Journal articles: 'Dopamine neurons, parkinson's disease, neuroscience'

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Granado, Noelia, Sara Ares-Santos, and Rosario Moratalla. "Methamphetamine and Parkinson's Disease." Parkinson's Disease 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/308052.

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Parkinson's disease (PD) is a neurodegenerative disorder predominantly affecting the elderly. The aetiology of the disease is not known, but age and environmental factors play an important role. Although more than a dozen gene mutations associated with familial forms of Parkinson's disease have been described, fewer than 10% of all cases can be explained by genetic abnormalities. The molecular basis of Parkinson's disease is the loss of dopamine in the basal ganglia (caudate/putamen) due to the degeneration of dopaminergic neurons in the substantia nigra, which leads to the motor impairment characteristic of the disease. Methamphetamine is the second most widely used illicit drug in the world. In rodents, methamphetamine exposure damages dopaminergic neurons in the substantia nigra, resulting in a significant loss of dopamine in the striatum. Biochemical and neuroimaging studies in human methamphetamine users have shown decreased levels of dopamine and dopamine transporter as well as prominent microglial activation in the striatum and other areas of the brain, changes similar to those observed in PD patients. Consistent with these similarities, recent epidemiological studies have shown that methamphetamine users are almost twice as likely as non-users to develop PD, despite the fact that methamphetamine abuse and PD have distinct symptomatic profiles.

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Bishop, Matthew W., Subhojit Chakraborty, Gillian A. C. Matthews, Antonios Dougalis, Nicholas W. Wood, Richard Festenstein, and Mark A. Ungless. "Hyperexcitable Substantia Nigra Dopamine Neurons in PINK1- and HtrA2/Omi-Deficient Mice." Journal of Neurophysiology 104, no. 6 (December 2010): 3009–20. http://dx.doi.org/10.1152/jn.00466.2010.

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The electrophysiological properties of substantia nigra pars compacta (SNC) dopamine neurons can influence their susceptibility to degeneration in toxin-based models of Parkinson's disease (PD), suggesting that excitotoxic and/or hypoactive mechanisms may be engaged during the early stages of the disease. It is unclear, however, whether the electrophysiological properties of SNC dopamine neurons are affected by genetic susceptibility to PD. Here we show that deletion of PD-associated genes, PINK1 or HtrA2/Omi, leads to a functional reduction in the activity of small-conductance Ca2+-activated potassium channels. This reduction causes SNC dopamine neurons to fire action potentials in an irregular pattern and enhances burst firing in brain slices and in vivo. In contrast, PINK1 deletion does not affect firing regularity in ventral tegmental area dopamine neurons or substantia nigra pars reticulata GABAergic neurons. These findings suggest that changes in SNC dopamine neuron excitability may play a role in their selective vulnerability in PD.

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Kesslak, J. Patrick. "Transplantation of embryonic dopamine neurons for severe Parkinson's disease." Neuroreport 12, no. 7 (May 2001): A47. http://dx.doi.org/10.1097/00001756-200105250-00002.

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Taylor, Tonya N., W. Michael Caudle, and Gary W. Miller. "VMAT2-Deficient Mice Display Nigral and Extranigral Pathology and Motor and Nonmotor Symptoms of Parkinson's Disease." Parkinson's Disease 2011 (2011): 1–9. http://dx.doi.org/10.4061/2011/124165.

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Dopamine is transported into synaptic vesicles by the vesicular monoamine transporter (VMAT2; SLC18A2). Disruption of dopamine storage has been hypothesized to damage the dopamine neurons that are lost in Parkinson's disease. By disrupting vesicular storage of dopamine and other monoamines, we have created a progressive mouse model of PD that exhibits catecholamine neuron loss in the substantia nigra pars compacta and locus coeruleus and motor and nonmotor symptoms. With a 95% reduction in VMAT2 expression, VMAT2-deficient animals have decreased motor function, progressive deficits in olfactory discrimination, shorter latency to behavioral signs of sleep, delayed gastric emptying, anxiety-like behaviors at younger ages, and a progressive depressive-like phenotype. Pathologically, the VMAT2-deficient mice display progressive neurodegeneration in the substantia nigra (SNpc), locus coeruleus (LC), and dorsal raphe (DR) coupled withα-synuclein accumulation. Taken together, these studies demonstrate that reduced vesicular storage of monoamines and the resulting disruption of the cytosolic environment may play a role in the pathogenesis of parkinsonian symptoms and neurodegeneration. The multisystem nature of the VMAT2-deficient mice may be useful in developing therapeutic strategies that go beyond the dopamine system.

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Denyer, Rachel, and Michael R. Douglas. "Gene Therapy for Parkinson's Disease." Parkinson's Disease 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/757305.

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Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field.

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Murase, S. "A Specific Survival Response in Dopamine Neurons at Most Risk in Parkinson's Disease." Journal of Neuroscience 26, no. 38 (September 20, 2006): 9750–60. http://dx.doi.org/10.1523/jneurosci.2745-06.2006.

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Bogetofte, Helle, Arezo Alamyar, Morten Blaabjerg, and Morten Meyer. "Levodopa Therapy for Parkinson's Disease: History, Current Status and Perspectives." CNS & Neurological Disorders - Drug Targets 19, no. 8 (December 24, 2020): 572–83. http://dx.doi.org/10.2174/1871527319666200722153156.

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Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by a preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta. This results in a profound decrease of striatal dopamine (DA) levels, which in turn leads to the cardinal motor symptoms of PD; muscle rigidity, hypo- and bradykinesia and resting tremor. Even 50 years after its initial use, the DA precursor levodopa (L-dopa), is still the most effective medical therapy for the symptomatic treatment of PD. Long-term L-dopa treatment is however, unfortunately associated with undesirable side effects such as motor fluctuations and dyskinesias. Furthermore, despite the disease alleviating effects of L-dopa, it is still discussed whether L-dopa has a neurotoxic or neuroprotective effect on dopaminergic neurons. Here we review the history of L-dopa, including its discovery, development and current use in the treatment of PD. We furthermore review current evidence of the L-dopa-induced side effects and perspectives of L-dopa treatment in PD compared to other established treatments such as DA-agonists and the inhibitors of catechol-o-methyltransferase and monoamine oxidase B.

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Barker, Roger A., Anders Björklund, Steven J. Frucht, and Clive N. Svendsen. "Stem Cell-Derived Dopamine Neurons: Will They Replace DBS as the Leading Neurosurgical Treatment for Parkinson’s Disease?" Journal of Parkinson's Disease 11, no. 3 (July 30, 2021): 909–17. http://dx.doi.org/10.3233/jpd-219008.

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The use of stem cell-derived dopamine neurons or deep brain stimulation (DBS) represents two alternative approaches to treat Parkinson’s Disease. DBS is a widely used FDA-approved treatment and stem cell-derived dopamine neuron replacement has now evolved to the first in-human clinical trials. In this debate, we discuss which of these approaches will evolve to be the treatment of choice for Parkinsonian patients in the future.

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FEDOROW, H., F. TRIBL, G. HALLIDAY, M. GERLACH, P. RIEDERER, and K. DOUBLE. "Neuromelanin in human dopamine neurons: Comparison with peripheral melanins and relevance to Parkinson's disease." Progress in Neurobiology 75, no. 2 (February 2005): 109–24. http://dx.doi.org/10.1016/j.pneurobio.2005.02.001.

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Parker, Krystal L., Kuan-Hua Chen, Johnathan R. Kingyon, James F. Cavanagh, and Nandakumar S. Narayanan. "Medial frontal ∼4-Hz activity in humans and rodents is attenuated in PD patients and in rodents with cortical dopamine depletion." Journal of Neurophysiology 114, no. 2 (August 2015): 1310–20. http://dx.doi.org/10.1152/jn.00412.2015.

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The temporal control of action is a highly conserved and critical mammalian behavior. Here, we investigate the neuronal basis of this process using an interval timing task. In rats and humans, instructional timing cues triggered spectral power across delta and theta bands (2–6 Hz) from the medial frontal cortex (MFC). Humans and rodents with dysfunctional dopamine have impaired interval timing, and we found that both humans with Parkinson's disease (PD) and rodents with local MFC dopamine depletion had attenuated delta and theta activity. In rodents, spectral activity in this range could functionally couple single MFC neurons involved in temporal processing. Without MFC dopamine, these neurons had less functional coupling with delta/theta activity and less temporal processing. Finally, in humans this 2- to 6-Hz activity was correlated with executive function in matched controls but not in PD patients. Collectively, these findings suggest that cue-evoked low-frequency rhythms could be a clinically important biomarker of PD that is translatable to rodent models, facilitating mechanistic inquiry and the development of neurophysiological biomarkers for human disease.

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Levy, R., J. O. Dostrovsky, A. E. Lang, E. Sime, W. D. Hutchison, and A. M. Lozano. "Effects of Apomorphine on Subthalamic Nucleus and Globus Pallidus Internus Neurons in Patients With Parkinson's Disease." Journal of Neurophysiology 86, no. 1 (July 1, 2001): 249–60. http://dx.doi.org/10.1152/jn.2001.86.1.249.

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This study examines the effect of apomorphine (APO), a nonselective D1- and D2-dopamine receptor agonist, on the firing activity of neurons in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) in patients with Parkinson's disease (PD). Single-unit microelectrode recordings were conducted in 13 patients undergoing implantation of deep brain stimulation electrodes in STN and 6 patients undergoing a pallidotomy. Doses of APO (2.5–8 mg) were sufficient to produce anon state, but not intended to induce dyskinetic movements. Following baseline recordings from a single neuron, APO was administered and the activity of the neuron followed for an average of 15 min. The spontaneous discharge of neurons encountered before ( n = 309), during ( n = 146, 10–60 min), and after the effect of APO had waned ( n = 127, >60 min) was also sampled, and the response to passive joint movements was noted. In both nuclei, APO increased the overall proportion of spikes in burst discharges (as detected with Poisson “surprise” analysis), and a greater proportion of cells with an irregular discharge pattern was observed. APO significantly decreased the overall firing rates of GPi neurons ( P < 0.01), but there was no change in the overall firing rate of neurons in the STN ( P = 0.68). However, the mean firing rates of STN neurons during APO-induced movements (choreic or dystonic dyskinesias) that occurred in four patients were significantly lower thanoff-period baseline values ( P < 0.05). Concurrent with a reduction in limb tremor, the percentage of cells with tremor-related activity (TCs) was found to be significantly reduced from 19 to 6% in the STN and 14 to 0% in the GPi following APO administration. APO also decreased the firing rate of STN TCs ( P < 0.05). During the off state, more than 15% of neurons tested (STN = 93, GPi = 63) responded to passive movement of two or more joints. After APO, this proportion decreased significantly to 7% of STN cells and 4% of GPi cells (STN = 28, GPi = 26). These findings suggest that the APO-induced amelioration of parkinsonian symptoms is not solely due to a decrease in overall activity in the GPi or STN as predicted by the current model of basal ganglia function in PD.

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Prieto, G. Aleph, Azucena Perez-Burgos, Marcela Palomero-Rivero, Elvira Galarraga, Rene Drucker-Colin, and Jose Bargas. "Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3 receptors acting on CaV2.1 channels via PIP2 depletion." Journal of Neurophysiology 105, no. 5 (May 2011): 2260–74. http://dx.doi.org/10.1152/jn.00516.2010.

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The loss of dopaminergic neurons in the substantia nigra compacta followed by striatal dopamine depletion is a hallmark of Parkinson's disease. After dopamine depletion, dopaminergic D2 receptor (D2R)-class supersensitivity develops in striatal neurons. The supersensitivity results in an enhanced modulation of Ca2+ currents by D2R-class receptors. However, the relative contribution of D2R, D3R, and D4R types to the supersensitivity, as well as the mechanisms involved, have not been elucidated. In this study, whole cell voltage-clamp recordings were performed to study Ca2+ current modulation in acutely dissociated striatal neurons obtained from rodents with unilateral 6-hydroxydopamine lesions in the substantia nigra compacta. Selective antagonists for D2R, D3R, and D4R types were used to identify whether the modulation by one of these receptors experiences a selective change after dopaminergic denervation. It was found that D3R-mediated modulation was particularly enhanced. Increased modulation targeted CaV2.1 (P/Q) Ca2+ channels via the depletion of phosphatidylinositol 4,5-bisphosphate, an intracellular signaling cascade hard to detect in control neurons and hypothesized as being amplified by dopamine depletion. An imbalance in the striatal expression of D3R and its splice variant, D3nf, accompanied enhanced D3R activity. Because CaV2.1 Ca2+ channels mediate synaptic GABA release from the terminals of striatal neurons, reinforcement of their inhibition by D3R may explain in part the profound decrease in synaptic strength in the connections among striatal projection neurons observed in the dopamine-depleted striatum.

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Migliore, Michele, Claudio Cannia, and Carmen C. Canavier. "A Modeling Study Suggesting a Possible Pharmacological Target to Mitigate the Effects of Ethanol on Reward-Related Dopaminergic Signaling." Journal of Neurophysiology 99, no. 5 (May 2008): 2703–7. http://dx.doi.org/10.1152/jn.00024.2008.

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Midbrain dopaminergic neurons are involved in several critical brain functions controlling goal-directed behaviors, reinforcing/reward processes, and motivation. Their dysfunctions alter dopamine release and contribute to a vast range of neural disorders, from Parkinson's disease to schizophrenia and addictive behaviors. These neurons have thus been a natural target of pharmacological treatments trying to ameliorate the consequences of several neuropathologies. From this point of view, a clear experimental link has been recently established between the increase in the pacemaker frequency of dopaminergic neurons in vitro after acute ethanol application and a particular ionic current ( Ih). The functional consequences in vivo, however, are not clear and they are very difficult to explore experimentally. Here we use a realistic computational model of dopaminergic neurons in vivo to suggest that ethanol, through its effects on Ih, modifies the temporal structure of the spiking activity. The model predicts that the dopamine level may increase much more during bursting than during pacemaking activity, especially in those brain regions with a slow dopamine clearance rate. The results suggest that a selective pharmacological remedy could thus be devised against the rewarding effects of ethanol that are postulated to mediate alcohol abuse and addiction, targeting the specific HCN genes expressed in dopaminergic neurons.

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Cáceres-Chávez, Verónica Alejandra, Ricardo Hernández-Martínez, Jesús Pérez-Ortega, Marco Arieli Herrera-Valdez, Jose J. Aceves, Elvira Galarraga, and José Bargas. "Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism." Journal of Neurophysiology 120, no. 6 (December 1, 2018): 2922–38. http://dx.doi.org/10.1152/jn.00579.2018.

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Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr), shifting their mostly tonic firing toward irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson’s disease (PD) patients and animal models of Parkinsonism (PS). Drug-induced Parkinsonism (DIP) represents 20–40% of clinical cases of PS, becoming a problem for differential diagnosis, and is still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug-induced pathological firing by using drugs that most likely produce it, DA-receptor antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis is that SNr firing would be similar under both conditions, a prerequisite to the proposal of a similar preparation to test other DIP-producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA depletion and acute DA-receptor blockade. Moreover, blockade of either nonselective cationic channels or Cav3 T-type calcium channels hyperpolarized the membrane and abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP-producing drug, reproduced DA-receptor antagonist firing modifications. Since acute DA-receptor blockade induces SNr neuron firing similar to that found in the 6-hydroxydopamine model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP-producing drugs. NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars reticulata (SNr) neuron bursting and irregular firing, hallmarks of Parkinsonism. Several drugs, including antipsychotics, antidepressants, and calcium channel antagonists, among others, produce drug-induced Parkinsonism. Here we show the first comparison between SNr neuron firing after DA depletion vs. firing found after acute blockade of DA receptors. It was found that firing in both conditions is similar, implying that pathological SNr neuron firing is also a physiological correlate of drug-induced Parkinsonism.

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Centonze, Diego, Paolo Gubellini, Barbara Picconi, Paolo Calabresi, Patrizia Giacomini, and Giorgio Bernardi. "Unilateral Dopamine Denervation Blocks Corticostriatal LTP." Journal of Neurophysiology 82, no. 6 (December 1, 1999): 3575–79. http://dx.doi.org/10.1152/jn.1999.82.6.3575.

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The nigrostriatal dopaminergic projection is crucial for the striatal processing of motor information received from the cortex. Lesion of this pathway in rats causes locomotor alterations that resemble some of the symptoms of Parkinson's disease and significantly alters the excitatory transmission in the striatum. We performed in vitro electrophysiological recordings to study the effects of unilateral striatal dopamine (DA) denervation obtained by omolateral nigral injection of 6-hydroxydopamine (6-OHDA) in the formation of corticostriatal long-term potentiation (LTP). Unilateral nigral lesion did not affect the intrinsic membrane properties of striatal spiny neurons. In fact, these cells showed similar pattern of firing discharge and current-voltage relationship in denervated striata and in naive controlateral striata. Moreover, excitatory postsynaptic potentials (EPSPs) evoked by stimulating corticostriatal fibers and recorded from DA-denervated slices showed a pharmacology similar to that observed in slices obtained from controlateral intact striata. Conversely, in magnesium-free medium, high-frequency stimulation (HFS) of corticostriatal fibers produced LTP in slices from nondenervated striata but not in slices from 6-OHDA–denervated rats. After denervation, in fact, no significant changes in the amplitude of extra- and intracellular synaptic potentials were recorded after the conditioning HFS. The absence of corticostriatal LTP in DA-denervated striata might represent the cellular substrate for some of the movement disorders observed in Parkinson's disease.

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Kamath, Tushar, Abdulraouf Abdulraouf, S. J. Burris, Jonah Langlieb, Vahid Gazestani, Naeem M. Nadaf, Karol Balderrama, Charles Vanderburg, and Evan Z. Macosko. "Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease." Nature Neuroscience 25, no. 5 (May 2022): 588–95. http://dx.doi.org/10.1038/s41593-022-01061-1.

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AbstractThe loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson’s disease (PD). Nevertheless, the molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed a protocol to enrich and transcriptionally profile DA neurons from patients with PD and matched controls, sampling a total of 387,483 nuclei, including 22,048 DA neuron profiles. We identified ten populations and spatially localized each within the SNpc using Slide-seq. A single subtype, marked by the expression of the gene AGTR1 and spatially confined to the ventral tier of SNpc, was highly susceptible to loss in PD and showed the strongest upregulation of targets of TP53 and NR2F2, nominating molecular processes associated with degeneration. This same vulnerable population was specifically enriched for the heritable risk associated with PD, highlighting the importance of cell-intrinsic processes in determining the differential vulnerability of DA neurons to PD-associated degeneration.

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Yamada, T., P. L. McGeer, K. G. Baimbridge, and E. G. McGeer. "Relative sparing in Parkinson's disease of substantia nigra dopamine neurons containing calbindin-D28K." Brain Research 526, no. 2 (September 1990): 303–7. http://dx.doi.org/10.1016/0006-8993(90)91236-a.

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Schlaudraff, Falk, Jan Gründemann, Michael Fauler, Elena Dragicevic, John Hardy, and Birgit Liss. "Orchestrated increase of dopamine and PARK mRNAs but not miR-133b in dopamine neurons in Parkinson's disease." Neurobiology of Aging 35, no. 10 (October 2014): 2302–15. http://dx.doi.org/10.1016/j.neurobiolaging.2014.03.016.

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Leranth, Csaba, Robert H. Roth, John D. Elsworth, Frederick Naftolin, Tamas L. Horvath, and D. Eugene Redmond. "Estrogen Is Essential for Maintaining Nigrostriatal Dopamine Neurons in Primates: Implications for Parkinson's Disease and Memory." Journal of Neuroscience 20, no. 23 (December 1, 2000): 8604–9. http://dx.doi.org/10.1523/jneurosci.20-23-08604.2000.

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Mena, Maria, Maria Casarejos, and Santiago Canals. "Nitric Oxide and Dopamine Neurons. Implications for Parkinsons Disease." Current Medicinal Chemistry-Central Nervous System Agents 5, no. 3 (September 1, 2005): 193–205. http://dx.doi.org/10.2174/1568015054863846.

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Masato, Anna, Luigi Bubacco, and Elisa Greggio. "Too much for your own good: Excessive dopamine damages neurons and contributes to Parkinson's disease." Journal of Neurochemistry 158, no. 4 (June 28, 2021): 833–36. http://dx.doi.org/10.1111/jnc.15442.

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Li, J. Y., and P. Brundin. "Grafting dopamine neurons in Parkinson's disease: do stem cells have a role in the future?" Journal of Neurochemistry 85 (May 8, 2003): 13. http://dx.doi.org/10.1046/j.1471-4159.85.s2.13_4.x.

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Hoffer, Barry J., Klaus L. Leenders, David Young, Greg Gerhardt, Gary O. Zerbe, Marc Bygdeman, Åke Seiger, Lars Olson, Ingrid Strömberg, and Robert Freedman. "Eighteen-month course of two patients with grafts of fetal dopamine neurons for severe Parkinson's disease." Experimental Neurology 118, no. 3 (December 1992): 243–52. http://dx.doi.org/10.1016/0014-4886(92)90181-o.

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Wang, Yuhan, Safa Bouabid, Martin Darvas, and Fu-Ming Zhou. "The antiparkinson drug ropinirole inhibits movement in a Parkinson's disease mouse model with residual dopamine neurons." Experimental Neurology 333 (November 2020): 113427. http://dx.doi.org/10.1016/j.expneurol.2020.113427.

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Yu, S. J., E. S. Lo, E. J. Cochran, D. H. Lin, C. J. Faselis, H. L. Klawans, and P. M. Carvey. "Cerebrospinal Fluid from Patients with Parkinson's Disease Alters the Survival of Dopamine Neurons in Mesencephalic Culture." Experimental Neurology 126, no. 1 (March 1994): 15–24. http://dx.doi.org/10.1006/exnr.1994.1038.

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Amos, Andrew. "A Computational Model of Information Processing in the Frontal Cortex and Basal Ganglia." Journal of Cognitive Neuroscience 12, no. 3 (May 2000): 505–19. http://dx.doi.org/10.1162/089892900562174.

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Performance on the Wisconsin Card Sort Test (WCST) of patients with schizophrenia, Parkinson's disease (PD), and Huntington's disease (HD) was simulated by a neural network model constructed on principles derived from neuroanatomic loops from the frontal cortex through the basal ganglia and thalamus. The model provided a computational rationale for the empirical pattern of perseverative errors associated with frontal cortex dysfunction and random errors associated with striatal dysfunction. The model displayed perseverative errors in performance when the gain parameter of the activation function in units representing frontal cortex neurons was reduced as an analog of reduced dopamine release. Random errors occurred when the gain parameter of the activation function in units representing striatal neurons was reduced, or when the activation level was itself reduced as an analog of a striatal lesion. The model demonstrated that the perseveration of schizophrenic, Huntington's, and demented Parkinsonian patients may be principally due to ineffective inhibition of previously learned contextual rules in the frontal cortex, while the random errors of Parkinson's and Huntington's patients are more likely to be due to unsystematic errors of matching in the striatum. The model also made specific, empirically falsifiable predictions that can be used to explore the utility of these putative mechanisms of information processing in the frontal cortex and basal ganglia.

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Lohrenz, Terry, Kenneth T. Kishida, and P. Read Montague. "BOLD and its connection to dopamine release in human striatum: a cross-cohort comparison." Philosophical Transactions of the Royal Society B: Biological Sciences 371, no. 1705 (October 5, 2016): 20150352. http://dx.doi.org/10.1098/rstb.2015.0352.

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Activity in midbrain dopamine neurons modulates the release of dopamine in terminal structures including the striatum, and controls reward-dependent valuation and choice. This fluctuating release of dopamine is thought to encode reward prediction error (RPE) signals and other value-related information crucial to decision-making, and such models have been used to track prediction error signals in the striatum as encoded by BOLD signals. However, until recently there have been no comparisons of BOLD responses and dopamine responses except for one clear correlation of these two signals in rodents. No such comparisons have been made in humans. Here, we report on the connection between the RPE-related BOLD signal recorded in one group of subjects carrying out an investment task, and the corresponding dopamine signal recorded directly using fast-scan cyclic voltammetry in a separate group of Parkinson's disease patients undergoing DBS surgery while performing the same task. The data display some correspondence between the signal types; however, there is not a one-to-one relationship. Further work is necessary to quantify the relationship between dopamine release, the BOLD signal and the computational models that have guided our understanding of both at the level of the striatum. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

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Cruz, Ana V., Nicolas Mallet, Peter J. Magill, Peter Brown, and Bruno B. Averbeck. "Effects of Dopamine Depletion on Network Entropy in the External Globus Pallidus." Journal of Neurophysiology 102, no. 2 (August 2009): 1092–102. http://dx.doi.org/10.1152/jn.00344.2009.

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Dopamine depletion in cortical-basal ganglia circuits in Parkinson's disease (PD) grossly disturbs movement and cognition. Classic models relate Parkinsonian dysfunction to changes in firing rates of basal ganglia neurons. However, disturbances in other dynamics of neural activity are also common. Taking both inappropriate firing rates and other dynamics into account and determining how changes in the properties of these neural circuits that occur during PD impact on information coding are thus imperative. Here, we examined in vivo network dynamics in the external globus pallidus (GPe) of rats before and after chronic dopamine depletion. Dopamine depletion led to decreases in the firing rates of GPe neurons and increases in synchronized network oscillations in the β frequency (13–30 Hz) band. Using logistic regression models, we determined the combined and separate impacts of these factors on network entropy, a measure of the upper bound of information coding capacity. Importantly, changes in these features in dopamine-depleted rats led to a significant decrease in GPe network entropy. Changes in firing rates had the largest impact on entropy, with changes in synchrony also decreasing entropy at the network level. Changes in autocorrelations tended to offset these effects because autocorrelations decreased entropy more in the control animals. Thus it is possible that reduced information coding capacity within basal ganglia networks may contribute to the behavioral deficits accompanying PD.

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Kerr, J. N. D., and J. R. Wickens. "Dopamine D-1/D-5 Receptor Activation Is Required for Long-Term Potentiation in the Rat Neostriatum In Vitro." Journal of Neurophysiology 85, no. 1 (January 1, 2001): 117–24. http://dx.doi.org/10.1152/jn.2001.85.1.117.

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Dopamine and glutamate are key neurotransmitters involved in learning and memory mechanisms of the brain. These two neurotransmitter systems converge on nerve cells in the neostriatum. Dopamine modulation of activity-dependent plasticity at glutamatergic corticostriatal synapses has been proposed as a cellular mechanism for learning in the neostriatum. The present research investigated the role of specific subtypes of dopamine receptors in long-term potentiation (LTP) in the corticostriatal pathway, using intracellular recording from striatal neurons in a corticostriatal slice preparation. In agreement with previous reports, LTP could be induced reliably under Mg2+-free conditions. This Mg2+-free LTP was blocked by dopamine depletion and by the dopamine D-1/D-5 receptor antagonist SCH 23390 but was not blocked by the dopamine D-2 receptor antagonist remoxipride or the GABAA antagonist picrotoxin. In dopamine-depleted slices, the ability to induce LTP could be restored by bath application of the dopamine D-1/D-5 receptor agonist, SKF 38393. These results show that activation of dopamine D-1/D-5 receptors by either endogenous dopamine or exogenous dopamine agonists is a requirement for the induction of LTP in the corticostriatal pathway. These findings have significance for current understanding of learning and memory mechanisms of the neostriatum and for theoretical understanding of the mechanism of action of drugs used in the treatment of psychotic illnesses and Parkinson's disease.

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Renko, Juho-Matti, Arun Kumar Mahato, Tanel Visnapuu, Konsta Valkonen, Mati Karelson, Merja H. Voutilainen, Mart Saarma, Raimo K. Tuominen, and Yulia A. Sidorova. "Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats." Journal of Parkinson's Disease 11, no. 3 (August 2, 2021): 1023–46. http://dx.doi.org/10.3233/jpd-202400.

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Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP+-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and seemed to protect dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying, therapy for PD.

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Anvret, Anna, Caroline Ran, Marie Westerlund, Ann-Christin Thelander, Olof Sydow, Charlotta Lind, Anna Håkansson, Hans Nissbrandt, Dagmar Galter, and Andrea Carmine Belin. "Possible Involvement of a Mitochondrial Translation Initiation Factor 3 Variant Causing Decreased mRNA Levels in Parkinson's Disease." Parkinson's Disease 2010 (2010): 1–5. http://dx.doi.org/10.4061/2010/491751.

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Genes important for mitochondrial function have been implicated in Parkinson's disease (PD). Mitochondrial translation initiation factor 3 (MTIF3) is a nuclear encoded protein required for the initiation of complex formation on mitochondrial ribosomes. Dysfunction of MTIF3 may impair mitochondrial function and dopamine neurons appear to be particularly vulnerable to oxidative stress, which may relate to their degeneration in PD. An association was recently reported between the synonymous rs7669(C>T) in MTIF3 and PD in a German case-control material. We investigated rs7669 in a Swedish Parkinson case-control material. The study revealed no significant association of the individual genotypes or alleles with PD. When comparing the combined TT/CT-genotypes versus the CC-genotype, we observed a significant association (P=.0473) with PD. We also demonstrated that the TT-genotype causes a significant decrease in MTIF3 mRNA expression compared to the CC-genotype (P=.0163). Our findings support the hypothesis that MTIF3 may be involved in the etiology of PD.

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Burke, Robert E. "Apoptosis in Degenerative Diseases of the Basal Ganglia." Neuroscientist 4, no. 4 (July 1998): 301–11. http://dx.doi.org/10.1177/107385849800400418.

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Degenerative disorders of the basal ganglia are characterized by disturbances of motor control. Prototypic examples are Parkinson's disease, which is caused by degeneration of dopamine neurons of the substantia nigra, and Huntington's disease, which is caused by degeneration of neurons of the striatum. In recent years, it has been postulated that some of these disorders may be caused by programmed cell death or apoptosis, a genetically regulated form of cell death. There is clear evidence that apoptosis occurs in neurons of the basal ganglia during normal development, that it can be regulated, and that it can be induced in some animal models of these disorders. Although there is some suggestive direct evidence that apoptosis may occur in the human brain in these disorders, the evidence to date is partial and not yet compelling. Nevertheless, programmed cell death is an important new hypothesis for the pathogenesis of these disorders and warrants vigorous further investigation, particularly with molecular markers in addition to classic morphological markers. The concept of programmed cell death is relevant not only to the pathogenesis of these diseases but also to therapeutic issues, such as transplantation approaches.

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Brundin, P., R. E. Strecker, H. Widner, D. J. Clarke, O. G. Nilsson, B. Åstedt, O. Lindvall, and A. Björklund. "Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release." Experimental Brain Research 70, no. 1 (March 1988): 192–208. http://dx.doi.org/10.1007/bf00271860.

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Kanaan, Nicholas M., Timothy J. Collier, Deanna M. Marchionini, Susan O. McGuire, Matthew F. Fleming, and Caryl E. Sortwell. "Exogenous erythropoietin provides neuroprotection of grafted dopamine neurons in a rodent model of Parkinson's disease." Brain Research 1068, no. 1 (January 2006): 221–29. http://dx.doi.org/10.1016/j.brainres.2005.10.078.

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Schneider, Andrew, Adam T. Sari, Hasan Alhaddad, and Youssef Sari. "Overview of Therapeutic Drugs and Methods for the Treatment of Parkinson’s Disease." CNS & Neurological Disorders - Drug Targets 19, no. 3 (August 17, 2020): 195–206. http://dx.doi.org/10.2174/1871527319666200525011110.

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Parkinson’s Disease (PD) is a neurodegenerative disease involving degeneration of dopaminergic neurons of the nigrostriatal pathways. Over the past decades, most of the medications for the treatment of PD patients have been used to modulate dopamine concentrations in the basal ganglia. This includes levodopa and its inhibitory metabolizing enzymes. In addition to modulating dopamine concentrations in the brain, there are D2-like dopamine receptor agonists that mimic the action of dopamine to compensate for the deficit in dopamine found in PD patients. Muscarinic antagonists’ drugs are used rarely due to some side effects. Monoamine oxidase inhibitors are among the first in line, and are considered popular drugs that reduce the metabolism of dopamine in PD patients. Furthermore, we discussed in this review the existence of certain glutamate receptor antagonists for the treatment of PD. Alternatively, we further discussed the potential therapeutic role of adenosine (2A) receptor antagonists, such as tozadenant and istradefylline in the treatment of PD. We also discussed the important role of serotonin1A receptor agonist, adrenergic autoreceptors (α2) antagonists and calcium channel blockers in the treatment of PD. Finally, neurotrophic factors, such as glial cell line-derived neurotrophic growth factor and brain-derived neurotrophic factor are considered the primary factors for neuroprotection in PD.

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Stanford, I. M. "Independent Neuronal Oscillators of the Rat Globus Pallidus." Journal of Neurophysiology 89, no. 3 (March 1, 2003): 1713–17. http://dx.doi.org/10.1152/jn.00864.2002.

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In vivo, neurons of the globus pallidus (GP) and subthalamic nucleus (STN) resonate independently around 70 Hz. However, on the loss of dopamine as in Parkinson's disease, there is a switch to a lower frequency of firing with increased bursting and synchronization of activity. In vitro, type A neurons of the GP, identified by the presence of Ih and rebound depolarizations, fire at frequencies (≤80 Hz) in response to glutamate pressure ejection, designed to mimic STN input. The profile of this frequency response was unaltered by bath application of the GABAA antagonist bicuculline (10 μM), indicating the lack of involvement of a local GABA neuronal network, while cross-correlations of neuronal pairs revealed uncorrelated activity or phase-locked activity with a variable phase delay, consistent with each GP neuron acting as an independent oscillator. This autonomy of firing appears to arise due to the presence of intrinsic voltage- and sodium-dependent subthreshold membrane oscillations. GABAA inhibitory postsynaptic potentials are able to disrupt this tonic activity while promoting a rebound depolarization and action potential firing. This rebound is able to reset the phase of the intrinsic oscillation and provides a mechanism for promoting coherent firing activity in ensembles of GP neurons that may ultimately lead to abnormal and pathological disorders of movement.

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Farooqui, Tahira, and Akhlaq A. Farooqui. "Lipid-Mediated Oxidative Stress and Inflammation in the Pathogenesis of Parkinson's Disease." Parkinson's Disease 2011 (2011): 1–9. http://dx.doi.org/10.4061/2011/247467.

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Parkinson's disease (PD) is a neurodegenerative movement disorder of unknown etiology. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, depletion of dopamine in the striatum, abnormal mitochondrial and proteasomal functions, and accumulation ofα-synuclein that may be closely associated with pathological and clinical abnormalities. Increasing evidence indicates that both oxidative stress and inflammation may play a fundamental role in the pathogenesis of PD. Oxidative stress is characterized by increase in reactive oxygen species (ROS) and depletion of glutathione. Lipid mediators for oxidative stress include 4-hydroxynonenal, isoprostanes, isofurans, isoketals, neuroprostanes, and neurofurans. Neuroinflammation is characterized by activated microglial cells that generate proinflammatory cytokines, such as TNF-αand IL-1β. Proinflammatory lipid mediators include prostaglandins and platelet activating factor, together with cytokines may play a prominent role in mediating the progressive neurodegeneration in PD.

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Lelos, M. J., R. J. Morgan, C. M. Kelly, E. M. Torres, A. E. Rosser, and S. B. Dunnett. "Amelioration of non-motor dysfunctions after transplantation of human dopamine neurons in a model of Parkinson's disease." Experimental Neurology 278 (April 2016): 54–61. http://dx.doi.org/10.1016/j.expneurol.2016.02.003.

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Lobb, C. J., A. K. Zaheer, Y. Smith, and D. Jaeger. "In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein-overexpressing mice highlights differences from toxin-based models of parkinsonism." Journal of Neurophysiology 110, no. 12 (December 15, 2013): 2792–805. http://dx.doi.org/10.1152/jn.00441.2013.

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Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha-synuclein is overexpressed (ASO) display progressive motor deficits and many nonmotor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e., increased beta oscillations, bursting, and synchronization) described in toxin-based, nigrostriatal dopamine-depletion models are also present in ASO mice. To address these issues, we first confirmed that 5- to 6-mo-old ASO mice have robust motor dysfunction, despite the absence of significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single units and local field potentials (LFPs) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age-matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6-hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared with wild-type control mice. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine-depletion models of parkinsonism.

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Moustafa, Ahmed A., and Mark A. Gluck. "A Neurocomputational Model of Dopamine and Prefrontal–Striatal Interactions during Multicue Category Learning by Parkinson Patients." Journal of Cognitive Neuroscience 23, no. 1 (January 2011): 151–67. http://dx.doi.org/10.1162/jocn.2010.21420.

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Most existing models of dopamine and learning in Parkinson disease (PD) focus on simulating the role of basal ganglia dopamine in reinforcement learning. Much data argue, however, for a critical role for prefrontal cortex (PFC) dopamine in stimulus selection in attentional learning. Here, we present a new computational model that simulates performance in multicue category learning, such as the “weather prediction” task. The model addresses how PD and dopamine medications affect stimulus selection processes, which mediate reinforcement learning. In this model, PFC dopamine is key for attentional learning, whereas basal ganglia dopamine, consistent with other models, is key for reinforcement and motor learning. The model assumes that competitive dynamics among PFC neurons is the neural mechanism underlying stimulus selection with limited attentional resources, whereas competitive dynamics among striatal neurons is the neural mechanism underlying action selection. According to our model, PD is associated with decreased phasic and tonic dopamine levels in both PFC and basal ganglia. We assume that dopamine medications increase dopamine levels in both the basal ganglia and PFC, which, in turn, increase tonic dopamine levels but decrease the magnitude of phasic dopamine signaling in these brain structures. Increase of tonic dopamine levels in the simulated PFC enhances attentional shifting performance. The model provides a mechanistic account for several phenomena, including (a) medicated PD patients are more impaired at multicue probabilistic category learning than unmedicated patients and (b) medicated PD patients opt out of reversal when there are alternative and redundant cue dimensions.

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Weinberger, M., W. D. Hutchison, A. M. Lozano, M. Hodaie, and J. O. Dostrovsky. "Increased Gamma Oscillatory Activity in the Subthalamic Nucleus During Tremor in Parkinson's Disease Patients." Journal of Neurophysiology 101, no. 2 (February 2009): 789–802. http://dx.doi.org/10.1152/jn.90837.2008.

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Rest tremor is one of the main symptoms in Parkinson's disease (PD), although in contrast to rigidity and akinesia, the severity of the tremor does not correlate well with the degree of dopamine deficiency or the progression of the disease. Studies suggest that akinesia in PD patients is related to abnormal increased beta (15–30 Hz) and decreased gamma (35–80 Hz) synchronous oscillatory activity in the basal ganglia. Here we investigated the dynamics of oscillatory activity in the subthalamic nucleus (STN) during tremor. We used two adjacent microelectrodes to simultaneously record neuronal firing and local field potential (LFP) activity in nine PD patients who exhibited resting tremor during functional neurosurgery. We found that neurons exhibiting oscillatory activity at tremor frequency are located in the dorsal region of STN, where neurons with beta oscillatory activity are observed, and that their activity is coherent with LFP oscillations in the beta frequency range. Interestingly, in 85% of the 58 sites examined, the LFP exhibited increased oscillatory activity in the low gamma frequency range (35–55 Hz) during periods with stronger tremor. Furthermore, in 17 of 26 cases where two LFPs were recorded simultaneously, their coherence in the gamma range increased with increased tremor. When averaged across subjects, the ratio of the beta to gamma coherence was significantly lower in periods with stronger tremor compared with periods of no or weak tremor. These results suggest that resting tremor in PD is associated with an altered balance between beta and gamma oscillations in the motor circuits of STN.

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Filipović, Marko, Maya Ketzef, Ramon Reig, Ad Aertsen, Gilad Silberberg, and Arvind Kumar. "Direct pathway neurons in mouse dorsolateral striatum in vivo receive stronger synaptic input than indirect pathway neurons." Journal of Neurophysiology 122, no. 6 (December 1, 2019): 2294–303. http://dx.doi.org/10.1152/jn.00481.2019.

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Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1- or D2-type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modeling of the striatal network has predicted that under healthy conditions dMSNs should receive more total input than iMSNs. To test this prediction, we analyzed in vivo whole cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (6OHDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials, we found that dMSNs depolarized toward the spike threshold significantly faster than iMSNs did. Together, these findings (in particular the STA analysis) corroborate the theoretical prediction that direct-pathway MSNs receive stronger total input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question of how the lack of dopamine may lead to behavioral deficits associated with Parkinson’s disease. NEW & NOTEWORTHY The direct and indirect pathways of the basal ganglia originate from the D1- and D2-type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs). Theoretical results have predicted that dMSNs should receive stronger synaptic input than iMSNs. Using in vivo intracellular membrane potential data, we provide evidence that dMSNs indeed receive stronger input than iMSNs, as has been predicted by the computational model.

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Mashima, Kyoko, Shinichi Takahashi, Kazushi Minami, Yoshikane Izawa, Takato Abe, Naoki Tsukada, Takako Hishiki, Makoto Suematsu, Mayumi Kajimura, and Norihiro Suzuki. "Neuroprotective Role of Astroglia in Parkinson Disease by Reducing Oxidative Stress Through Dopamine-Induced Activation of Pentose-Phosphate Pathway." ASN Neuro 10 (January 2018): 175909141877556. http://dx.doi.org/10.1177/1759091418775562.

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Oxidative stress plays an important role in the onset and progression of Parkinson disease. Although released dopamine at the synaptic terminal is mostly reabsorbed by dopaminergic neurons, some dopamine is presumably taken up by astroglia. This study examined the dopamine-induced astroglial protective function through the activation of the pentose-phosphate pathway (PPP) to reduce reactive oxygen species (ROS). In vitro experiments were performed using striatal neurons and cortical or striatal astroglia prepared from Sprague-Dawley rats or C57BL/6 mice. The rates of glucose phosphorylation in astroglia were evaluated using the [14C]deoxyglucose method. PPP activity was measured using [1-14C]glucose and [6-14C]glucose after acute (60 min) or chronic (15 hr) exposure to dopamine. ROS production was measured using 2′,7′-dichlorodihydrofluorescein diacetate. The involvement of the Kelch-like ECH-associated protein 1 (Keap1) or nuclear factor-erythroid-2-related factor 2 (Nrf2) system was evaluated using Nrf2 gene knockout mice, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction analysis for heme oxygenase-1. Acute exposure to dopamine elicited increases in astroglial glucose consumption with lactate release. PPP activity in astroglia was robustly enhanced independently of Na+-dependent monoamine transporters. In contrast, chronic exposure to dopamine induced moderate increases in PPP activity via the Keap1/Nrf2 system. ROS production from dopamine increased gradually over 12 hr. Dopamine induced neuronal cell damage that was prevented by coculturing with astroglia but not with Nrf2-deficient astroglia. Dopamine-enhanced astroglial PPP activity in both acute and chronic manners may possibly reduce neuronal oxidative stress.

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Lebel, Manon, Pierre Robinson, and Michel Cyr. "Canadian Association of Neurosciences Review: The Role of Dopamine Receptor Function in Neurodegenerative Diseases." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 34, no. 1 (February 2007): 18–29. http://dx.doi.org/10.1017/s0317167100005746.

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Dopamine (DA) receptors, which are heavily expressed in the caudate/putamen of the brain, represent the molecular target of several drugs used in the treatment of various neurological disorders, such as Parkinson's disease. Although most of the drugs are very effective in alleviating the symptoms associated with these conditions, their long-term utilization could lead to the development of severe side-effects. In addition to uncovering novel mediators of physiological DA receptor functions, recent research advances are suggesting a role of these receptors in toxic effects on neurons. For instance, accumulating evidence indicates that DA receptors, particularly D1 receptors, are central in the neuronal toxicity induced by elevated synaptic levels of DA. In this review, we will discuss recent findings on DA receptors as regulators of long term neuronal dysfunction and neurodegenerative processes.

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Lu, Jing-Shan, Qi-Yu Chen, Xiang Chen, Xu-Hui Li, Zhaoxiang Zhou, Qin Liu, Yuwan Lin, Miaomiao Zhou, Ping-Yi Xu, and Min Zhuo. "Cellular and synaptic mechanisms for Parkinson’s disease-related chronic pain." Molecular Pain 17 (January 2021): 174480692199902. http://dx.doi.org/10.1177/1744806921999025.

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Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. Chronic pain is experienced by the vast majority of patients living with Parkinson’s disease. The degeneration of dopaminergic neuron acts as the essential mechanism of Parkinson’s disease in the midbrain dopaminergic pathway. The impairment of dopaminergic neurons leads to dysfunctions of the nociceptive system. Key cortical areas, such as the anterior cingulate cortex (ACC) and insular cortex (IC) that receive the dopaminergic projections are involved in pain transmission. Dopamine changes synaptic transmission via several pathway, for example the D2-adenly cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway and D1-G protein-coupled receptor kinase 2 (GRK2)-fragile X mental retardation protein (FMRP) pathway. The management of Parkinson’s disease-related pain implicates maintenance of stable level of dopaminergic drugs and analgesics, however a more selective drug targeting at key molecules in Parkinson’s disease-related pain remains to be investigated.

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Ziv, Ilan, Eldad Melamed, Nurit Nardi, Drorit Luria, Anat Achiron, Daniel Offen, and Ari Barzilai. "Dopamine induces apoptosis-like cell death in cultured chick sympathetic neurons — A possible novel pathogenetic mechanism in Parkinson's disease." Neuroscience Letters 170, no. 1 (March 1994): 136–40. http://dx.doi.org/10.1016/0304-3940(94)90258-5.

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Ivanova, Svetlana A., and Anton J. M. Loonen. "Levodopa-Induced Dyskinesia Is Related to Indirect Pathway Medium Spiny Neuron Excitotoxicity: A Hypothesis Based on an Unexpected Finding." Parkinson's Disease 2016 (2016): 1–5. http://dx.doi.org/10.1155/2016/6461907.

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A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington’s disease. Huntington’s disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson’s disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia.

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Fink, Jackson, Heather Pathak, John Smith, Cindy Achat-Mendes, and Robert L. Haining. "Development of a Competition-Binding Assay to Determine Binding Affinity of Molecules to Neuromelanin via Fluorescence Spectroscopy." Biomolecules 9, no. 5 (May 8, 2019): 175. http://dx.doi.org/10.3390/biom9050175.

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Neuromelanin, the polymeric form of dopamine which accumulates in aging neuronal tissue, is increasingly recognized as a functional and critical component of a healthy and active adult human brain. Notorious in plant and insect literature for their ability to bind and retain amines for long periods of time, catecholamine polymers known colloquially as ‘melanins’ are nevertheless curiously absent from most textbooks regarding biochemistry, neuroscience, and evolution. Recent research has brought attention to the brain pigment due to its possible role in neurodegeneration. This linkage is best illustrated by Parkinson’s disease, which is characterized by the loss of pigmented dopaminergic neurons and the ‘white brain’ pathological state. As such, the ability to determine the binding affinity of neurotoxic agents, as well as any potential specific endogenous ligands to neuromelanin are of interest and potential value. Neuromelanin has been shown to have saturable binding interactions with nicotine as monitored by a fluorimeter. This interaction provides a signal to allow for a competition-binding assay with target molecules which do not themselves produce signal. The current report establishes the viability of this competition assay toward three compounds with central relevance to Parkinson’s disease. The Kd of binding toward neuromelanin by methyl-phenyl-pyridinium ion (MPP+), dopamine, and 6-hydroxydopamine were found to be 1 mM, 0.05 mM, and 0.1 mM, respectively in the current study. In addition, we demonstrate that 6-hydroxydopamine polymerizes to form neuromelanin granules in cultured dopaminergic neurons that treated with 2,4,5-trihydroxy-l-phenylalanine. Immunohistochemical analysis using fluor-tagged anti-dopamine antibodies suggests that the incorporation of 6-hydroxydopamine (following internalization and decarboxylation analogous to levodopa and dopamine) alters the localized distribution of bound dopamine in these cells.

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Inamdar, Arati A., Anathbandhu Chaudhuri, and Janis O’Donnell. "The Protective Effect of Minocycline in a Paraquat-Induced Parkinson's Disease Model inDrosophilais Modified in Altered Genetic Backgrounds." Parkinson's Disease 2012 (2012): 1–16. http://dx.doi.org/10.1155/2012/938528.

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Epidemiological studies link the herbicide paraquat to increased incidence of Parkinson's disease (PD). We previously reported thatDrosophilaexposed to paraquat recapitulate PD symptoms, including region-specific degeneration of dopaminergic neurons. Minocycline, a tetracycline derivative, exerts ameliorative effects in neurodegenerative disease models, includingDrosophila. We investigated whether our environmental toxin-based PD model could contribute to an understanding of cellular and genetic mechanisms of minocycline action and whether we could assess potential interference with these drug effects in altered genetic backgrounds. Cofeeding of minocycline with paraquat prolonged survival, rescued mobility defects, blocked generation of reactive oxygen species, and extended dopaminergic neuron survival, as has been reported previously for a genetic model of PD inDrosophila. We then extended this study to identify potential interactions of minocycline with genes regulating dopamine homeostasis that might modify protection against paraquat and found that deficits in GTP cyclohydrolase adversely affect minocycline rescue. We further performed genetic studies to identify signaling pathways that are necessary for minocycline protection against paraquat toxicity and found that mutations in theDrosophilagenes that encode c-Jun N-terminal kinase (JNK) and Akt/Protein kinase B block minocycline rescue.

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Dejean, Cyril, Christian E. Gross, Bernard Bioulac, and Thomas Boraud. "Dynamic Changes in the Cortex-Basal Ganglia Network After Dopamine Depletion in the Rat." Journal of Neurophysiology 100, no. 1 (July 2008): 385–96. http://dx.doi.org/10.1152/jn.90466.2008.

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It is well established that parkinsonian syndrome is associated with alterations in the temporal pattern of neuronal activity and local field potentials in the basal ganglia (BG). An increase in synchronized oscillations has been observed in different BG nuclei in parkinsonian patients and animal models of this disease. However, the mechanisms underlying this phenomenon remain unclear. This study investigates the functional connectivity in the cortex-BG network of a rodent model of Parkinson's disease. Single neurons and local field potentials were simultaneously recorded in the motor cortex, the striatum, and the substantia nigra pars reticulata (SNr) of freely moving rats, and high-voltage spindles (HVSs) were used to compare signal transmission before and after dopaminergic depletion. It is shown that dopaminergic lesion results in a significant enhancement of oscillatory synchronization in the BG: the coherence between pairs of structures increased significantly and the percentage of oscillatory auto- and cross-correlograms. HVS episodes were also more numerous and longer. These changes were associated with a shortening of the latency of SNr response to cortical activation, from 40.5 ± 4.8 to 10.2 ± 1.07 ms. This result suggests that, in normal conditions, SNr neurons are likely to be driven by late inputs from the indirect pathway; however, after the lesion, their shorter latency also indicates an overactivation of the hyperdirect pathway. This study confirms that neuronal signal transmission is altered in the BG after dopamine depletion but also provides qualitative evidence for these changes at the cellular level.

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Journal articles on the topic 'Dopamine neurons, parkinson's disease, neuroscience'

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