Acute monoaminergic depletion in the rat potentiates the excitatory effect of the subthalamic nucleus in the substantia nigra pars reticulata but not in the pallidal complex.
TL;DR: The data suggest that the spontaneous pattern of discharge of theSTH is probably under monoaminergic control and suggest a reciprocal interaction between dopamine and glutamatergic afferent terminals from the STH within the SNpr, but not in the pallidal complex.
Abstract: Recent neurochemical evidence suggests that chemical or electrial stimulation of the subthalamic nucleus (STH) increases dopamine release in the substantia nigra (SN) with a subsequent decrease in the striatum. In a previous paper, we reported that bicuculline-induced activation of the STH increases neuronal activity in the substantia nigra pars reticulata (SNpr) and in the pallidal complex. In order to investigate the role played by the dopaminergic system in the observed activation, the neuronal responses of subthalamic nucleus target structures were studied in amine depleted rats following subthalamic stimulation. Amine depletion was accomplished by pretreating the rats with reserpine (2 mg/kg; S.C.) and with alpha-methyl-para-tyrosine (α-mpt; 50 mg/kg; I.P.).Following this treatment, dopamine levels were reduced by 94% in the striatum as measured by HPLC. Amine depletion significantly increased the spontaneous activity of subthalamic cells by 53%. In the SNpr, no significant changes in the spontaneous neuronal activity were observed, but the excitatory responses to bicuculline-induced stimulation of the STH were potentiated as compared to non-treated animals. In the pallidial complex (GP-EP), no potentiation was found. The data suggest that the spontaneous pattern of discharge of the STH is probably under monoaminergic control. They also suggest a reciprocal interaction between dopamine and glutamatergic afferent terminals from the STH within the SNpr, but not in the pallidal complex.
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TL;DR: The MPTP‐treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti‐parkinsonian medications have been shown to be effective, is undoubtedly the most clinically‐relevant of all available models.
Abstract: Animal models of Parkinson's disease (PD) have proved highly effective in the discovery of novel treatments for motor symptoms of PD and in the search for clues to the underlying cause of the illness. Models based on specific pathogenic mechanisms may subsequently lead to the development of neuroprotective agents for PD that stop or slow disease progression. The array of available rodent models is large and ranges from acute pharmacological models, such as the reserpine- or haloperidol-treated rats that display one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro-striatal pathway, such as the classical 6-hydroxydopamine (6-OHDA) rat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models. All of these have provided test beds in which new molecules for treating the motor symptoms of PD can be assessed. In addition, the emergence of abnormal involuntary movements (AIMs) with repeated treatment of 6-OHDA-lesioned rats with L-DOPA has allowed for examination of the mechanisms responsible for treatment-related dyskinesia in PD, and the detection of molecules able to prevent or reverse their appearance. Other toxin-based models of nigro-striatal tract degeneration include the systemic administration of the pesticides rotenone and paraquat, but whilst providing clues to disease pathogenesis, these are not so commonly used for drug development. The MPTP-treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti-parkinsonian medications have been shown to be effective, is undoubtedly the most clinically-relevant of all available models. The MPTP-treated primate develops clear dyskinesia when repeatedly exposed to L-DOPA, and these parkinsonian animals have shown responses to novel dopaminergic agents that are highly predictive of their effect in man. Whether non-dopaminergic drugs show the same degree of predictability of response is a matter of debate. As our understanding of the pathogenesis of PD has improved, so new rodent models produced by agents mimicking these mechanisms, including proteasome inhibitors such as PSI, lactacystin and epoximycin or inflammogens like lipopolysaccharide (LPS) have been developed. A further generation of models aimed at mimicking the genetic causes of PD has also sprung up. Whilst these newer models have provided further clues to the disease pathology, they have so far been less commonly used for drug development. There is little doubt that the availability of experimental animal models of PD has dramatically altered dopaminergic drug treatment of the illness and the prevention and reversal of drug-related side effects that emerge with disease progression and chronic medication. However, so far, we have made little progress in moving into other pharmacological areas for the treatment of PD, and we have not developed models that reflect the progressive nature of the illness and its complexity in terms of the extent of pathology and biochemical change. Only when this occurs are we likely to make progress in developing agents to stop or slow the disease progression. The overarching question that draws all of these models together in the quest for better drug treatments for PD is how well do they recapitulate the human condition and how predictive are they of successful translation of drugs into the clinic? This article aims to clarify the current position and highlight the strengths and weaknesses of available models.
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This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4
596 citations
Cites background from "Acute monoaminergic depletion in th..."
...For example, firing of the subthalamic nucleus (STN) is increased approximately 50% (Robledo and Feger, 1991), an increase that occurs in PD (Hutchison et al., 1998; Benazzouz et al., 2002), and extracellular glutamate levels are elevated in the basal ganglia output regions, specifically the…...
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...For example, firing of the subthalamic nucleus (STN) is increased approximately 50% (Robledo and Feger, 1991), an increase that occurs in PD (Hutchison et al....
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TL;DR: Patterns of electrophysiological activity and changes in indices of GABA-dependent transmission in the external pallidum lead to a reconsideration of the mechanisms responsible for these changes in output activity.
399 citations
TL;DR: The results indicate that the increased activity of the subthalamic neurons following a midbrain dopaminergic lesion cannot be due solely to inhibition-disinhibition involving the striato-pallido-subthalamic pathway and induced by the striatal dopaminaergic depletion.
351 citations
TL;DR: The results suggest that STN lesions have multiple, dissociable effects on attentional performance, including discriminative deficits, impulsivity and perseverative behaviour, which is consistent with a hypothesized role of the STN in recent models of basal ganglia function in areaction selection and inhibition.
Abstract: Lesioning the subthalamic nucleus (STN) has been suggested as possible therapy for the treatment of parkinsonism. Previous experiments investigating this hypothesis in rats confirmed that excitotoxic STN lesions alleviate the motor impairment induced by striatal dopamine depletion, which reproduced the degeneration observed in parkinsonism, but elicited presumed non-motor deficits such as premature responding, suggesting that the STN could be involved in other aspects of response control. The aim of the present study was to extend this analysis to choice paradigms. We thus investigated the behavioural effects of bilateral excitotoxic lesions of the STN in rats performing a five-choice test of divided and sustained visual attention, modelled on the human continuous performance task. This task required the animals to detect a brief visual stimulus presented in one of five possible locations and respond by a nose-poke in this illuminated hole within a fixed delay, for food reinforcement. Bilateral lesions of the STN severely impaired several aspects of performance, including discriminative accuracy, but also increased premature, anticipatory responding as well as perseverative panel pushes and nose-poke responses. While increasing the stimulus duration and reducing the waiting period for the stimulus partially alleviated the accuracy deficit and the premature responding deficit respectively, other deficits, such as perseverative panel pushes and nose-poke responses, were sustained under these conditions. Systemic injection of the mixed dopaminergic D1/D2 receptor antagonist, alpha-flupenthixol (0.03-0.18 mg/kg), reduced premature responses and perseverative panel pushing without affecting the perseverative nose-poke responses, suggesting that some of the deficits were independent of striatal dopaminergic transmission. These results suggest that STN lesions have multiple, dissociable effects on attentional performance, including discriminative deficits, impulsivity and perseverative behaviour. They are consistent in part with a hypothesized role of the STN in recent models of basal ganglia function in action selection and inhibition. The results also show that other aspects of behaviour should be monitored when examining the capacity of STN lesions to reverse the parkinsonian deficit induced by striatal dopamine depletion.
271 citations
TL;DR: The premise that therapeutic efficacy in the treatment of Parkinson’s disease is associated with a decrease in the activity of the STN is supported, but assumptions about the roles of D1 and D2 receptors in the regulation of neuronal activity ofThe STN in both the intact and dopamine-depleted states are challenged.
Abstract: Overactivity in the subthalamic nucleus (STN) is believed to contribute to the pathophysiology of Parkinson’s disease. It is hypothesized that dopamine receptor agonists reduce neuronal output from the STN. The present study tests this hypothesis by using in vivo extracellular single unit recording techniques to measure neuronal activity in the STN of rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway (a model of Parkinson’s disease). As predicted, firing rates of STN neurons in lesioned rats were tonically elevated under basal conditions and were decreased by the nonselective dopamine receptor agonists apomorphine and l-3,4-dihydroxyphenylalanine (l-DOPA). STN firing rates were also decreased by the D2 receptor agonist quinpirole when administered after the D1 receptor agonist (±)- 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393). Results of the present study challenge the prediction that dopaminergic agonists reduce STN activity predominantly through actions at striatal dopamine D2 receptors. Firing rates of STN neurons were not altered by selective stimulation of D2 receptors and were increased by selective stimulation of D1 receptors. Moreover, there was a striking difference between the responses of the STN to D1/D2 receptor stimulation in the lesioned and intact rat; apomorphine inhibited STN firing in the lesioned rat and increased STN firing in the intact rat. These findings support the premise that therapeutic efficacy in the treatment of Parkinson’s disease is associated with a decrease in the activity of the STN, but challenge assumptions about the roles of D1 and D2 receptors in the regulation of neuronal activity of the STN in both the intact and dopamine-depleted states.
187 citations
References
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Journal Article•
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
289,852 citations
"Acute monoaminergic depletion in th..." refers methods in this paper
...The protein content of the pellet was analyzed according to the Lowry method (Lowry et al., 1961)....
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01 Jan 1983
TL;DR: This paper presents a meta-analyses of the determinants of earthquake-triggered landsliding in the Czech Republic over a period of 18 months in order to establish a probabilistic framework for estimating the intensity of the earthquake.
Abstract: Preface. Acknowledgements. Introduction. References. List of Structures. Index of Abbreviations. Diagrams.
57,116 citations
TL;DR: The postulated role of excessive activity in the subthalamic nucleus in Parkinson's disease is supported by the effects of lesions evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Abstract: 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.
1,848 citations
"Acute monoaminergic depletion in th..." refers result in this paper
...Similar results have recently been found in the monkey rendered parkinsonian by MPTP injection (Bergman et al., 1990)....
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TL;DR: Dopamine can be released in the substantia nigra from the dendrites of nigrostriatal dopaminergic neurones to be involved there in the self-regulation of the dopamina cells, to control the release of neurotransmitters from nigral afferent fibres and to influence the activity of nigral non-dopaminergic cells.
Abstract: Dopamine can be released in the substantia nigra for the dendrites of nigrostriatal dopaminergic neurones, to be involved there in the self-regulation of the dopaminergic cells, to control the release of neurotransmitters from nigral afferent fibres and to influence the activity of nigral non-dopaminergic cells.
740 citations
"Acute monoaminergic depletion in th..." refers background or result in this paper
...However, neurophysiological data point to a potential for these interactions in the SN (Kornhuber et al., 1984; Cheramy et al., 1981)....
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...Our results showing no change were rather surprising since they suggest that dopamine spontaneously released from dendrites of dopaminergic neurons (Cheramy et al., 1981) may not tonically...
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TL;DR: It is found that NA and cyclic AMP block the Ca2-activated K+ conductance in hippocampal pyramidal cells and that this blockade occurs at a step subsequent to the entry of Ca2+ into the neurone, which greatly increases the number of spikes elicited by a depolarizing stimulus.
Abstract: The hippocampus, as well as a variety of other brain regions, is known to receive a diffuse projection of noradrenaline (NA) containing fibres which originates in the brain stem1–4. Although there is considerable evidence for the involvement of this system in a variety of behaviours5–7, the precise cellular actions of NA are poorly understood. Early studies emphasized the direct inhibitory effects of NA8–12; more recent experiments have shown that at several sites, NA, or stimulation of NA-containing afferents, can also facilitate excitatory synaptic responses13–18. This has led to the concept that NA increases the ‘signal-to-noise’ ratio of neurones13, acting as an ‘enabling’ device4 which allows cells to respond more briskly to conventional synaptic excitation. In the olfactory bulb, NA reduces inhibitory postsyn-aptic potentials by a presynaptic action19, which could contribute to enhanced excitatory synaptic responses. However, in other systems, NA has been reported to enhance excitatory responses to iontophoretically applied transmitters, and it was proposed that NA increases the sensitivity of the neurone to these excitatory transmitters13–15. We report here experiments that could explain such direct effects. We have found that NA and cyclic AMP block the Ca2+-activated K+ conductance in hippocampal pyramidal cells and that this blockade occurs at a step subsequent to the entry of Ca2+ into the neurone. As a consequence, the spike frequency adaptation or accommodation which normally occurs with depolarizing stimuli is severely reduced. Thus, NA greatly increases the number of spikes elicited by a depolarizing stimulus.
588 citations