeutic cell, gene or pharmacotherapy approaches in restoring the functionality of the striatal circuitry.
Hypericum polyanthemum cyclohexane extract potentiates behavioral effects and neurodegeneration induced by nigral infusions of 6-hydroxydopamine in rats
2018, Neuroscience Letters
Parkinson’s Disease (PD) is a progressive neurodegenerative disorder, hallmark of which is loss of nigral dopaminergic neurons. Since a Hypericum polyanthemum extract inhibits monoamine reuptake and some of its constituents present cytotoxic properties, the aim of this study was to evaluate the effect of this extract in an animal PD model.
Adult Wistar rats (110 days old) received 6-hydroxydopamine (6-OHDA) infusions into the right medial forebrain bundle. A cyclohexane extract from aerial parts of H. polyanthemum (POL; 90 mg/kg/administration; gavage) was administered in three different regimens. In Regimens 1 and 2, rats received 3 administrations of POL starting 4 or 24 h after 6-OHDA infusion, respectively. In Regimen 3, these administrations were carried out 1 day before any evaluation of ipsilateral rotational activity induced by methylphenidate (MP, 20 mg/kg, i.p.). MP was administered 10, 45, and 85 days after 6-OHDA infusion in all groups. Nigral tyrosine hydroxylase (TH) immunocontent was evaluated 120 days after 6-OHDA infusion in animals submitted to Regimen 2 only. The effect of POL on apomorphine-induced climbing behavior in non-lesioned adult CF1 mice (60 days old) treated with POL was also evaluated.
Regimen 2 increased MP-induced rotational activity and decreased nigral TH levels in 6-OHDA-lesioned rats. Rotational activity was not altered in regimens 1 and 3. In addition, no change in climbing behavior was observed in non-lesioned mice.
Together, these results indicate that, in 6-OHDA-lesioned rats, a cyclohexane H. polyanthemum extract potentiates neurotoxicity and MP-induced motor asymmetry depending on the time of administration. In the short term, it seems to not act directly on mice dopaminergic receptors.
Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson's disease by activation of sphingosine kinase 1 and Akt kinase
2018, Neuropharmacology
Parkinson's disease (PD) is one of the most severe neurodegenerative diseases with unknown pathogenesis and currently unsuccessful therapies. Recently, neuroprotection via sphingosine-1-phosphate (S1P)-dependent signalling has become a promising target for the treatment of neurodegenerative disorders. Our previous study demonstrated down-regulation and inhibition of the S1P-synthesizing enzyme sphingosine kinase 1 (SPHK1) in a PD cellular model. Moreover, we have previously identified a neuroprotective effect of fingolimod (FTY720), a first S1P receptor modulator utilized in the clinic. This study focused on the effects of FTY720 and the dopamine D2/D3 receptor agonist pramipexole (PPX) in a PD mouse model, induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Administration of FTY720, similar to PPX, abolished an observed loss of tyrosine hydroxylase (TH) immunoreactivity in MPTP-lesioned brain regions. Moreover, significant changes in SPHK1 expression/activity in MPTP-lesioned mouse midbrain were identified. PPX, but not FTY720 treatment, significantly protected against these alterations. Both drugs activate another pro-survival enzyme, Akt kinase, which is a crucial protein downstream of S1PR(s). FTY720 increased BAD protein phosphorylation and in this way may protect mitochondria against the BAD-induced apoptotic signalling pathway. Both FTY720 and PPX enhanced the locomotor activity of PD mice in the rotarod tests. Our data suggest a neuroprotective role for FTY720 related to the S1PR/Akt kinase signalling pathways as a beneficial treatment target in planning new PD therapeutic options. Moreover, our findings have shed new light on a neuroprotective mechanism of PPX action associated with SPHK1 activation, which provides an opportunity for evaluating multi-target (SPHK1/S1P/S1PR) effects in the context of PD.
Dissociation between dopaminergic response and motor behavior following intrastriatal, but not intravenous, transplant of bone marrow mononuclear stem cells in a mouse model of Parkinson's disease
2017, Behavioural Brain Research
Parkinson’s disease is characterized by the progressive loss of dopaminergic neurons from the substantia nigra, a process that leads to a dopamine deficiency in the striatum. This deficiency is responsible for the development of motor symptoms, including resting tremor, bradykinesia, rigidity and postural instability. Based on the observation of substantial neuronal death, alternatives to Parkinson’s disease treatment have been studied, including cell-based therapies. The present study aimed to assess the therapeutic potential of intravenous and intrastriatal transplant of bone marrow mononuclear cells in a mouse model of Parkinson’s disease. Animals underwent stereotaxic surgery and received an injection of 6-hydroxydopamine into their medial forebrain bundle. Three weeks later, mice were injected with bone marrow mononuclear cells or saline through the caudal vein or directly into their right striatum. Motor function was assessed using the rotarod and apomorphine-induced rotation tests. Our results showed that intrastriatal bone marrow mononuclear cells, but not intravenous, have a short-term therapeutic effect on dopaminergic response in this mice model of parkinsonism assessed by the apomorphine-induced rotation test. This phenomenon was not identified on the rotarod test, showing dissociation between dopaminergic response and motor behavior. Further experiments are needed to elucidate the precise mechanisms involved in these effects.
Vocal training, levodopa, and environment effects on ultrasonic vocalizations in a rat neurotoxin model of Parkinson disease
2016, Behavioural Brain Research
Levodopa does not improve dysarthria in patients with Parkinson Disease (PD), although vocal exercise therapy, such as “LSVT/LOUD^®”, does improve vocal communication. Most patients receive vocal exercise therapy while concurrently being treated with levodopa, although the interaction between levodopa and vocal exercise therapy on communication in PD is relatively unknown. Further, carryover of vocal exercise therapy to novel situations is critical for successful outcomes, but the influence of novel situations on rehabilitated vocal communication is not well understood. To address the influence of exercise, medications, and environment on vocal communication with precise experimental control, we employed the widely used 6-OHDA rat neurotoxin model of PD (infusion to the medial forebrain bundle), and assessed ultrasonic vocalizations after: vocal exercise, vocal exercise with levodopa, levodopa alone, and control conditions. We tested USVs in the familiar training environment of the home cage and a novel cage. We hypothesized that parkinsonian rats that undergo vocal exercise would demonstrate significant improvement of ultrasonic vocalization (USV) acoustic parameters as compared to the control exercise and levodopa-only treatment groups. We further hypothesized that vocal exercise in combination with levodopa administration, similar to what is common in humans, would lead to improvement in USV outcomes, particularly when tested in a familiar versus a novel environment. We found that the combination of exercise and levodopa lead to some improvement in USV acoustic parameters and these effects were stronger in a familiar vs. a novel environment. Our results suggest that although treatment can improve aspects of communication, environment can influence the benefits of these effects.

View all citing articles on Scopus

View full text

Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization

Abstract

J. neurol. Sci.

Europ. J. Pharmacol.

Biochem. Pharmacol.

Brain Research

Life Sci.

Brain Research

J. biol. Chem.

Brain Research

Brain Research

Brain Research

Life Sci.

Brain Research

Brain Research

Europ. J. Pharmacol.

Analyt. Biochem.

Dopamine ‘autoreceptors’: pharmacological characterization by microiontophoretic single cell recording studies

Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak.

Hyperactivity of remaining dopaminergic neurons after partial destruction of the nigrostriatal dopaminergic system in the rat

Nature New Biol.

Degenerative processes after punctate intracerebral administration of 6-hydroxydopamine

J. neural. Transm.

Simultaneous measurement of tyrosine and tryptophane hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decar☐ylase

Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak.

Effects of peripheral and local administration of picrotoxin on the release of newly synthesized3H-dopamine in the caudate nucleus of the cat

Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak.

Effects of peripheral and local administration of picrotoxin on the release of newly synthesized³H-dopamine in the caudate nucleus of the cat