6-Hydroxydopamine-Induced Lesions of Dopaminergic Neurons Alter the Function of Postsynaptic Cholinergic Neurons without Changing Cytoskeletal Proteins

Muma, Nancy A.; Lee, John M.; Gorman, Linda K.; Heidenreich, Byron A.; Mitrovic, Igor; Napier, T. Celeste

doi:10.1006/exnr.2000.7582

Cited by 15 publications

(11 citation statements)

References 40 publications

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“…The precise reasons for the reduced M1/4 receptor following a 6-OHDA lesion are not yet known. However, it has been documented that dopaminergic denervation in the striatal pathway resulted in hyperactivity of the cholinergic systems (Muma et al, 2001;Zhang et al, 2008). Therefore, we hypothesize that the possible mechanisms for the reduced M1/4 receptors involved in our study is due to enhanced striatal cholinergic neuron firing following dopamine denervation in the nigrostriatal pathway; however, we cannot exclude the possibility that the reduced M1/4 receptors in the observed brain areas may reflect the receptor hypo-innervations.…”

Section: Discussionmentioning

confidence: 70%

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

et al. 2014

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. (2014). Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: the association with improvements in long-term memory. Neuroscience, 267 57-66.Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: the association with improvements in long-term memory AbstractBackground It is believed that muscarinic M1/4 receptors are closely correlated to the dopaminergic system and are strongly involved in the pathogenesis of Parkinson's disease (PD). In addition to regulating lipid metabolism and protection from stroke, statins have been used to regulate the declined cognition. We aimed to explore the regional changes in M1/4 receptors in the 6-hydroxydopamine (6-OHDA)-lesioned rat brain. Methods PD rat model was set up by injecting 6-OHDA into the unilateral medial forebrain bundle; while simvastatin (10 mg/kg/day) or saline was orally administrated for 3 weeks, respectively. Long-term memory was measured using the Morris water maze.[3H]pirenzepine binding autoradiography was applied to investigate the alterations of M1/4 receptors in the PD rat brains. Results 6-OHDA induced long-term memory deficits along with downregulation of M1/4 receptors in the hippocampus, the medial amygdala, the posteromedial cortical and the piriform cortex; simvastatin administration significantly ameliorated the impaired memory and reversed the downregulation of M1/4 receptors in the examined brain regions. Profound positive correlations were verified between the decline in long-term memory activity and the restoration of M1/4 receptors in different brain regions after simvastatin treatment. Conclusions/significance Our results provide strong evidence that M1/4 receptor modulation after simvastatin administration did, at least partially, contribute to the improvement in the long-term memory in 6-OHDA-induced PD rats. These results provide a possible mechanism for simvastatin treatment in psycho-neurological diseases such as PD via M1/4 receptors.

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Section: Discussionmentioning

confidence: 70%

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

et al. 2014

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“…In some experiments, immunohistochemistry for tyrosine hydroxylase was performed following previously established protocols (Muma et al, 2001;Heidenreich et al, 2004) to verify the placement of the CFM and to confirm that the regions examined were also DA rich, as demonstrated in other rodents (e.g., Bjorklund and Lindvall, 1984). Hamsters were transcardially perfused with 0.9% saline and then 4% p-formaldehyde in 0.1 M phosphate buffer (PB).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Voltammetric measurement of electrically evoked dopamine levels in the striatum of the anesthetized Syrian hamster

Greco

Meisel

Heidenreich

et al. 2006

Journal of Neuroscience Methods

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“…A notable exception is the inhibitory VP projection to midbrain dopaminergic neurons (Groenewegen et al 1993;Maurice et al 1997) that in turn project to the mSTN (Campbell et al 1985;Canteras et al 1990;Feger et al 1997;Hassani et al 1997). The majority of the dopaminergic neurons that input the mSTN arise from the substantia nigra pars compacta Hassani et al 1997), and our prior work verified that these neurons are completely destroyed with the 6-OHDA treatment protocol employed here (Muma et al 2001;Turner et al 2002). But as the ability of VP NMDA to activate mSTN neurons was not altered in the rats with 6-OHDA-induced lesions in the current study, other circuits must be involved.…”

Section: Discussionmentioning

confidence: 52%

“…The neuroanatomical substrates associated with the nonmotor symptoms are unclear, but as the VP is known to regulate reward and motor function (including those mediated by dopaminergic agents), cognition, motivated behaviors [e.g., (Bardo 1998;Gong et al 1996;Napier and Rehman 1992;Panagis et al 1995;Robbins et al 1989;Tindell, et al 2006;Waraczynski and Demco 2006)], it is likely that the VP may be involved in PD pathology. We have characterized several changes in the VP in the 6-OHDA treated rat model of PD (Heidenreich et al 2004;Muma et al 2001;Turner et al 2002) including an electrophysiological demonstration that NMDA-mediated excitatory amino acid transmission in the VP is altered (Turner et al 2002). In the current study, we extended this work to test the hypothesis that the circuit-related outcomes of intra-VP injections of NMDA are altered in the parkinsonian brain.…”

Section: Introductionmentioning

confidence: 98%

Fos expression following activation of the ventral pallidum in normal rats and in a model of Parkinson’s Disease: implications for limbic system and basal ganglia interactions

et al. 2008

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The circuit-related consequences of activating the ventral pallidum (VP) are not well known, and lacking in particular is how these effects are altered in various neuropathological states. To help to address these paucities, this study investigated the brain regions affected by VP activation by quantifying neurons that stain for Fos-like immunoreactivity (ir). Fos-ir was assessed after intra-pallidal injections of the excitatory amino acid agonist, NMDA, or the GABA(A) antagonist, bicuculline in normal rats and in those rendered Parkinsonian-like by lesioning dopaminergic neurons with the neurotoxin, 6-OHDA. We hypothesized that activation of the VP will alter the activity state of brain regions associated with both the basal ganglia and limbic system, and that this influence would be modified in the Parkinsonian state. Blocking tonically activated GABA(A) receptors with bicuculline (50 ng/0.5 microl) elevated Fos-ir in the VP to 423% above the contralateral, vehicle-injected side. Likewise, intra-VP NMDA (0.23 microg or 0.45 microg/0.5 microl), dose-dependently increased the number of pallidal neurons expressing Fos-ir by 224 and 526%, respectively. At higher NMDA doses, the density of Fos-ir neurons was not elevated above control levels. This inverted U-shaped profile was mirrored by a VP output structure, the medial subthalamic nucleus (mSTN). The mSTN showed a 289% increase in Fos-ir neurons with intra-VP injections of 0.45 microg NMDA, and this response was halved following intra-VP injections of 0.9 microg NMDA. Of the 12 other brain regions measured, three showed VP NMDA-induced enhancements in Fos-ir: the frontal cortex, entopeduncular nucleus and substantia nigra pars reticulata, all regions associated with the basal ganglia. In a second study, we evaluated the NMDA activation profile in a rat model of Parkinson's Disease (PD) which was created by a unilateral injection of 6-OHDA into the rostral substantia nigra pars compacta. Comparisons of responses to intra-VP NMDA between the hemispheres ipsilateral and contralateral to the lesion revealed that Fos-ir cells in the pedunculopontine nucleus was reduced by 62%, whereas Fos-ir for the basolateral amygdala and STN was reduced by 32 and 42%, respectively. These findings support the concept that the VP can influence both the basal ganglia and the limbic system, and that that the nature of this influence is modified in an animal model of PD. As the VP regulates motivation and cognition, adaptations in this system may contribute to the mood and mnemonic disorders that can accompany PD.

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6-Hydroxydopamine-Induced Lesions of Dopaminergic Neurons Alter the Function of Postsynaptic Cholinergic Neurons without Changing Cytoskeletal Proteins

Cited by 15 publications

References 40 publications

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

Voltammetric measurement of electrically evoked dopamine levels in the striatum of the anesthetized Syrian hamster

Fos expression following activation of the ventral pallidum in normal rats and in a model of Parkinson’s Disease: implications for limbic system and basal ganglia interactions

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