Experimental Models Of Parkinson's Disease Research Articles

Epidemiology of alcoholism in the European Russian North

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a preferential loss of the dopaminergic neurons of the substantia nigra pars compacta. Although the etiology of PD is unknown, major biochemical processes such as oxidative stress and mitochondrial inhibition are largely described. However, despite these findings, the actual therapeutics are essentially symptomatical and are not able to block the degenerative process. Recent histological studies performed on brains from PD patients suggest that nigral cell death could be apoptotic. However, since post-mortem studies do not allow precise determination of the sequence of events leading to this apoptotic cell death, the molecular pathways involved in this process have been essentially studied on experimental models reproducing the human disease. These latter are created by using neurotoxic compounds such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or dopamine (DA). Extensive study of these models have shown that they mimick, in vitro and in vivo, the histological and/or the biochemical characteristics of PD and thus help to define important cellular actors of cell death presumably critical for the nigral degeneration. This review reports recent data concerning the biochemical and molecular apoptotic mechanisms underlying the experimental models of PD and correlates them to the phenomena occurring in human disease.

L-DOPA inhibits spontaneous acetylcholine release from the striatum of experimental Parkinson's model rats

Acetylcholine (ACh) release was measured by microdialysis. Addition of 10 nM l-DOPA to the perfusate significantly decreased ACh release, from the striatum of rats lesioned with 6-hydroxydopamine (6-OHDA), but not sham-operated rats. The l-DOPA-induced decrease was not affected by (−)-sulpiride which completely blocked D 2- and D 3-agonist-induced decrease in ACh release in lesioned rats. Neither 10 nM d-DOPA nor 100 nM dopamine caused any change in ACh release. These findings suggest that l-DOPA-sensitive mechanisms are supersensitized in Parkinson's disease model rats.

Neurobiologia do parkinsonismo: II. modelos experimentais

The study of experimental models of parkinsonism has contributed to the knowledge of basal ganglia functions, as well as to the establishment of several hypothesis for the explanation of the cause and expression of central neurodegenerative disorders. In this review we present and discuss several models such as 6-hydroxydopamine, MPTP and manganese, all of them widely used to characterize the behavioral, cellular and molecular mechanisms of parkinsonism.

Supersensitization of neurochemical responses by L-DOPA and dopamine receptor agonists in the striatum of experimental Parkinson's disease model rats

We studied the mechanisms of dopamine receptor agonist- and L-DOPA-mediated supersensitization in experimental Parkinson's disease model rats, by measuring in vivo acetylcholine (ACh) release, GTPase activities, and mRNA expression in the striatum of 6-hydroxydopamine-treated rats. D1 agonist (SKF38393) and D2/D3 agonists (bromocriptine and quinpirole) showed more potent stimulation or inhibitions on ACh release in the model rat than in the control. However, quinpirole-evoked stimulation of GTPase activity was enhance in the model rats, compared to the control, while there was no significant enhancement of the bromocriptine-evoked stimulation. On the other hand, L-DOPA at 0.3-10 pM showed a biphasic action including significant inhibition on the GTPase activity in the lesioned striatal membranes, but not in the control. In the RNAase protection assay, neither D1, D2, Gi1 alpha, GoA alpha nor Gs alpha mRNA expression in the model was significantly different from the control. These findings suggest that there is supersensitization of D1 and D2/D3 receptors in the experimental Parkinson's disease model, while the upregulation of their receptors or GTP-binding proteins (G-proteins) to be coupled to their receptors is unlikely involved in major parts of such mechanisms. In addition, the present report provides the first evidence that L-DOPA mediates neurochemical responses in the plasma membranes, possibly through its receptor.

Cinnarizine-induced parkinsonism in primates.

We describe the production of an experimental model of parkinsonism induced by cinnarizine (CNZ) in three healthy sylvanna monkeys. The drug produced a severe but reversible parkinsonism in all animals. After discontinuation of CNZ, all animals recovered but the oldest one was akinetic for 6 weeks. CNZ produced a persistent reduction in HVA and 5-HIAA levels in the CSF. Our data suggest a predominant presynaptic effect on DA and 5-HT neurons; and could account for the longstanding parkinsonism induced by calcium antagonist in some patients as well as the depression observed in these subjects.

A new dopamine agonist in dopamine deprived systems: FCE 23884

FCE 23884, a newly synthesized ergoline-derivative, shows a unique pharmacological profile, displaying a full dopamine (DA) antagonism in normal animals but a full DA agonism indenervated animal models. In normal animals FCE 23884, administered by different routes, showed a variety of pharmacological effects similar to those seen with standard DA antagonists (Table 1). In fact the compound potently, dose-dependently, antagonized the apomorphine-induced climbing behaviour in mice, the apomorphine-induced yawning in rats and the amphetamine-induced toxicity in grouped mice. The compound depressed per s~ spontaneous locomotor activity in both mice and rats, impaired the Sidman's avoidance in rats and completely antagonized apomorphine-induced emesis in Beagle dogs. The above reported results are all compatible with the antidopaminergic properties displayed by antipsychotic agents (Worms et al., 1983) and support that FCE 23884 acts mainly as a central D-2 antagonist in normal animals. On the contrary, in denervated animals, FCE 23884 behaves as a strong DA-ergic agent (Table 2). The compound stimulated the contralateral turning behavior in 6-OHDA lesioned rats. This effect was almost completely antagonized (81%) by the selective DI receptor antagonist SCH 23390, but slightly affected by the selective D--2 antagonist l-sulpiride. These results indicate that FCE 23884, in this context, stimulates motor activity mainly via DI receptors. In an experimental Parkinson's model, i.e. in MPTPtreated monkeys showing severe parkinsunian symptoms, FCE 23884 completely reversed the MPTPinduced akinesia and restored normal behavior. In reserpinized mice FCE 23884 reversed the induced akinesia restoring the locomotor activity. Taken as a whole, these results strongly support that FCE 23884 exerts a potent DA agonist activity in DA deprived animals. To better understand the relevance of the DA presence for FCE 23884 antagonist/agonist activity, the model of rcserpinized mice was chosen because of the reproducibility of DA depletion and the absence of the DA receptors supersensitivity (Liberini et al., 1989). Interaction studies with the DA precursor LDOPA and with the mixed or selective DI /D-2 direct agonists were performed in the model of the locomotor recovery in reserpinized mice.

Transplantation of Polymer Encapsulated Neurotransmitter Secreting Cells: Effect of the Encapsulation Technique

Deficits associated with neurological diseases may be improved by the transplantation within the brain lesioned target structure of polymer encapsulated cells releasing the missing neurotransmitter. Surrounding cells with a permselective membrane of appropriate molecular weight cut-off allows inward diffusion of nutrients and outward diffusion of neurotransmitters, but prevents immunoglobulins or immune cells from reaching the transplant. This technique therefore allows transplantation of post-mitotic cells across species. It also permits neural grafting of transformed cell lines since the polymer capsule prevents the formation of tumors by physically sequestering the transplanted tissue. In the present study, we compared the ability of dopamine-secreting cells, encapsulated by 2 different methods, to reverse experimental Parkinson's disease, a neurodegenerative disease characterized by motor disturbances due to a lack of dopamine within the striatum following degeneration of the dopaminergic nigro-striatal pathway. PC12 cells were loaded in polyelectrolyte-based microcapsules or thermoplastic-based macrocapsules and maintained in vitro or transplanted in a rat experimental Parkinson model for 4 weeks. Chemically-induced depolarization increased the in vitro release of dopamine from macrocapsules over time, while no increase in release was observed from microcapsules. Encapsulated PC12 cells were able to reduce lesion-induced rotational asymmetry in rats for at least 4 weeks, regardless of the encapsulation technique used. With both encapsulation methods, PC12 cell viability was greater in vivo than in vitro which suggests that the striatum releases trophic factors for PC12 cells. More brain tissue damage was observed with microcapsules than macrocapsules, possibly the result of the difficulty of manipulating the more fragile microcapsules.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraventricular infusion of epidermal growth factor restores dopaminergic pathway in hemiparkinsonian rats

We assessed the effect of a 35-day delayed intracerebroventricular (ICV) infusion of epidermal growth factor (EGF) on the survival and function of the substantia nigra (SN) dopaminergic neurons after a unilateral mechanical transection of rat nigrostriatal pathway. EGF infusion for 28 days resulted in a twofold increase in the number of surviving tyrosine-hydroxylase (TH)-positive SN neurons and a significant increase in ipsilateral striatal TH-positive fiber staining compared to controls at 200 days following the injury. In addition, there was a persistent enhancement of behavioral recovery, as indicated by a reduction in amphetamine-induced rotations. We conclude that EGF exerts a neurotrophic effect on the dopaminergic neurons in this experimental model of parkinsonism.

Neurotoxin-induced impairment of biopterin synthesis and function: Initial stage of a Parkinson-like dopamine deficiency syndrome

Disorders of the function of the tyrosine hydroxylase play an important role in the occurrence of the Parkinson syndrome. The enzyme that catalyses the first, rate-limiting step in the biosynthesis to dopamine requires the cofactor tetrahydrobiopterin. This compound supplies the reduction equivalent for activation of molecular oxygen. Binding of the cofactor to the enzyme is affected by phosphorylation or dephosphorylation of the enzyme protein and, thereby, influences the activity. Nerve and chromaffin cells that synthesize dopamine, noradrenaline and serotonin are able to synthesize the cofactor tetrahydrobiopterin de novo from guanosine-triphosphate as a precursor. In patients suffering from Parkinson's disease a remarkable decrease in biopterin content was found in the brain. The function of the dopaminergic system was studied with an experimental Parkinson model. The antimetabolite 6-aminonicotinamide induces a dopamine deficit in the striatum with a significant slowdown in the utilization of this transmitter. The abolition of the 6-aminonicotinamide-induced muscular rigidity by l-DOPA and dopamine agonists implies that the antimetabolite produces a Parkinson-like syndrome in rats. There are reports on the molecular basis of this effect which are also important for understanding possible disturbances of the synthesis of biopterins. The effector 6-aminonicotinamide-adenine-dinucleotide-phosphate (6-ANADP), which blocks the pentose phosphate pathway, is formed by an enzymatic neurotoxic synthesis. The clonal cell line PC-12 was used to study the molecular basis of the disturbances occurring in the dopaminergic system. These cells contain all the enzymes for catecholamine synthesis, including those for the synthesis of the cofactor tetrahydrobiopterin. Addition of 6-aminonicotinamide to the culture medium resulted in the synthesis of the neurotoxic agent, 6-ANADP, by a glycohydrolase localized in the endoplasmic reticulum. The synthesis of biopterin was depressed after application of 6-aminonicotinamide. The decrease of intracellular tetrahydrobiopterin and total biopterin resulted in reduced DOPA production. The decreased content of biopterin cofactor synthesis was compensated for by the addition of the precursor sepiapterin, indicating that the NADPH-dependent reductases in biopterin synthesis were not inhibited by the antimetabolic nucleotide 6-ANADP. DOPA production was not fully normalized by sepiapterin. Addition of NADH to the medium resulted in a further increase of DOPA production, probably by activation of the recycling pathway. The first step in the synthesis of biopterin from GTP to 7,8-neopterin-triphosphate seems to be particularly sensitive to the action of exogenous neurotoxins. A further sensitive site of action in synthesis to the cofactor BH(4) concerns the function of the dihydropteridin-reductase, which recycles qBH(2) to BH(4). Neurotoxin-induced impairment of biopterin synthesis is probably a pathogenetically important disorder at the initial stage of Parkinson's disease.

Transplantation of ventral mesencephalic anlagen to hosts with genetic nigrostriatal dopamine deficiency.

Attempts to reconstruct the damaged nigrostriatal pathway in experimental models of Parkinson disease have thus far been carried out in animals with neurotoxically induced dopamine deficiency. The present study establishes the weaver (wv/wv) mutant mouse as a genetic model of chronic striatal dopamine denervation by demonstrating a marked decrease of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta. Moreover, grafts of embryonic ventral mesencephalon taken from genetically normal mice and transplanted into the lateral ventricle of adult weaver mutants can survive and grow in the mutant host environment, express tyrosine hydroxylase immunoreactivity, and reinnervate the target regions of the recipient. These results provide evidence of integration of graft and host tissue and suggest that transplantation of dopamine neurons may be effectively applied to overcome nigrostriatal degeneration of genetic etiology.

Aphagia and adipsia produced by unilateral hypothalamic lesions in rats.

ARTICLESAphagia and adipsia produced by unilateral hypothalamic lesions in ratsRM GoldRM GoldPublished Online:01 Nov 1966https://doi.org/10.1152/ajplegacy.1966.211.5.1274MoreSectionsPDF (797 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByRelapse to opioid seeking in rat models: behavior, pharmacology and circuits6 October 2018 | Neuropsychopharmacology, Vol. 44, No. 3Context-induced relapse after extinction versus punishment: similarities and differences24 May 2018 | Psychopharmacology, Vol. 236, No. 1Enhanced CRFR1-Dependent Regulation of a Ventral Tegmental Area to Prelimbic Cortex Projection Establishes Susceptibility to Stress-Induced Cocaine Seeking24 October 2018 | The Journal of Neuroscience, Vol. 38, No. 50Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking in rats7 September 2015 | Psychopharmacology, Vol. 233, No. 10Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence16 March 2016 | The Journal of Neuroscience, Vol. 36, No. 11Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress15 May 2015 | Neuropsychopharmacology, Vol. 41, No. 1Role of corticostriatal circuits in context-induced reinstatement of drug seekingBrain Research, Vol. 1628Metabolic hormones, dopamine circuits, and feedingFrontiers in Neuroendocrinology, Vol. 31, No. 1Ibotenic acid lesion of the lateral hypothalamus increases preference and aversion thresholds for saccharin and alters the morphine modulation of tastePharmacology Biochemistry and Behavior, Vol. 36, No. 3Effects of lateral hypothalamic lesions on thermoregulation in the ratPhysiology & Behavior, Vol. 38, No. 2Amine accumulation in behavioural pathologyBrain Research Reviews, Vol. 9, No. 2The physiological control of appetite in fishComparative Biochemistry and Physiology Part A: Physiology, Vol. 78, No. 4The behavioural effects of intrahypothalamic multistage versus single injections of 6-hydroxydopamineBrain Research, Vol. 245, No. 2Depletion of dopamine in the striatum as an experimental model of parkinsonism: direct effects and adaptive mechanismsProgress in Neurobiology, Vol. 18, No. 2-3Accelerated recovery from eating behavior deficits after sequential lesions of cortex and hypothalamus: Is dopamine involved?Experimental Neurology, Vol. 70, No. 2Serial lateral hypothalamic destruction with various interlesion intervalsExperimental Neurology, Vol. 67, No. 3Effects of serial lateral hypothalamic destruction on feeding behavior, body weight, and neocortical and hippocampal EEG activityExperimental Neurology, Vol. 66, No. 2A role for the dopaminergic nigrostriatal bundle in the pathogenesis of altered brain glucose consumption after lateral hypothalamic lesions. Evidence using the14C-labeled deoxyglucose techniqueBrain Research, Vol. 158, No. 1Body weight and regulatory deficits following unilateral nigrostriatal lesionsBrain Research, Vol. 132, No. 3Serial lateral hypothalamic destruction: Infancy and adulthoodExperimental Neurology, Vol. 53, No. 3Gustatory neural coding in the ponsBrain Research, Vol. 110, No. 2The Influence of Experience on Recovery Following Brain Damage in Rodents: Hypotheses Based on Development ResearchRecovery of function after serial or one-stage lesions of the lateral hypothalamic area in ratsBehavioral Biology, Vol. 14, No. 3The pontine taste area in the ratBrain Research, Vol. 91, No. 1Gustatory afferents to ventral forebrainBrain Research, Vol. 81, No. 2Effect of coagulation of the dorsal hippocampus and mesencephalic reticular formation of the food responseBulletin of Experimental Biology and Medicine, Vol. 78, No. 4Autonomic and behavioral temperature regulationPfl�gers Archiv European Journal of Physiology, Vol. 352, No. 2Increased food intake elicited by adrenergic stimulation of the diencephalon in rhesus monkeysBrain Research, Vol. 65, No. 3Hyperphagia produced by knife cuts between the medial and lateral hypothalamus in the ratPhysiology & Behavior, Vol. 4, No. 4THE INTERRELATIONSHIP OF FOREBRAIN AND MIDBRAIN STRUCTURES INVOLVED IN FEEDING BEHAVIORActa Neurologica Scandinavica, Vol. 44, No. 5Effects of unilateral hypothalamic lesions on drinking and self-stimulation in the rat4 November 2013 | Psychonomic Science, Vol. 10, No. 9Aphagia and adipsia following unilateral and bilaterally asymmetrical lesions in ratsPhysiology & Behavior, Vol. 2, No. 2 More from this issue > Volume 211Issue 5November 1966Pages 1274-1276 Copyright & PermissionsCopyright © 1966 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1966.211.5.1274PubMed5924054History Published online 1 November 1966 Published in print 1 November 1966 Metrics

Pyramidal tract activity associated with a conditioned hand movement in the monkey.

Pyramidal tract activity associated with a conditioned hand movement in the monkey.