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Sample records for nigrostriatal dopaminergic system

  1. Effects of HZE particle on the nigrostriatal dopaminergic system in a future Mars mission.

    PubMed

    Koike, Yu; Frey, M A; Sahiar, F; Dodge, R; Mohler, S

    2005-02-01

    Because of long duration travel outside the Earth's magnetic field, the effect of iron-rich high charge and energy (HZE) particles in Galactic Cosmic Rays on human body is the major concern in radiation protection. Recently attention has been directed to effects on the central nervous system in addition to mutagenic effects. In particular, a reduction in striatal dopamine content on nigrostriatal dopaminergic system has been reported by investigators using accelerated iron ions in ground-based mammalian studies. In addition, studies of the pathophysiology of Parkinson's disease demonstrated that excess iron cause a reduction in the dopamine content in the substantia nigra. This suggests an intriguing possibility to explain the selective detrimental effects of HZE particles on the dopaminergic system. Should these particles have biochemical effects, possible options for countermeasures are: (1) nutritional prevention, (2) medication, and (3) surgical placement of a stimulator electrode at a specific anatomic site in the basal ganglia. c2004 Elsevier Ltd. All rights reserved.

  2. Subclinical nigrostriatal dopaminergic denervation in the cerebellar subtype of multiple system atrophy (MSA-C).

    PubMed

    Muñoz, Esteban; Iranzo, Alex; Rauek, Sebastian; Lomeña, Francisco; Gallego, Judith; Ros, Doménec; Santamaría, Joan; Tolosa, Eduardo

    2011-12-01

    Nigrostriatal involvement is considered an additional feature in the new consensus criteria for the diagnosis of the cerebellar variant of multiple system atrophy (MSA-C). However, so far, only a few studies, which include a relative small number of patients, give support to this criterion. Our objective was to assess nigrostriatal dopaminergic innervation in patients with MSA-C without parkinsonism by use of dopamine transporter single photon emission computed tomography (DAT SPECT). Thirteen patients that fulfilled criteria for possible or probable MSA-C and presented no parkinsonian signs, and 12 age-matched healthy controls underwent ((123)I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ([(123)I]FP-CIT) SPECT. Patients were also evaluated through the Unified Multiple System Atrophy Rating Scale (UMSARS) and brain magnetic resonance imaging (MRI). The mean duration of the cerebellar syndrome was 3.8 ± 1.7 years. DAT SPECT showed a significant decrease of striatal [(123)I]FP-CIT uptake ratios in patients (p < 0.001). Radiotracer uptake reduction was 21% in the entire striatum, 19% in putamen, and 24% in caudate nuclei. Striatal binding ratios were within the normal range in 3 patients. We did not find correlation between striatal uptake and disease duration, age of patients, UMSARS-II score, and pontine diameter. [(123)I]FP-CIT SPECT shows that most but not all MSA-C patients without parkinsonism have subclinical nigrostriatal dopaminergic denervation which is not related to disease duration, cerebellar dysfunction, or pontine atrophy.

  3. GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function.

    PubMed

    Kumar, Anmol; Kopra, Jaakko; Varendi, Kärt; Porokuokka, Lauriina L; Panhelainen, Anne; Kuure, Satu; Marshall, Pepin; Karalija, Nina; Härma, Mari-Anne; Vilenius, Carolina; Lilleväli, Kersti; Tekko, Triin; Mijatovic, Jelena; Pulkkinen, Nita; Jakobson, Madis; Jakobson, Maili; Ola, Roxana; Palm, Erik; Lindahl, Maria; Strömberg, Ingrid; Võikar, Vootele; Piepponen, T Petteri; Saarma, Mart; Andressoo, Jaan-Olle

    2015-12-01

    Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson's disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3'UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson's disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3'UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct spatial

  4. Atrazine Causes Autophagy- and Apoptosis-Related Neurodegenerative Effects in Dopaminergic Neurons in the Rat Nigrostriatal Dopaminergic System

    PubMed Central

    Song, Xiao-Yao; Li, Jia-Nan; Wu, Yan-Ping; Zhang, Bo; Li, Bai-Xiang

    2015-01-01

    Atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) is widely used as a broad-spectrum herbicide. Animal studies have demonstrated that ATR exposure can cause cell death in dopaminergic neurons. The molecular mechanisms underlying ATR-induced neuronal cell death, however, are unknown. In this study, we investigated the autophagy and apoptosis induced by ATR in dopaminergic neurons in vivo. Wistar rats were administered with ATR at doses of 10, 50 and 100 mg/kg body weight by oral gavage for three months. In terms of histopathology, the expression of autophagy- and apoptosis-related genes as well as proteins related to the Beclin-1/B-cell lymphoma 2 (Bcl-2) autophagy and apoptosis pathways were examined in the rat nigrostriatal dopaminergic system. We observed degenerative micromorphology indicative of neuronal apoptosis and mitochondrial autophagy by electron microscopy in ATR-exposed rat striatum. The rat ventral mesencephalon in the ATR-exposed groups also showed increased expression of Beclin-1, LC3-II, Bax and Caspase-9, and decreased expression of tyrosine hydroxylase (TH), Bcl-xl and Bcl-2. These findings indicate that ATR may induce autophagy- and apoptosis-related changes in doparminergic neurons. Furthermore, this induction may be regulated by the Beclin-1 and Bcl-2 autophagy and apoptosis pathways, and this may help to better understand the mechanism underlying the neurotoxicity of ATR. PMID:26075868

  5. Effect of estrogen upon methamphetamine-induced neurotoxicity within the impaired nigrostriatal dopaminergic system.

    PubMed

    Liu, Bin; Dluzen, Dean E

    2006-10-01

    In the present study, we investigated whether estrogen remains effective as a neuroprotectant within an impaired nigrostriatal dopaminergic (NSDA) system of gonadectomized female and male mice. In Experiment 1, mice were treated with four different regimens of methamphetamine (MA) to establish a protocol for an impaired NSDA system to be used in subsequent experiments. Based upon the results of Experiment 1, in Experiment 2 gonadectomized female mice received a treatment with either control (saline), low- or high-dose of MA to produce an initial NSDA impairment. At one week post-MA, mice received either estradiol benzoate (10 microg) or vehicle followed 24 h later with low-MA or saline. Estrogen altered the toxic effects of the second invasion of MA as indicated by a significant decrease in striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations. In addition, DA and DOPAC depletion was greater in high- vs. low-dose MA. In gonadectomized male mice (Experiment 3), striatal DA and DOPAC concentrations showed greater decreases following high-, vs. low-doses of MA; however, estrogen did not alter these responses. These results demonstrate that the capacity for estrogen to protect or worsen MA-induced neurotoxicity of dopaminergic neurons is limited to female mice and depends on the condition of the NSDA system.

  6. GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function

    PubMed Central

    Porokuokka, Lauriina L.; Panhelainen, Anne; Kuure, Satu; Marshall, Pepin; Karalija, Nina; Härma, Mari-Anne; Vilenius, Carolina; Lilleväli, Kersti; Tekko, Triin; Mijatovic, Jelena; Pulkkinen, Nita; Jakobson, Madis; Jakobson, Maili; Ola, Roxana; Palm, Erik; Lindahl, Maria; Strömberg, Ingrid; Võikar, Vootele; Piepponen, T. Petteri; Saarma, Mart; Andressoo, Jaan-Olle

    2015-01-01

    Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson’s disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson’s disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3’UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson’s disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3’UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct

  7. [Criteria of efficiency of transplantation of embryonic nervous tissue preparations in rats with 6-OHDA-impaired dopaminergic nigrostriatal system].

    PubMed

    Chekhonin, V P; Lebedev, S V; Dmitrieva, T B; Baklaushev, V P; Savchenko, E A; Lazarenko, I P; Gurina, O I; Belopasov, V V

    2002-01-01

    Effectiveness of transplantation of cells from embryonal nervous tissue of the ventral mesencephalon (VM ENT) and striatum (STR ENT) by apomorphin-induced motor asymmetry (APO-test), consolidation of the transplant (the degree of glyal reaction and amount of dopaminergic neurons) and blood serum levels of GFAP was studied for 3 months in Wistar rats with 6-OHDA-impaired dopaminergic nigrostriatal system. Marked therapeutic effectiveness was registered in VM ENT transplantation in the denervated striatum and in combined transplantation of VM ENT into the lateral cerebral ventricle simultaneously with STR ENT transplantation in the striatum. Separate transplantation of VM ENT in the lateral ventricle and STR ENT in the striatum had no positive effect on recovery of the dopaminergic nigrostriatal system. A correlation was found between the degree of glial reaction of ENT transplants, severity of rotation asymmetry and serum levels of gliofibrillary protein (GFAP). GFAP in the serum for lifetime assessment of transplant consolidation and prognosis of neurotransplantation efficiency was assayed.

  8. The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease

    SciTech Connect

    Leenders, K.L.; Salmon, E.P.; Tyrrell, P.; Perani, D.; Brooks, D.J.; Sager, H.; Jones, T.; Marsden, C.D.; Frackowiak, R.S. )

    1990-12-01

    A group of healthy control subjects and patients with Parkinson's disease were investigated using positron emission tomography and two tracers as indicators of different specific properties of the presynaptic dopaminergic system in caudate nucleus and putamen. The first tracer, 6-L-(18F)-fluorodopa, was used as an analog of levodopa to assess its regional brain uptake, conversion into, and retention as dopamine and further metabolites. The second tracer, (11C)-nomifensine was employed as an indicator of striatal monaminergic reuptake sites that are principally dopaminergic. We have used this tracer to assess dopaminergic nerve terminal density. In patients with Parkinson's disease, striatal uptake of both tracers was decreased, putamen being significantly more affected than caudate. Side-to-side differences of uptake in putamen, but not caudate, correlated with corresponding left-right differences of scored clinical motor performance. Both 6-L(18F)-fluorodopa and (11C)-nomifensine tracer uptake in putamen was decreased on average to 40% of normal values, suggesting that a substantial part of the cellular elements of the dopaminergic nigrostriatal system is still intact in living parkinsonian patients. This is in contrast to the generally extreme depletion of endogenous dopamine in the putamen of patients found at postmortem. Our results lend support to the search for drug treatments that protect against further nigrostriatal cell loss and that could be exhibited as soon as the disease manifests clinically. If successful, a sufficient striatal nerve terminal pool would remain so that the effectiveness of levodopa as a dopamine repletor could persist.

  9. Enriched environment protects the nigrostriatal dopaminergic system and induces astroglial reaction in the 6-OHDA rat model of Parkinson's disease

    PubMed Central

    Anastasía, Agustín; Torre, Luciana; de Erausquin, Gabriel A.; Mascó, Daniel H.

    2009-01-01

    Enriched environment (EE) is neuroprotective in several animal models of neurodegeneration. It stimulates the expression of trophic factors and modifies the astrocyte cell population which has been said to exert neuroprotective effects. We have investigated the effects of EE on 6-hydroxydopamine (6-OHDA)-induced neuronal death after unilateral administration to the medial forebrain bundle, which reaches 85–95% of dopaminergic neurons in the substantia nigra after 3 weeks. Continuous exposure to EE 3 weeks before and after 6-OHDA injection prevents neuronal death (assessed by tyrosine hydroxylase staining), protects the nigrostriatal pathway (assessed by Fluorogold retrograde labeling) and reduces motor impairment. Four days after 6-OHDA injection, EE was associated with a marked increase in glial fibrillary acidic protein staining and prevented neuronal death (assessed by Fluoro Jade-B) but not partial loss of tyrosine hydroxylase staining in the anterior substantia nigra. These results robustly demonstrate that EE preserves the entire nigrostriatal system against 6-OHDA-induced toxicity, and suggests that an early post-lesion astrocytic reaction may participate in the neuro-protective mechanism. PMID:19245661

  10. Neonatal systemic exposure to lipopolysaccharide enhances susceptibility of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life

    PubMed Central

    Cai, Zhengwei; Fan, Lir-Wan; Kaizaki, Asuka; Tien, Lu-Tai; Ma, Tangeng; Pang, Yi; Lin, Shuying; Lin, Rick C. S.; Simpson, Kimberly L.

    2013-01-01

    Brain inflammation via intracerebral injection with lipopolysaccharide (LPS) in early life has been shown to increase risks for the development of neurodegenerative disorders in adult rats. To determine if neonatal systemic LPS exposure has the same effects on enhancement of adult dopaminergic neuron susceptibility to rotenone neurotoxicity as centrally-injected LPS does, LPS (2 μg/g body weight) was administered intraperitoneally into post-natal day 5 (P5) rats and when grown to P70, rats were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25 mg/kg per day for 14 days. Systemically administered LPS can penetrate into the neonatal rat brain and cause acute and chronic brain inflammation, as evidenced by persistent increases in IL-1β levels, cyclooxygenase-2 expression and microglial activation in the substantia nigra (SN) of P70 rats. Neonatal LPS exposure resulted in suppression of tyrosine hydroxylase (TH) expression, but not actual death of dopaminergic neurons in the SN, as indicated by the reduced number of TH+ cells and unchanged total number of neurons (NeuN+) in the SN. Neonatal LPS exposure also caused motor function deficits, which were spontaneously recoverable by P70. A small dose of rotenone at P70 induced loss of dopaminergic neurons, as indicated by reduced numbers of both TH+ and NeuN+ cells in the SN, and Parkinson’s disease (PD)-like motor impairment in P98 rats that had experienced neonatal LPS exposure, but not in those without the LPS exposure. These results indicate that although neonatal systemic LPS exposure may not necessarily lead to death of dopaminergic neurons in the SN, such an exposure could cause persistent functional alterations in the dopaminergic system and indirectly predispose the nigrostriatal system in the adult brain more vulnerable to be damaged by environmental toxins at an ordinarily non-toxic or sub-toxic dose to develop PD-like pathological features and

  11. Acupuncture prevents 6-hydroxydopamine-induced neuronal death in the nigrostriatal dopaminergic system in the rat Parkinson's disease model.

    PubMed

    Park, Hi-Joon; Lim, Sabina; Joo, Wan-Seok; Yin, Chang-Shik; Lee, Hyang-Sook; Lee, Hye-Jung; Seo, Jung Chul; Leem, Kanghyun; Son, Yang-Sun; Kim, Youn-Jung; Kim, Chang-Ju; Kim, Yong-Sik; Chung, Joo-Ho

    2003-03-01

    Parkinson's disease (PD) is a chronic neurodegenerative disorder, and it has been suggested that treatments promoting survival and functional recovery of affected dopaminergic neurons could have a significant and long-term therapeutic value. In the present study, we investigated the neuroprotective effects of acupuncture on the nigrostriatal system in rat unilaterally lesioned with 6-hydroxydopamine (6-OHDA, 4 microg/microl, intrastriatal injection) using tyrosine hydroxylase (TH) and receptor for brain-derived neurotrophic factor, trkB, immunohistochemistries. Two weeks after the lesions were made, rats presented with asymmetry in rotational behavior (118.3 +/- 17.5 turns/h) following injection with apomorphine, a dopamine receptor agonist (0.5 mg/kg, sc). In contrast, acupunctural treatment at acupoints GB34 and LI3 was shown to significantly reduce this motor deficit (14.6 +/- 13.4 turns/h). Analysis via TH immunohistochemistry revealed a substantial loss of cell bodies in the substantia nigra (SN) (45.7% loss) and their terminals in the dorsolateral striatum ipsilateral to the 6-OHDA-induced lesion. However, acupunctural treatment resulted in the enhanced survival of dopaminergic neurons in the SN (21.4% loss) and their terminals in the dorsolateral striatum. Acupuncture also increased the expression of trkB significantly (35.6% increase) in the ipsilateral SN. In conclusion, we observed that only acupuncturing without the use of any drug has the neuroprotective effects against neuronal death in the rat PD model and these protective properties of acupuncture could be mediated by trkB.

  12. Peripheral inflammation increases the deleterious effect of CNS inflammation on the nigrostriatal dopaminergic system.

    PubMed

    Hernández-Romero, Ma Carmen; Delgado-Cortés, M José; Sarmiento, Manuel; de Pablos, Rocío M; Espinosa-Oliva, Ana María; Argüelles, Sandro; Bández, Manuel J; Villarán, Ruth F; Mauriño, Raquel; Santiago, Marti; Venero, José L; Herrera, Antonio J; Cano, Josefina; Machado, Alberto

    2012-06-01

    Evidence supports the role of inflammation in the development of neurodegenerative diseases. In this work, we are interested in inflammation as a risk factor by itself and not only as a factor contributing to neurodegeneration. We tested the influence of a mild to moderate peripheral inflammation (injection of carrageenan into the paws of rats) on the degeneration of dopaminergic neurons in an animal model based on the intranigral injection of lipopolysaccharide (LPS), a potent inflammatory agent. Overall, the treatment with carrageenan increased the effect of the intranigral injection of LPS on the loss of dopaminergic neurons in the SN along with all the other parameters studied, including: serum levels of the inflammatory markers TNF-α, IL-1β, IL-6 and C-reactive protein; activation of microglia, expression of proinflammatory cytokines, the adhesion molecule ICAM and the enzyme iNOS, loss of astrocytes and damage to the blood brain barrier (BBB). The possible implication of BBB rupture in the increased loss of dopaminergic neurons has been studied using another Parkinson's disease animal model based on the intraperitoneal injection of rotenone. In this experiment, loss of dopaminergic neurons was also strengthened by carrageenan, without affecting the BBB. In conclusion, our data show that a mild to moderate peripheral inflammation can exacerbate the degeneration of dopaminergic neurons caused by a harmful stimulus.

  13. Is there a role for ghrelin in central dopaminergic systems? Focus on nigrostriatal and mesocorticolimbic pathways.

    PubMed

    Stievenard, Alicia; Méquinion, Mathieu; Andrews, Zane B; Destée, Alain; Chartier-Harlin, Marie-Christine; Viltart, Odile; Vanbesien-Mailliot, Christel C

    2017-02-01

    The gastro-intestinal peptide ghrelin has been assigned many functions. These include appetite regulation, energy metabolism, glucose homeostasis, intestinal motility, anxiety, memory or neuroprotection. In the last decade, this pleiotropic peptide has been proposed as a therapeutic agent in gastroparesis for diabetes and in cachexia for cancer. Ghrelin and its receptor, which is expressed throughout the brain, play an important role in motivation and reward. Ghrelin finely modulates the mesencephalic dopaminergic signaling and is thus currently studied in pathological conditions including dopamine-related disorders. Dopamine regulates motivated behaviors, modulating reward processes, emotions and motor functions to enable the survival of individuals and species. Numerous dopamine-related disorders including Parkinson's disease or eating disorders like anorexia nervosa involve altered ghrelin levels. However, despite the growing interest for ghrelin in these pathological conditions, global integrative studies investigating its role in brain dopaminergic structures are still lacking. In this review, we discuss the role of ghrelin on dopaminergic neurons and its relevance in the search for new therapeutics for Parkinson's disease- and anorexia nervosa-related dopamine deficits.

  14. Effects of estrogen and related agents upon methamphetamine-induced neurotoxicity within an impaired nigrostriatal dopaminergic system of ovariectomized mice.

    PubMed

    Liu, Bin; Dluzen, Dean E

    2006-01-01

    Estrogen increases methamphetamine (MA)-induced neurotoxicity within the impaired nigrostriatal dopaminergic (NSDA) system of ovariectomized female mice, as defined by enhanced striatal dopamine (DA) depletion. In this study we compared the effects of a lower dose of estradiol benzoate (EB, 1 microg) with related agents--tamoxifen (TMX, 12.5 microg), testosterone (5 microg) and dehydroepiandrosterone (DHEA, 3 mg) in this paradigm. In experiment 1, ovariectomized mice received an initial treatment with MA. At 1 week after MA, mice were treated with EB, TMX, testosterone, DHEA or oil vehicle and 24 h later a second MA treatment. Striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations in the MA-treated groups were decreased compared to the non-MA-treated control. Neither EB nor any of the other agents tested showed enhanced neurodegenerative or neuroprotective effects against a second MA invasion. To verify that estrogen was capable of showing a neuroprotective effect under a condition of two administrations of MA, in experiment 2, EB was administered either once or twice prior to each of the two MA treatments. EB treatment prior to the first MA invasion or first and second MA protected the NSDA system against DA and DOPAC depletion. These results imply that a lower dose of EB, TMX, testosterone and DHEA cannot exert neurodegenerative or neuroprotective effects in the impaired NSDA model. However, EB administered prior to the introduction of neurotoxicity can protect the NSDA system. This study may provide an understanding of the variations in results on the effects of estrogen upon the NSDA neurodegenerative disorder, Parkinson's disease.

  15. Repeated heat exposure impairs nigrostriatal dopaminergic neurons in mice.

    PubMed

    Kim, Hyo Geun; Kim, Tae-mi; Park, Gunhyuk; Lee, Tae Hee; Oh, Myung Sook

    2013-01-01

    Environmental heat stress is associated with physical stress responses, including changes in monoamines, protein expression, and neuronal circuits and damage to neurons in the brain. This study determined the effects of heat stress on the nigrostriatal dopaminergic system based on behavioral, histological, and neurochemical analyses. To evaluate behavioral changes after heat exposure, we subjected mice to the pole and open field tests. The data suggested that heat stress for 7 d significantly impaired movement. Then, we conducted a histological analysis using tyrosine hydroxylase (TH) immunoreactivity in the striatum and substantia nigra (SN). Heat stress induced a significant deficit in TH-positive fibers and cells after 14- and 21-d exposure, respectively. We also measured the striatal dopamine (DA), 4-hydroxy-3-methoxy-phenylacetic acid, and 3,4-dihydroxyphenylacetic acid levels. The data suggested that DA turnover rate increased with heat exposure in a time-dependent manner, resulting in the significant decrease of DA after 28 d. Moreover, the expression of heat shock protein 70 (HSP70) was increased in the mouse SN with up to 14-d heat exposure, but decreased after 21 d of the stress. And glucose-regulated protein 78 (GRP78) was gradually increased in the mouse SN with 28-d heat exposure. The caspase-3 activity was also increased after 14-d heat exposure. These findings are the first evidence that repeated heat stress impairs nigrostriatal dopaminergic neurons, motor function, and DA availability with changes of HSP70 and GRP78 expressions and caspase-3 activity in mice.

  16. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system.

    PubMed

    Ismaiel, Afrah A K; Espinosa-Oliva, Ana M; Santiago, Martiniano; García-Quintanilla, Albert; Oliva-Martín, María J; Herrera, Antonio J; Venero, José L; de Pablos, Rocío M

    2016-05-01

    Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease.

  17. Deficits in coordinated motor behavior and in nigrostriatal dopaminergic system ameliorated and VMAT2 expression up-regulated in aged male rats by administration of testosterone propionate.

    PubMed

    Wang, Li; Kang, Yunxiao; Zhang, Guoliang; Zhang, Yingbo; Cui, Rui; Yan, Wensheng; Tan, Huibing; Li, Shuangcheng; Wu, Baiyila; Cui, Huixian; Shi, Geming

    2016-06-01

    The effects of testosterone propionate (TP) supplements on the coordinated motor behavior and nigrostriatal dopaminergic (NSDA) system were analyzed in aged male rats. The present study showed the coordinated motor behavioral deficits, the reduced activity of NSDA system and the decreased expression of vesicular monoamine transporter 2 (VMAT2) in 24 month-old male rats. Long term TP treatment improved the motor coordination dysfunction with aging. Increased tyrosine hydroxylase and dopamine transporter, as well as dopamine and its metabolites were found in the NSDA system of TP-treated 24 month-old male rats, indicative of the amelioratory effects of TP supplements on NSDA system of aged male rats. The enhancement of dopaminergic (DAergic) activity of NSDA system by TP supplements might underlie the amelioration of the coordinated motor dysfunction in aged male rats. TP supplements up-regulated VMAT2 expression in NSDA system of aged male rats. Up-regulation of VMAT2 expression in aged male rats following chronic TP treatment might be involved in the maintenance of DAergic function of NSDA system in aged male rats.

  18. A Current Review of Cypermethrin-Induced Neurotoxicity and Nigrostriatal Dopaminergic Neurodegeneration

    PubMed Central

    Singh, Anand Kumar; Tiwari, Manindra Nath; Prakash, Om; Singh, Mahendra Pratap

    2012-01-01

    Cypermethrin, a class II pyrethroid pesticide, is used to control insects in the household and agricultural fields. Despite beneficial roles, its uncontrolled and repetitive applications lead to unintended effects in non-target organisms. Cypermethrin crosses the blood-brain barrier and induces neurotoxicity and motor deficits. Cypermethrin prolongs the opening of sodium channel, a major site of its action, leading to hyper-excitation of the central nervous system. In addition to sodium channel, cypermethrin modulates chloride, voltage-gated calcium and potassium channels, alters the activity of glutamate and acetylcholine receptors and adenosine triphosphatases and induces DNA damage and oxidative stress in the neuronal cells. Cypermethrin also modulates the level of neurotransmitters, including gamma-aminobutyric acid and dopamine. It is one of the most commonly used pesticides in neurotoxicology research not only because of its variable responses depending upon the doses, time and routes of exposure and strain, age, gender and species of animals used across multiple studies but also owing to its ability to induce the nigrostriatal dopaminergic neurodegeneration. This article describes the effect of acute, chronic, developmental and adulthood exposures to cypermethrin in experimental animals. The article sheds light on cypermethrin-induced changes in the central nervous system, including its contribution in the onset of specific features, which are associated with the nigrostriatal dopaminergic neurodegeneration. Resemblances and dissimilarities of cypermethrin-induced nigrostriatal dopaminergic neurodegeneration with sporadic and chemicals-induced disease models along with its advantages and pitfalls are also discussed. PMID:22942879

  19. Effect of different doses of estrogen on the nigrostriatal dopaminergic system in two 6-hydroxydopamine-induced lesion models of Parkinson's disease.

    PubMed

    Cordellini, Marcela Ferreira; Piazzetta, Giovana; Pinto, Karin Cristine; Delattre, Ana Márcia; Matheussi, Francesca; Carolino, Ruither O G; Szawka, Raphael Escorsim; Anselmo-Franci, Janete A; Ferraz, Anete Curte

    2011-06-01

    Parkinson's disease results from a degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) and it is more prevalent in men than in women. Estrogen has neuroprotective action of the nigrostriatal dopaminergic (NSDA) neurons. It was investigated whether differences in plasma 17β-estradiol (E2) levels alter the degree of neuroprotection in NSDA neurons. Ovariectomized rats, implanted with subcutaneous capsules containing 400, 800 or 1,600 μg of E2 or corn oil, were injected with 1 μg of 6-OHDA in the SNpc or the medial forebrain bundle (MFB). Striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and plasma E2 levels were measured. Only at 400 μg, E2 protected striatal DA against lesion of the MFB. In the SNpc, E2 failed to prevent DA depletion, but increased DOPAC/DA ratio in the striatum. In an NSDA moderate lesion, E2 has a neuroprotective action. In a severe lesion, E2 could stimulate DA activity in remaining neurons.

  20. Chronic Deprivation of TrkB Signaling Leads to Selective Late-onset Nigrostriatal Dopaminergic Degeneration

    PubMed Central

    Baydyuk, Maryna; Nguyen, Madeline T.; Xu, Baoji

    2011-01-01

    The pathological hallmark of Parkinson's disease (PD) is a selective and progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). In the vast majority of cases the appearance of PD is sporadic, and its etiology remains unknown. Several postmortem studies demonstrate reduced levels of brain-derived neurotrophic factor (BDNF) in the SNc of PD patients. Application of BDNF promotes the survival of DA neurons in PD animal models. Here we show that BDNF signaling via its TrkB receptor tyrosine kinase is important for survival of nigrostriatal DA neurons in aging brains. Immunohistochemistry revealed that the TrkB receptor was expressed in DA neurons located in the SNc and ventral tegmental area (VTA). However, a significant loss of DA neurons occurred at 12-24 months of age only in the SNc but not in the VTA of TrkB hypomorphic mice in which the TrkB receptor was expressed at a quarter to a third of the normal amount. The neuronal loss was accompanied by a decrease in dopaminergic axonal terminals in the striatum and by gliosis in both the SNc and striatum. Furthermore, nigrostriatal DA neurons in the TrkB mutant mice were hypersensitive to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I inhibitor that selectively kills DA neurons. These results suggest that BDNF-to-TrkB signaling plays an important role in the long-term maintenance of the nigrostriatal system and that its deficiency may contribute to the progression of PD. PMID:21192928

  1. Treadmill exercise alleviates nigrostriatal dopaminergic loss of neurons and fibers in rotenone-induced Parkinson rats.

    PubMed

    Shin, Mal-Soon; Kim, Tae-Woon; Lee, Jae-Min; Ji, Eun-Sang; Lim, Baek-Vin

    2017-02-01

    Parkinson disease is one of the common brain diseases caused by dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. In the present study, the effects of treadmill exercise on motor performance, dopaminergic loss of neurons and fibers, and α-synuclein expression in the nigrostriatum were evaluated using rotenone-induced Parkinson rats. For the induction of Parkinson rats, 3-mg/kg rotenone was injected, once a day for 14 consecutive days. Treadmill running was conducted for 30 min once a day during 14 consecutive days. Rota-rod test for motor balance and coordination and immunohistochemistry for tyrosine hydroxylase and α-synuclein in the nigrostriatum were performed. In the present study, motor balance and coordination was disturbed by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated motor dysfunction in the rotenone-induced Parkinson rats. Nigrostriatal dopaminergic loss of neurons and fibers was occurred by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated nigrostriatal dopaminergic loss of neurons and fibers in the rotenone-induced Parkinson rats. α-Synuclein expression in the nigrostriatum was enhanced by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise suppressed α-synuclein expression in the rotenone-induced Parkinson rats. Treadmill exercise improved motor function through preservation of nigrostriatal dopaminergic neurons and fibers and suppression of nigrostriatal formation of Lewy bodies in rotenone-induced Parkinson rats.

  2. Treadmill exercise alleviates nigrostriatal dopaminergic loss of neurons and fibers in rotenone-induced Parkinson rats

    PubMed Central

    Shin, Mal-Soon; Kim, Tae-Woon; Lee, Jae-Min; Ji, Eun-Sang; Lim, Baek-Vin

    2017-01-01

    Parkinson disease is one of the common brain diseases caused by dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. In the present study, the effects of treadmill exercise on motor performance, dopaminergic loss of neurons and fibers, and α-synuclein expression in the nigrostriatum were evaluated using rotenone-induced Parkinson rats. For the induction of Parkinson rats, 3-mg/kg rotenone was injected, once a day for 14 consecutive days. Treadmill running was conducted for 30 min once a day during 14 consecutive days. Rota-rod test for motor balance and coordination and immunohistochemistry for tyrosine hydroxylase and α-synuclein in the nigrostriatum were performed. In the present study, motor balance and coordination was disturbed by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated motor dysfunction in the rotenone-induced Parkinson rats. Nigrostriatal dopaminergic loss of neurons and fibers was occurred by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated nigrostriatal dopaminergic loss of neurons and fibers in the rotenone-induced Parkinson rats. α-Synuclein expression in the nigrostriatum was enhanced by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise suppressed α-synuclein expression in the rotenone-induced Parkinson rats. Treadmill exercise improved motor function through preservation of nigrostriatal dopaminergic neurons and fibers and suppression of nigrostriatal formation of Lewy bodies in rotenone-induced Parkinson rats. PMID:28349030

  3. Paraquat induces selective dopaminergic nigrostriatal degeneration in aging C57BL/6 mice.

    PubMed

    Li, Xia; Yin, Jun; Cheng, Chun-mei; Sun, Jin-lai; Li, Zheng; Wu, Ying-liang

    2005-08-20

    Paraquat (PQ; 1, 1'-dimethyl-4, 4'-bipyridinium), a widely used herbicide that is structurally similar to the known dopaminergic neurotoxicant MPTP (1-methyl-1, 2, 3, 6-tetrahydropyridine), has been suggested as a potential etiologic factor for the development of Parkinson's disease (PD). Aging is an accepted risk factor for idiopathic Parkinson's disease. The aim of this study was to test the hypothesis that paraquat could induce PD-like nigrostriatal dopaminergic degeneration in aging C57BL/6 mice. Senile male C57BL/6 mice were intraperitoneally injected with either saline or PQ at 2-day intervals for a total of 10 doses. Locomotor activity and performance on the pole test were measured 7 days after the last injection and animals were sacrificed one day later. Level of dopamine (DA) and its metabolites levels in the striatum were measured by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD), and numbers of tyrosine hydroxylase (TH) positive neurons were estimated using immunohistochemistry. Locomotor activities were significantly decreased and the behavioral performance on the pole test were significantly impaired in the PQ treated group. Level of DA and its metabolites levels in the striatum were declined by 8 days after the last injection. Immunohistochemical analyses showed that PQ was associated with a reduction in numbers of tyrosine hydroxylase positive neurons. Long-term repeated exposes to PQ can selectively impair the nigrostriatal dopaminergic system of senile mice, suggesting that PQ could play an important role in the pathogenesis of Parkinson's disease (PD). Our results also validate a novel model of PD induced by exposure to a toxic environmental agent.

  4. Attenuation of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity in mice by lipopolysaccharide pretreatment.

    PubMed

    Lin, Yin Chiu; Kuo, Yu-Min; Liao, Pao-Chi; Cherng, Chianfang G; Su, Su-Wen; Yu, Lung

    2007-04-30

    Immunological activation has been proposed to play a role in methamphetamine-induced dopaminergic terminal damage. In this study, we examined the roles of lipopolysaccharide, a pro-inflammatory and inflammatory factor, treatment in modulating the methamphetamine-induced nigrostriatal dopamine neurotoxicity. Lipopolysaccharide pretreatment did not affect the basal body temperature or methamphetamine-elicited hyperthermia three days later. Such systemic lipopolysaccharide treatment mitigated methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions in a dose-dependent manner. As the most potent dose (1 mg/kg) of lipopolysaccharide was administered two weeks, one day before or after the methamphetamine dosing regimen, methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions remained unaltered. Moreover, systemic lipopolysaccharide pretreatment (1 mg/kg) attenuated local methamphetamine infusion-produced dopamine and 3,4-dihydroxyphenylacetic acid depletions in the striatum, indicating that the protective effect of lipopolysaccharide is less likely due to interrupted peripheral distribution or metabolism of methamphetamine. We concluded a critical time window for systemic lipopolysaccharide pretreatment in exerting effective protection against methamphetamine-induced nigrostriatal dopamine neurotoxicity.

  5. Clinical Features Indicating Nigrostriatal Dopaminergic Degeneration in Drug-Induced Parkinsonism

    PubMed Central

    Lee, Seung Ha; Kim, Han Kyeol; Lee, Young Gun; Lyoo, Chul Hyoung; Ahn, Sung Jun; Lee, Myung Sik

    2017-01-01

    Objective Patients with drug-induced parkinsonism (DIP) may have nigrostriatal dopaminergic degeneration. We studied the clinical features that may indicate nigrostriatal dopaminergic degeneration in patients with DIP. Methods Forty-one DIP patients were classified into normal and abnormal [18F] FP-CIT scan groups. Differences in 32 clinical features and drug withdrawal effects were studied. Results Twenty-eight patients had normal (Group I) and 13 patients had abnormal (Group II) scans. Eight patients of Group I, but none of Group II, had taken calcium channel blockers (p = 0.040). Three patients of Group I and six of Group II had hyposmia (p = 0.018). After drug withdrawal, Group I showed greater improvement in Unified Parkinson’s Disease Rating Scale total motor scores and subscores for bradykinesia and tremors than Group II. Only hyposmia was an independent factor associated with abnormal scans, but it had suboptimal sensitivity. Conclusion None of the clinical features were practical indicators of nigrostriatal dopaminergic degeneration in patients with DIP. PMID:28122428

  6. Predictive value of the smell identification test for nigrostriatal dopaminergic depletion in Korean tremor patients.

    PubMed

    Hong, Jin Yong; Chung, Seok Jong; Lee, Ji E; Sunwoo, Mun Kyung; Lee, Phil Hyu; Sohn, Young H

    2013-11-01

    The predictive value of Cross-Cultural Smell Identification Test for nigrostriatal dopaminergic depletion in Korean tremor patients has yet to be assessed. Three hundred nineteen drug-naive patients who visited our clinic for the diagnosis of their tremor, and took both Cross-Cultural Smell Identification Test and dopamine transporter PET were included in the data analysis. Visual grading of each PET image was performed by two independent neurologists. Smell test scores were significantly correlated to the striatal dopaminergic activity (Kendall's τb = -0.291, p < 0.001). However, smell test score alone appeared to have relatively weak power for predicting dopaminergic depletion (area under the curve = 0.693). Multivariate logistic regression model with inclusion of the patient's age and symptom duration as independent variables enhanced predictive power for dopaminergic depletion (area under the curve = 0.812). These results demonstrated that Cross-Cultural Smell Identification Test measurements alone may be insufficient to predict striatal dopaminergic depletion in Korean tremor patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate.

    PubMed

    Harrison, Ian F; Anis, Hiba K; Dexter, David T

    2016-02-12

    Parkinson's disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection.

  8. Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate

    PubMed Central

    Harrison, Ian F.; Anis, Hiba K.; Dexter, David T.

    2016-01-01

    Parkinson’s disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection. PMID:26742637

  9. Anatomical and Electrophysiological Changes in Striatal TH Interneurons after Loss of the Nigrostriatal Dopaminergic Pathway

    PubMed Central

    Ünal, Bengi; Shah, Fulva; Kothari, Janish; Tepper, James M.

    2013-01-01

    Using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the tyrosine hydroxylase (TH) promoter, we have previously shown that there are approximately 3000 striatal EGFP-TH interneurons per hemisphere in mice. Here we report that striatal TH-EGFP interneurons exhibit a small, transient but significant increase in number after unilateral destruction of the nigrostriatal dopaminergic pathway. The increase in cell number is accompanied by electrophysiological and morphological changes. The intrinsic electrophysiological properties of EGFP-TH interneurons ipsilateral to 6-OHDA lesion were similar to those originally reported in intact mice except for a significant reduction in the duration of a characteristic depolarization induced plateau potential. There was a significant change in the distribution of the four previously described electrophysiologically distinct subtypes of striatal TH interneurons. There was a concomitant increase in the frequency of both spontaneous excitatory and inhibitory postsynaptic currents, while their amplitudes did not change. Nigrostriatal lesions did not affect somatic size or dendritic length or branching, but resulted in an increase in the density of proximal dendritic spines and spine-like appendages in EGFP-TH interneurons. The changes indicate that electrophysiology properties and morphology of striatal EGFP-TH interneurons depend on endogenous levels of dopamine arising from the nigrostriatal pathway. Furthermore, these changes may serve to help compensate for the changes in activity of spiny projection neurons that occur following loss of the nigrostriatal innervation in experimental or in early idiopathic Parkinson’s disease by increasing feedforward GABAergic inhibition exerted by these interneurons. PMID:24173616

  10. Locomotion of aged rats: relationship to neurochemical but not morphological changes in nigrostriatal dopaminergic neurons.

    PubMed

    Emerich, D F; McDermott, P; Krueger, P; Banks, M; Zhao, J; Marszalkowski, J; Frydel, B; Winn, S R; Sanberg, P R

    1993-01-01

    Spontaneous locomotion and motor coordination was evaluated in young (5-6 month old) and aged (24-25 month old) rats. Animals were tested for spontaneous locomotor activity in Digiscan Animal Activity Monitors during the nocturnal cycle. Aged animals exhibited a significant hypoactivity compared to their young counterparts. Evaluation of the time course of activity revealed that the young animals had a cyclical pattern of activity during the 12-hour testing period with clear peaks at 2-4 hours after the initiation of testing and at 8- to 10-hour intervals thereafter. In contrast, the aged animals exhibited a blunted initial activity peak. During the remainder of the test period the aged animals activity was stable with no further peaks in activity. Compared to the young animals the aged animals also (a) remained suspended from a horizontal wire for less time, (b) were unable to descend a wooden pole covered with wire mesh in a coordinated manner, (c) fell more rapidly from a rotating rod and (d) were unable to maintain their balance on a series of wooden beams with either a square or rounded top of varying widths. Histological analysis demonstrated that there was no reduction in the number, area, or length of tyrosine hydroxylase-immunoreactive neurons within the A8, A9, or A10 region of the aged animals. Neurochemical analysis revealed that while DA and HVA levels were not decreased in the aged rats, DOPAC levels, as well as the ratios of DA/DOPAC and DA/HVA, were decreased. These results indicate that neurochemical but not morphological changes within the nigrostriatal dopaminergic system underlie the deficits in motor behavior observed in aged rats.

  11. Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

    PubMed Central

    Hutson, Che Brown; Lazo, Carlos R.; Mortazavi, Farzad; Giza, Christopher C.; Hovda, David

    2011-01-01

    Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk. PMID:21644813

  12. Chronic organic manganese administration in the rat does not damage dopaminergic nigrostriatal neurons.

    PubMed

    Yong, V W; Perry, T L; Godolphin, W J; Jones, K A; Clavier, R M; Ito, M; Foulks, J G

    1986-01-01

    In an attempt to produce an animal model of Parkinson's disease, we injected rats repeatedly with high doses of methylcyclopentadienyl manganese tricarbonyl (MMT), a compound which has been reported to lower striatal dopamine content in mice. Chronic MMT administration for up to 5 months, even though it produced a substantial elevation in brain manganese content during the period of exposure, did not destroy dopaminergic nigrostriatal neurons. This was assessed by measurements of tyrosine hydroxylase activity and contents of dopamine and its metabolites in the striatum, and by histological examination of the substantia nigra. Our results differ from those of others who administered manganese chloride in drinking water to rats. This discrepancy is unlikely to be a consequence of differences in duration of exposure or route of administration. It could be due to our having used an organic rather than an inorganic manganese compound, or to a species difference in vulnerability to organic manganese between rats and mice.

  13. Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life

    PubMed Central

    Fan, Lir-Wan; Tien, Lu-Tai; Lin, Rick C. S.; Simpson, Kimberly L.; Rhodes, Philip G.; Cai, Zhengwei

    2011-01-01

    Brain inflammation in early life has been proposed to play important roles in the development of neurodegenerative disorders in adult life. To test this hypothesis, we used a neonatal rat model of lipopolysaccharide (LPS) exposure (1,000 EU/g body weight, intracerebral injection on P5) to produce brain inflammation. By P70, when LPS-induced behavioral deficits were spontaneously recovered, animals were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25 mg/kg per day for 14 days. This rotenone treatment regimen ordinarily does not produce toxic effects on behaviors in normal adult rats. Our results show that neonatal LPS exposure enhanced vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Rotenone treatment resulted in motor neurobehavioral impairments in rats with the neonatal LPS exposure, but not in those without the neonatal LPS exposure. Rotenone induced losses of tyrosine hydroxylase immunoreactive neurons in the substantia nigra and decreased mitochondrial complex I activity in the striatum of rats with neonatal LPS exposure, but not in those without this exposure. Neonatal LPS exposure with later exposure to rotenone decreased retrogradely labeled nigrostriatal dopaminergic projecting neurons. The current study suggests that perinatal brain inflammation may enhance adult susceptibility to the development of neurodegenerative disorders triggered later on by environmental toxins at an ordinarily non-toxic or sub-toxic dose. Our model may be useful for studying mechanisms involved in the pathogenesis of nonfamilial Parkinson’s disease and the development of potential therapeutic treatments. PMID:21798348

  14. Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life.

    PubMed

    Fan, Lir-Wan; Tien, Lu-Tai; Lin, Rick C S; Simpson, Kimberly L; Rhodes, Philip G; Cai, Zhengwei

    2011-12-01

    Brain inflammation in early life has been proposed to play important roles in the development of neurodegenerative disorders in adult life. To test this hypothesis, we used a neonatal rat model of lipopolysaccharide (LPS) exposure (1000 EU/g body weight, intracerebral injection on P5) to produce brain inflammation. By P70, when LPS-induced behavioral deficits were spontaneously recovered, animals were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25 mg/kg per day for 14 days. This rotenone treatment regimen ordinarily does not produce toxic effects on behaviors in normal adult rats. Our results show that neonatal LPS exposure enhanced the vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Rotenone treatment resulted in motor neurobehavioral impairments in rats with the neonatal LPS exposure, but not in those without the neonatal LPS exposure. Rotenone induced losses of tyrosine hydroxylase immunoreactive neurons in the substantia nigra and decreased mitochondrial complex I activity in the striatum of rats with neonatal LPS exposure, but not in those without this exposure. Neonatal LPS exposure with later exposure to rotenone decreased retrogradely labeled nigrostriatal dopaminergic projecting neurons. The current study suggests that perinatal brain inflammation may enhance adult susceptibility to the development of neurodegenerative disorders triggered later on by environmental toxins at an ordinarily non-toxic or sub-toxic dose. Our model may be useful for studying mechanisms involved in the pathogenesis of nonfamilial Parkinson's disease and the development of potential therapeutic treatments. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Mesolimbic and Nigrostriatal Dopaminergic Systems: Behavioral Neuropharmacology.

    DTIC Science & Technology

    1985-08-01

    entopeduncular nucleus of the rat is similar to the internal segment of the globus pallidus in primates and humans), and thence to the ventral nuclei of the...slightly modified from existing methods (Moore and Phillipson 1975; Umez-1 and Moore 1979; Osterburg et al. 1981). Brain tissue was weighed and homogenized...of 0.1 M sodium phosphate buffer containing 10 mM EGTA, pH 7.0, and 90 ul of catechol-O- methyltransferase prepared as described previously (Moore and

  16. The nigrostriatal dopamine system of aging GFRalpha-1 heterozygous mice: neurochemistry, morphology and behavior.

    PubMed

    Zaman, Vandana; Boger, Heather A; Granholm, Ann-Charlotte; Rohrer, Baerbel; Moore, Alfred; Buhusi, Mona; Gerhardt, Greg A; Hoffer, Barry J; Middaugh, Lawrence D

    2008-10-01

    Given the established importance of glial cell line-derived neurotrophic factor (GDNF) in maintaining dopaminergic neurotransmitter systems, the nigrostriatal system and associated behaviors of mice with genetic reduction of its high-affinity receptor, GDNF receptor (GFR)alpha-1 (GFRalpha-1(+/-)), were compared with wild-type controls. Motor activity and the stimulatory effects of a dopamine (DA) D1 receptor agonist (SKF 82958) were assessed longitudinally at 8 and 18 months of age. Monoamine concentrations and dopaminergic nerve terminals in the striatum and the number of dopaminergic neurons in the substantia nigra (SN) were assessed. The results support the importance of GFRalpha-1 in maintaining normal function of the nigrostriatal dopaminergic system, with deficits being observed for GFRalpha-1(+/-) mice at both ages. Motor activity was lower and the stimulatory effects of the DA agonist were enhanced for the older GFRalpha-1(+/-) mice. DA in the striatum was reduced in the GFRalpha-1(+/-) mice at both ages, and tyrosine hydroxylase-positive cell numbers in the SN were reduced most substantially in the older GFRalpha-1(+/-) mice. The combined behavioral, pharmacological probe, neurochemical and morphological measures provide evidence of abnormalities in GFRalpha-1(+/-) mice that are indicative of an exacerbated aging-related decline in dopaminergic system function. The noted deficiencies, in turn, suggest that GFRalpha-1 is necessary for GDNF to maintain normal function of the nigrostriatal dopaminergic system. Although the precise mechanism(s) for the aging-related changes in the dopaminergic system remain to be established, the present study clearly establishes that genetic reductions in GFRalpha-1 can contribute to the degenerative changes observed in this system during the aging process.

  17. Estrogenic modulation of delta(9)-Tetrahydrocannabinol effects on nigrostriatal dopaminergic activity in the female rat brain.

    PubMed

    Bonnin, A; Ferández-Ruiz, J J; Martín, M; De Fonseca, F R; De Miguel, R; Ramos, J A

    1992-08-01

    In this work we studied the possible estrogenic modulation of the effects of delta(9)-tetrahydrocannabinol (THC) on nigrostriatal dopaminergic activity. Thus, we examined the effects of an acute dose of this cannabinoid: (i) during the three phases of the estrous cycle; (ii) after ovariectomy, chronic estrogen replacement, and/or tamoxifen (TMX)-induced blockade of cytosolic estrogenic receptors; and (iii) combined with a single and physiological injection of estradiol to ovariectomized rats, whose effects were measured early, with no time for genomic induction. THC increased the activity of tyrosine hydroxylase in the striatum of ovariectomized rats implanted with estradiol-filled Silastic capsules or ovariectomized rats. This effect: (i) depended on the presence of an intact estrogenic receptor mechanism, because it was prevented by pretreatment with TMX, and (ii) did not appear when THC was coadministered with estradiol, suggesting an inhibitory modulation of cannabinoid effect by the nongenomic mechanism of action of this steroid. The striatal content of l-3,4-dihydroxyphenylacetic acid and its ratio with dopamine content, which can be used as an index of neuronal activity, also increased following acute THC administration. However, this effect was seen only in ovariectomized rats without estrogen replacement. The administration of THC in combination with a single estradiol injection or to estradiol-implanted ovariectomized rats was ineffective for both parameters. All these effects appeared after ovariectomy with/without estrogen replacement. However, we did not observe any statistically significant effects when THC was administered to normal cycling rats during each phase of the estrous cycle. This observation might be related to the fact that the affinity of striatal cannabinoid receptors, which are the main candidates to mediate cannabinoid effects on this area, significantly increased after ovariectomy compared with that measured in normal cycling rats. In

  18. Selective Vulnerability in Striosomes and in the Nigrostriatal Dopaminergic Pathway After Methamphetamine Administration

    PubMed Central

    Granado, Noelia; Ares-Santos, Sara; O’Shea, Esther; Vicario-Abejón, Carlos; Colado, M. Isabel

    2009-01-01

    Methamphetamine (METH), a commonly abused psychostimulant, causes dopamine neurotoxicity in humans, rodents, and nonhuman primates. This study examined the selective neuroanatomical pattern of dopaminergic neurotoxicity induced by METH in the mouse striatum. We examined the effect of METH on tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity in the different compartments of the striatum and in the nucleus accumbens. The levels of dopamine and its metabolites, 3,4-dihidroxyphenylacetic acid and homovanillic acid, as well as serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid, were also quantified in the striatum. Mice were given three injections of METH (4 mg/kg, i.p.) at 3 h intervals and sacrificed 7 days later. This repeated METH injection induced a hyperthermic response and a decrease in striatal concentrations of dopamine and its metabolites without affecting 5-HT concentrations. In addition, the drug caused a reduction in TH- and DAT-immunoreactivity when compared to saline-treated animals. Interestingly, there was a significantly greater loss of TH- and DAT-immunoreactivity in striosomes than in the matrix. The predominant loss of dopaminergic terminals in the striosomes occurred along the rostrocaudal axis of the striatum. In contrast, METH did not decrease TH- or DAT-immunoreactivity in the nucleus accumbens. These results provide the first evidence that compartments of the mouse striatum, striosomes and matrix, and mesolimbic and nigrostriatal pathways have different vulnerability to METH. This pattern is similar to that observed with other neurotoxins such as MPTP, the most widely used model of Parkinson’s disease, in early Huntington’s disease and hypoxic/ischemic injury, suggesting that these conditions might share mechanisms of neurotoxicity. PMID:19760475

  19. Paradoxical sleep deprivation modulates tyrosine hydroxylase expression in the nigrostriatal pathway and attenuates motor deficits induced by dopaminergic depletion.

    PubMed

    Lima, Marcelo M S; Andersen, Monica L; Reksidler, Angela B; Ferraz, Anete C; Vital, Maria A B F; Tufik, Sergio

    2012-06-01

    The nigrostriatal pathway is very likely involved in sleep regulation, considering the occurrence and high prevalence of sleep-related disorders in patients with Parkinson's disease. Indeed, dopaminergic neurons in the ventral tegmental area were recently shown to fire in bursts during paradoxical sleep (PS), but little is known about the activity of the nigrostriatal dopamine (DA) cells in relation to PS. In view of that we hypothesized that paradoxical sleep deprivation (PSD) may play a relevant role in nigrostriatal tyrosine hydroxylase (TH) expression and, subsequently, in sleep rebound. The present study was designed to determine the effects of PSD in the nigrostriatal pathway in mice by means of neurochemical and behavioral approaches. Intraperitoneal reserpine (1 mg/kg) associated to α-methyl-p-tyrosine (αMT) (250 mg/kg) to produce catecholamine depletion, or rotenone (10 mg/kg) to increase striatal DA turnover were injected 30 min before the 24 h of PSD. Catalepsy and open-field tests indicated that motor deficits induced by reserpine-αMT were counteracted by PSD, which, in contrast, potentiated the motor impairment induced by rotenone. Besides, PSD produced down-regulation on TH expression within the substantia nigra pars compacta and striatum, without affecting the number or the optical density of dopaminergic neurons present in the respective areas. Interestingly, PSD potentiated the downregulation of TH expression in the substantia nigra pars compacta and striatum induced by the co-administration of reserpine-αMT. These results reinforce the notion of a strong participation of DA in PS, as a consequence of the modulation of TH protein expression in the nigrostriatal pathway.

  20. Ectopic pregnancy-derived human trophoblastic stem cells regenerate dopaminergic nigrostriatal pathway to treat parkinsonian rats.

    PubMed

    Lee, Tony Tung-Yin; Tsai, Cheng-Fang; Hsieh, Tsung-Hsun; Chen, Jia-Jin Jason; Wang, Yu-Chih; Kao, Mi-Chun; Wu, Ruey-Meei; Singh, Sher; Tsai, Eing-Mei; Lee, Jau-Nan

    2012-01-01

    Stem cell therapy is a potential strategy to treat patients with Parkinson's disease (PD); however, several practical limitations remain. As such, finding the appropriate stem cell remains the primary issue in regenerative medicine today. We isolated a pre-placental pluripotent stem cell from the chorionic villi of women with early tubal ectopic pregnancies. Our objectives in this study were (i) to identify the characteristics of hTS cells as a potential cell source for therapy; and (ii) to test if hTS cells can be used as a potential therapeutic strategy for PD. hTS cells expressed gene markers of both the trophectoderm (TE) and the inner cell mass (ICM). hTS cells exhibited genetic and biological characteristics similar to that of hES cells, yet genetically distinct from placenta-derived mesenchymal stem cells. All-trans retinoic acid (RA) efficiently induced hTS cells into trophoblast neural stem cells (tNSCs) in 1-day. Overexpression of transcription factor Nanog was possibly achieved through a RA-induced non-genomic c-Src/Stat3/Nanog signaling pathway mediated by the subcellular c-Src mRNA localization for the maintenance of pluripotency in tNSCs. tNSC transplantation into the lesioned striatum of acute and chronic PD rats not only improved behavioral deficits but also regenerated dopaminergic neurons in the nigrostriatal pathway, evidenced by immunofluorescent and immunohistological analyses at 18-weeks. Furthermore, tNSCs showed immunological advantages for the application in regenerative medicine. We successfully isolated and characterized the unique ectopic pregnancy-derived hTS cells. hTS cells are pluripotent stem cells that can be efficiently induced to tNSCs with positive results in PD rat models. Our data suggest that the hTS cell is a dynamic stem cell platform that is potentially suitable for use in disease models, drug discovery, and cell therapy such as PD.

  1. MMP-3 contributes to nigrostriatal dopaminergic neuronal loss, BBB damage, and neuroinflammation in an MPTP mouse model of Parkinson's disease.

    PubMed

    Chung, Young Cheul; Kim, Yoon-Seong; Bok, Eugene; Yune, Tae Young; Maeng, Sungho; Jin, Byung Kwan

    2013-01-01

    The present study examined whether matrix metalloproteinase-3 (MMP-3) participates in the loss of dopaminergic (DA) neurons in the nigrostriatal pathway in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease with blood brain barrier (BBB) damage and infiltration of peripheral immune cells. Tyrosine hydroxylase (TH) immunostaining of brain sections from MPTP-treated mice showed that MPTP induced significant degeneration of nigrostriatal DA neurons. Moreover, FITC-labeled albumin detection and immunostaining revealed that MPTP caused damage to the BBB and increased the number of ED-1- and CD-3-immunopositive cells in the substantia nigra (SN). Genetic ablation of MMP-3 reduced the nigrostriatal DA neuron loss and improved motor function. This neuroprotective effect afforded by MMP-3 deletion was associated with the suppression of BBB disruption and a decrease in the number of ED-1- and CD-3-immunopositive cells in the SN. These data suggest that MMP-3 could play a crucial role in neurodegenerative diseases such as PD in which BBB damage and neuroinflammation are implicated.

  2. Effect of prenatal lead exposure on nigrostriatal neurotransmission and hydroxyl radical formation in rat neostriatum: dopaminergic-nitrergic interaction.

    PubMed

    Nowak, Przemysław; Szczerbak, Grazyna; Nitka, Dariusz; Kostrzewa, Richard M; Sitkiewicz, Tomasz; Brus, Ryszard

    2008-04-03

    The present study was designed to explore the role of ontogenetic lead (Pb(2+)) exposure on a putative dopaminergic-nitrergic interaction in the nigrostriatal pathway. Pregnant Wistar rats were given tap water containing 250-ppm lead acetate, for the duration of pregnancy, with regular tap water (without Pb(2+)) being substituted at birth. Control rats were derived from dams that consumed tap water throughout pregnancy, and had no exposure to Pb(2+) afterwards. At 12 weeks after birth in vivo microdialysis of the neostriatum was employed to demonstrate that maternal Pb(2+) exposure was without effect on the baseline dopamine (DA) microdialysate concentration as well as amphetamine (AMPH, 1.0mg/kg i.p.)-evoked release of striatal DA. Also, prenatal Pb(2+) exposure did not enhance AMPH- and 7-nitroindazole (neuronal nitric oxide synthase inhibitor) (7-NI, 20mg/kg i.p.)-induced hydroxyl radical (HO) formation in the striatum, as indicated by analysis of the salicylate spin-trap product 2,5-dihydroxybenzoic acid. However, in rats exposed prenatally to Pb(2+), the facilitatory effect of 7-NI on DA exocytosis was attenuated. On the basis of the current study we conclude that maternal Pb(2+) exposure distorts the dopaminergic-nitrergic interaction in the nigrostriatal pathway, but without involvement of reactive oxygen species (ROS).

  3. Persistent nigrostriatal dopaminergic abnormalities in ex-users of MDMA ('Ecstasy'): an 18F-dopa PET study.

    PubMed

    Tai, Yen F; Hoshi, Rosa; Brignell, Catherine M; Cohen, Lisa; Brooks, David J; Curran, H Valerie; Piccini, Paola

    2011-03-01

    Ecstasy (±3,4-methylenedioxymethamphetamine, MDMA) is a popular recreational drug with known serotonergic neurotoxicity. Its long-term effects on dopaminergic function are less certain. Studying the long-term effects of ecstasy is often confounded by concomitant polydrug use and the short duration of abstinence. We used (18)F-dopa positron emission tomography (PET) to investigate the long-term effects of ecstasy on nigrostriatal dopaminergic function in a group of male ex-recreational users of ecstasy who had been abstinent for a mean of 3.22 years. We studied 14 ex-ecstasy users (EEs), 14 polydrug-using controls (PCs) (matched to the ex-users for other recreational drug use), and 12 drug-naive controls (DCs). Each participant underwent one (18)F-dopa PET, cognitive assessments, and hair and urinary analyses to corroborate drug-use history. The putamen (18)F-dopa uptake of EEs was 9% higher than that of DCs (p=0.021). The putamen uptake rate of PCs fell between the other two groups, suggesting that the hyperdopaminergic state in EEs may be due to the combined effects of ecstasy and polydrug use. There was no relationship between the amount of ecstasy used and striatal (18)F-dopa uptake. Increased putaminal (18)F-dopa uptake in EEs after an abstinence of >3 years (mean) suggests that the effects are long lasting. Our findings suggest potential long-term effects of ecstasy use, in conjunction with other recreational drugs, on nigrostriatal dopaminergic functions. Further longitudinal studies are required to elucidate the significance of these findings as they may have important public health implications.

  4. Persistent Nigrostriatal Dopaminergic Abnormalities in Ex-Users of MDMA (‘Ecstasy'): An 18F-Dopa PET Study

    PubMed Central

    Tai, Yen F; Hoshi, Rosa; Brignell, Catherine M; Cohen, Lisa; Brooks, David J; Curran, H Valerie; Piccini, Paola

    2011-01-01

    Ecstasy (±3,4-methylenedioxymethamphetamine, MDMA) is a popular recreational drug with known serotonergic neurotoxicity. Its long-term effects on dopaminergic function are less certain. Studying the long-term effects of ecstasy is often confounded by concomitant polydrug use and the short duration of abstinence. We used 18F-dopa positron emission tomography (PET) to investigate the long-term effects of ecstasy on nigrostriatal dopaminergic function in a group of male ex-recreational users of ecstasy who had been abstinent for a mean of 3.22 years. We studied 14 ex-ecstasy users (EEs), 14 polydrug-using controls (PCs) (matched to the ex-users for other recreational drug use), and 12 drug-naive controls (DCs). Each participant underwent one 18F-dopa PET, cognitive assessments, and hair and urinary analyses to corroborate drug-use history. The putamen 18F-dopa uptake of EEs was 9% higher than that of DCs (p=0.021). The putamen uptake rate of PCs fell between the other two groups, suggesting that the hyperdopaminergic state in EEs may be due to the combined effects of ecstasy and polydrug use. There was no relationship between the amount of ecstasy used and striatal 18F-dopa uptake. Increased putaminal 18F-dopa uptake in EEs after an abstinence of >3 years (mean) suggests that the effects are long lasting. Our findings suggest potential long-term effects of ecstasy use, in conjunction with other recreational drugs, on nigrostriatal dopaminergic functions. Further longitudinal studies are required to elucidate the significance of these findings as they may have important public health implications. PMID:21160467

  5. Mitochondrial Permeability Transition Pore Component Cyclophilin D Distinguishes Nigrostriatal Dopaminergic Death Paradigms in the MPTP Mouse Model of Parkinson's Disease

    PubMed Central

    Banerjee, Rebecca; Starkova, Natalia N.; Zhang, Steven F.; Calingasan, Noel Y.; Yang, Lichuan; Wille, Elizabeth; Lorenzo, Beverly J.; Ho, Daniel J.; Beal, M. Flint

    2012-01-01

    Abstract Aims: Mitochondrial damage due to Ca2+ overload-induced opening of permeability transition pores (PTP) is believed to play a role in selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Genetic ablation of mitochondrial matrix protein cyclophilin D (CYPD) has been shown to increase Ca2+ threshold of PTP in vitro and to prevent cell death in several in vivo disease models. We investigated the role of CYPD in a mouse model of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. Results: We demonstrate that in vitro, brain mitochondria isolated from CYPD knockout mice were less sensitive to MPP+ (1-methyl-4-phenyl-pyridinium ion)-induced membrane depolarization, and free radical generation compared to wild-type mice. CYPD knockout mitochondria isolated from ventral midbrain of mice treated with MPTP in vivo exhibited less damage as judged from respiratory chain Complex I activity, State 3 respiration rate, and respiratory control index than wild-type mice, whereas assessment of apoptotic markers showed no differences between the two genotypes. However, CYPD knockout mice were significantly resistant only to an acute regimen of MPTP neurotoxicity in contrast to the subacute and chronic MPTP paradigms. Innovation: Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity. Conclusion: Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity. Antioxid. Redox Signal. 16, 855–868. PMID:21529244

  6. Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease.

    PubMed

    Thomas, Bobby; Banerjee, Rebecca; Starkova, Natalia N; Zhang, Steven F; Calingasan, Noel Y; Yang, Lichuan; Wille, Elizabeth; Lorenzo, Beverly J; Ho, Daniel J; Beal, M Flint; Starkov, Anatoly

    2012-05-01

    Mitochondrial damage due to Ca(2+) overload-induced opening of permeability transition pores (PTP) is believed to play a role in selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Genetic ablation of mitochondrial matrix protein cyclophilin D (CYPD) has been shown to increase Ca(2+) threshold of PTP in vitro and to prevent cell death in several in vivo disease models. We investigated the role of CYPD in a mouse model of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. We demonstrate that in vitro, brain mitochondria isolated from CYPD knockout mice were less sensitive to MPP+ (1-methyl-4-phenyl-pyridinium ion)-induced membrane depolarization, and free radical generation compared to wild-type mice. CYPD knockout mitochondria isolated from ventral midbrain of mice treated with MPTP in vivo exhibited less damage as judged from respiratory chain Complex I activity, State 3 respiration rate, and respiratory control index than wild-type mice, whereas assessment of apoptotic markers showed no differences between the two genotypes. However, CYPD knockout mice were significantly resistant only to an acute regimen of MPTP neurotoxicity in contrast to the subacute and chronic MPTP paradigms. Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity. Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity.

  7. Selective destruction of nigrostriatal dopaminergic neurons does not alter [3H]-ryanodine binding in rat striatum.

    PubMed

    Noël, F; Geurts, M; Maloteaux, J M

    2000-02-01

    Dopamine nigrostriatal neurons are important for motor control and may contain a particularly dense population of ryanodine receptors involved in the control of dopamine release. To test this hypothesis, we used a classical model of unilateral selective lesion of these neurons in rats based on 6-hydroxydopamine (6-OHDA) injection into the substantia nigra. Binding of [3H]-GBR 12935, used as a presynaptic marker since it labels specifically the dopamine uptake complex, was dramatically decreased by 83-100% in striatum homogenates after 6-OHDA lesion. On the contrary, no reduction of [3H]-ryanodine binding was observed. The present data indicate that [3H]-ryanodine binding sites present in rat striatum are not preferentially localized in dopaminergic terminals.

  8. Toxic influence of chronic oral administration of paraquat on nigrostriatal dopaminergic neurons in C57BL/6 mice.

    PubMed

    Ren, Jin-peng; Zhao, Yu-wu; Sun, Xiao-jiang

    2009-10-05

    Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium), a widely used herbicide, has been repeatedly suggested as a potential etiologic factor for the development of Parkinson's disease (PD), owing to its structural similarity to the known dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This study aimed to observe the influence of paraquat on nigrostriatal dopaminergic neurons in C57BL/6 mice. A total of 24 male C57BL/6 mice were assigned randomly to 3 groups: control group (treated by saline), PQ treated group, and MPTP treated group. Mice in PQ treated group were taken orally with PQ (10 mg/kg) daily for four months. Locomotor activity was measured. Level of dopamine (DA) and its metabolites levels in the striatum were measured by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD), and tyrosine hydroxylase (TH) positive neurons were detected by using immunohistochemistry. At the same time, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and the content of malondialdehyde (MDA) in substantia nigra were measured by spectrophotometry. mRNA expression of dopamine transporter (DAT) in dopaminergic neurons of substantia nigra was also determined by reverse transcription (RT)-PCR technique. Locomotor activities were significantly impaired in the PQ treated group. Level of DA and its metabolites levels in the striatum were declined. The activities of SOD and GSH-PX were decreased, and the content of MDA was increased in PQ treated mice compared with that in control group. Numbers of TH positive neurons and the mRNA expression of DAT in substantia nigra of mice were also decreased after PQ taken orally for four months. The present study suggests that chronic oral administration of PQ could trigger dopaminergic neuron degeneration. Oxidative stress could be involved in the pathogenic mechanism of PD induced by PQ.

  9. Overexpression of parkin in rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity

    PubMed Central

    Liu, Bin; Traini, Roberta; Killinger, Bryan; Schneider, Bernard; Moszczynska, Anna

    2013-01-01

    Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum, sparing other striatal terminals and cell bodies. We previously detected a deficit in parkin after binge METH in rat striatal synaptosomes. Parkin is an ubiquitin-protein E3 ligase capable of protecting dopamine neurons from diverse cellular insults. Whether the deficit in parkin mediates the toxicity of METH and whether parkin can protect from toxicity of the drug is unknown. The present study investigated whether overexpression of parkin attenuates degeneration of striatal dopaminergic terminals exposed to binge METH. Parkin overexpression in rat nigrostriatal dopamine system was achieved by microinjection of adeno-associated viral transfer vector 2/6 encoding rat parkin (AAV2/6-parkin) into the substantia nigra pars compacta. The microinjections of AAV2/6-parkin dose-dependently increased parkin levels in both the substantia nigra pars compacta and striatum. The levels of dopamine synthesizing enzyme, tyrosine hydroxylase, remained at the control levels; therefore, tyrosine hydroxylase immunoreactivity was used as an index of dopaminergic terminal integrity. In METH-exposed rats, the increase in parkin levels attenuated METH-induced decreases in striatal tyrosine hydroxylase immunoreactivity in a dose-dependent manner, indicating that parkin can protect striatal dopaminergic terminals against METH neurotoxicity. PMID:23313192

  10. Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity.

    PubMed

    Liu, Bin; Traini, Roberta; Killinger, Bryan; Schneider, Bernard; Moszczynska, Anna

    2013-09-01

    Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum, sparing other striatal terminals and cell bodies. We previously detected a deficit in parkin after binge METH in rat striatal synaptosomes. Parkin is an ubiquitin-protein E3 ligase capable of protecting dopamine neurons from diverse cellular insults. Whether the deficit in parkin mediates the toxicity of METH and whether parkin can protect from toxicity of the drug is unknown. The present study investigated whether overexpression of parkin attenuates degeneration of striatal dopaminergic terminals exposed to binge METH. Parkin overexpression in rat nigrostriatal dopamine system was achieved by microinjection of adeno-associated viral transfer vector 2/6 encoding rat parkin (AAV2/6-parkin) into the substantia nigra pars compacta. The microinjections of AAV2/6-parkin dose-dependently increased parkin levels in both the substantia nigra pars compacta and striatum. The levels of dopamine synthesizing enzyme, tyrosine hydroxylase, remained at the control levels; therefore, tyrosine hydroxylase immunoreactivity was used as an index of dopaminergic terminal integrity. In METH-exposed rats, the increase in parkin levels attenuated METH-induced decreases in striatal tyrosine hydroxylase immunoreactivity in a dose-dependent manner, indicating that parkin can protect striatal dopaminergic terminals against METH neurotoxicity. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Regeneration of nigrostriatal dopaminergic axons after transplantation of olfactory ensheathing cells and fibroblasts prevents fibrotic scar formation at the lesion site.

    PubMed

    Teng, Xichuan; Nagata, Isao; Li, Hong-Peng; Kimura-Kuroda, Junko; Sango, Kazunori; Kawamura, Koki; Raisman, Geoffrey; Kawano, Hitoshi

    2008-11-01

    The fibrotic scar formed after central nervous system injury has been considered an obstacle to axonal regeneration. The present study was designed to examine whether cell transplantation into a damaged central nervous system can reduce fibrotic scar formation and promote axonal regeneration. Nigrostriatal dopaminergic axons were unilaterally transected in rats and cultures of olfactory-ensheathing cells (OECs), and olfactory nerve fibroblasts were transplanted into the lesion site. In the absence of transplants, few tyrosine hydroxylase-immunoreactive axons extended across the lesion 2 weeks after the transection. Reactive astrocytes increased around the lesion, and a fibrotic scar containing type IV collagen deposits developed in the lesion center. The immunoreactivity of chondroitin sulfate side chains and core protein of NG2 proteoglycan increased in and around the lesion. One and 2 weeks after transection and simultaneous transplantation, dopaminergic axons regenerated across the transplanted tissues, which consisted of p75-immunoreactive OECs and fibronectin-immunoreactive fibroblasts. Reactive astrocytes and chondroitin sulfate immunoreactivity increased around the transplants, whereas the deposition of type IV collagen and fibrotic scar formation were completely prevented at the lesion site. Transplantation of meningeal fibroblasts similarly prevented the formation of the fibrotic scar, although its effect on regeneration was less potent than transplantation of OECs and olfactory nerve fibroblasts. The present results suggest that elimination of the inhibitory fibrotic scar is important for neural regeneration.

  12. GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function

    PubMed Central

    Horvath, Tamas L.; Erion, Derek M.; Elsworth, John D.; Roth, Robert H.; Shulman, Gerald I.; Andrews, Zane B.

    2012-01-01

    Guanidinopropionic acid (GPA) increases AMPK activity, mitochondrial function and biogenesis in muscle and improves physiological function, for example during aging. Mitochondrial dysfunction is a major contributor to the pathogenesis of Parkinson’s disease. Here we tested whether GPA prevents neurodegeneration of the nigrostriatal dopamine system in MPTP-treated mice. Mice were fed a diet of 1% GPA or normal chow for 4 weeks and then treated with either MPTP or saline. Indices of nigrostriatal function were examined by HPLC, immunohistochemistry, stereology, electron microscopy and mitochondrial respiration. MPTP intoxication decreased TH neurons in the SNpc of normal chow-fed mice, however GPA-fed mice remarkably exhibited no loss of TH neurons in the SNpc. MPTP caused a decrease in striatal dopamine of both normal chow- and GPA-fed mice, although this effect was significantly attenuated in GPA-fed mice. GPA-fed mice showed increased AMPK activity, mitochondrial respiration and mitochondrial number in nigrostriatal TH neurons, suggesting the neuroprotective effects of GPA involved AMPK-dependent increases in mitochondrial function and biogenesis. MPTP treatment produced a decrease in mitochondrial number and volume in normal chow-fed mice but not GPA-fed mice. Our results show the neuroprotective properties of GPA in a mouse model of Parkinson’s disease are partially mediated by AMPK and mitochondrial function. Mitochondrial dysfunction is a common problem in neurodegeneration and thus GPA may slow disease progression in other models of neurodegeneration. PMID:21406233

  13. GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function.

    PubMed

    Horvath, Tamas L; Erion, Derek M; Elsworth, John D; Roth, Robert H; Shulman, Gerald I; Andrews, Zane B

    2011-07-01

    Guanidinopropionic acid (GPA) increases AMPK activity, mitochondrial function and biogenesis in muscle and improves physiological function, for example during aging. Mitochondrial dysfunction is a major contributor to the pathogenesis of Parkinson's disease. Here we tested whether GPA prevents neurodegeneration of the nigrostriatal dopamine system in MPTP-treated mice. Mice were fed a diet of 1% GPA or normal chow for 4 weeks and then treated with either MPTP or saline. Indices of nigrostriatal function were examined by HPLC, immunohistochemistry, stereology, electron microscopy and mitochondrial respiration. MPTP intoxication decreased TH neurons in the SNpc of normal chow-fed mice; however GPA-fed mice remarkably exhibited no loss of TH neurons in the SNpc. MPTP caused a decrease in striatal dopamine of both normal chow- and GPA-fed mice, although this effect was significantly attenuated in GPA-fed mice. GPA-fed mice showed increased AMPK activity, mitochondrial respiration and mitochondrial number in nigrostriatal TH neurons, suggesting that the neuroprotective effects of GPA involved AMPK-dependent increases in mitochondrial function and biogenesis. MPTP treatment produced a decrease in mitochondrial number and volume in normal chow-fed mice but not GPA-fed mice. Our results show the neuroprotective properties of GPA in a mouse model of Parkinson's disease are partially mediated by AMPK and mitochondrial function. Mitochondrial dysfunction is a common problem in neurodegeneration and thus GPA may slow disease progression in other models of neurodegeneration. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Brain renin-angiotensin system and dopaminergic cell vulnerability

    PubMed Central

    Labandeira-García, Jose L.; Garrido-Gil, Pablo; Rodriguez-Pallares, Jannette; Valenzuela, Rita; Borrajo, Ana; Rodríguez-Perez, Ana I.

    2014-01-01

    Although the renin-angiotensin system (RAS) was classically considered as a circulating system that regulates blood pressure, many tissues are now known to have a local RAS. Angiotensin, via type 1 receptors, is a major activator of the NADPH-oxidase complex, which mediates several key events in oxidative stress (OS) and inflammatory processes involved in the pathogenesis of major aging-related diseases. Several studies have demonstrated the presence of RAS components in the basal ganglia, and particularly in the nigrostriatal system. In the nigrostriatal system, RAS hyperactivation, via NADPH-oxidase complex activation, exacerbates OS and the microglial inflammatory response and contributes to progression of dopaminergic degeneration, which is inhibited by angiotensin receptor blockers and angiotensin converting enzyme (ACE) inhibitors. Several factors may induce an increase in RAS activity in the dopaminergic system. A decrease in dopaminergic activity induces compensatory upregulation of local RAS function in both dopaminergic neurons and glia. In addition to its role as an essential neurotransmitter, dopamine may also modulate microglial inflammatory responses and neuronal OS via RAS. Important counterregulatory interactions between angiotensin and dopamine have also been observed in several peripheral tissues. Neurotoxins and proinflammatory factors may also act on astrocytes to induce an increase in RAS activity, either independently of or before the loss of dopamine. Consistent with a major role of RAS in dopaminergic vulnerability, increased RAS activity has been observed in the nigra of animal models of aging, menopause and chronic cerebral hypoperfusion, which also showed higher dopaminergic vulnerability. Manipulation of the brain RAS may constitute an effective neuroprotective strategy against dopaminergic vulnerability and progression of Parkinson’s disease. PMID:25071471

  15. Acetyl-l-carnitine protects dopaminergic nigrostriatal pathway in 6-hydroxydopamine-induced model of Parkinson's disease in the rat.

    PubMed

    Afshin-Majd, Siamak; Bashiri, Keyhan; Kiasalari, Zahra; Baluchnejadmojarad, Tourandokht; Sedaghat, Reza; Roghani, Mehrdad

    2017-02-12

    Parkinson's disease (PD) is a movement disorder and the second most common neurodegenerative disease worldwide in which nigrostriatal dopaminergic neurons within substantia nigra pars compacta (SNC) are lost, with clinical motor and non-motor symptoms including bradykinesia, resting tremor, rigidity, stooping posture and cognitive deficits. This study was undertaken to evaluate the neuroprotective potential of acetyl-l-carnitine (ALC) against unilateral striatal 6-hydroxydopamine (6-OHDA)-induced model of PD and to explore some involved mechanisms. In this experimental study, intrastriatal 6-OHDA-lesioned rats received ALC at doses of 100 or 200mg/kg/day for 1 week. ALC (200mg/kg) lowered apomorphine-induced rotational asymmetry and reduced the latency to initiate and the total time in the narrow beam test, reduced striatal malondialdehyde (MDA), increased catalase activity and glutathione (GSH) level, prevented reduction of nigral tyrosine hydroxylase (TH)-positive neurons and striatal TH-immunoreactivity, and lowered striatal glial fibrillary acidic protein (GFAP) and its immunoreactivity as an indicator of astrogliosis, and nuclear factor NF-kappa B and Toll-like receptor 4 (TLR4) as reliable markers of neuroinflammation. Meanwhile, ALC at both doses mitigated nigral DNA fragmentation as a valuable marker of apoptosis. The results of this study clearly suggest the neuroprotective effect of ALC in 6-OHDA-induced model of PD through abrogation of neuroinflammation, apoptosis, astrogliosis, and oxidative stress and it may be put forward as an ancillary therapeutic candidate for controlling PD.

  16. Progressive loss of nigrostriatal dopaminergic neurons induced by inflammatory responses to fipronil.

    PubMed

    Park, Jae Hyeon; Park, Youn Sun; Koh, Hyun Chul

    2016-09-06

    Inflammatory responses are involved in mechanisms of neuronal cell damage in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). We investigated the mechanisms whereby inflammatory responses contribute to loss of dopaminergic neurons in fipronil (FPN)-treated rats. After stereotaxic injection of FPN in the substantia nigra (SN), the number of tyrosine hydroxylase (TH)-positive neurons and the levels of TH expression in the SN decreased at 7days, and a significant decrease was observed at 14days with a subsequent reduction in striatal TH expression. Decreases in dopamine (DA) levels, however, began at 3days post-injection, preceding the changes in TH expression. In contrast, glial fibrillary acidic protein (GFAP) expression was significantly increased at 3days and persisted for up to 14days post-lesion; these changes in GFAP expression appeared to be inversely correlated with TH expression. Furthermore, we found that FPN administration induced an inflammatory response characterized by increased levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α), which was mediated by activated microglia following infusion of FPN unilaterally into the SN. Intranigral injection of FPN underwent an inflammatory response with a resultant ongoing loss of dopaminergic neurons, indicating that pesticides may have important implication for the study of PD. Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.

  17. A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment

    PubMed Central

    Fryer, Tim D.; Hong, Young T.; Smith, Rob; Brichard, Laurent; Acosta-Cabronero, Julio; Chamberlain, Samuel R.; Tait, Roger; Izquierdo, David; Regenthal, Ralf; Dowson, Jonathan; Suckling, John; Baron, Jean-Claude; Aigbirhio, Franklin I.; Robbins, Trevor W.; Sahakian, Barbara J.; Müller, Ulrich

    2013-01-01

    Through the combined use of 18F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto

  18. PET studies of the striatal dopaminergic system in Parkinson's disease (PD).

    PubMed

    Piccini, P; Turjanski, N; Brooks, D J

    1995-01-01

    Positron emission tomography (PET) is a functional imaging technique which allows detection of biochemical and pharmacological dysfunction of the nigrostriatal dopaminergic system and provides the opportunity to investigate living patients with PD. This paper reviews the contribution of PET studies to the understanding of neurochemical changes underlying Parkinson's disease.

  19. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease

    PubMed Central

    Reynolds, Ashley D.; Stone, David K.; Hutter, Jessica A.L.; Benner, Eric J.; Mosley, R. Lee; Gendelman, Howard E.

    2010-01-01

    Nitrated alpha synuclein (N-α-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated with CD4+CD25+ regulatory T cell (Treg) dysfunction seen amongst populations of N-α-syn induced T cells. In contrast, purified vasoactive intestinal peptide (VIP)-induced and natural Treg reversed N-α-syn T cell nigrostriatal degeneration. Combinations of adoptively transferred N-α-syn and VIP immunocytes or natural Treg administered to MPTP mice attenuated microglial inflammatory responses and led to robust nigrostriatal protection. Taken together, these results demonstrate a putative mechanism for Treg control of N-α-syn-induced neurodestructive immunity and as such provide a sound rationale for future PD immunization strategies. PMID:20118279

  20. Microglia-Derived Cytokines/Chemokines Are Involved in the Enhancement of LPS-Induced Loss of Nigrostriatal Dopaminergic Neurons in DJ-1 Knockout Mice

    PubMed Central

    Chien, Chia-Hung; Lee, Ming-Jen; Liou, Houng-Chi; Liou, Horng-Huei; Fu, Wen-Mei

    2016-01-01

    Mutation of DJ-1 (PARK7) has been linked to the development of early-onset Parkinson’s disease (PD). However, the underlying molecular mechanism is still unclear. This study is aimed to compare the sensitivity of nigrostriatal dopaminergic neurons to lipopolysaccharide (LPS) challenge between DJ-1 knockout (KO) and wild-type (WT) mice, and explore the underlying cellular and molecular mechanisms. Our results found that the basal levels of interferon (IFN)-γ (the hub cytokine) and interferon-inducible T-cell alpha chemoattractant (I-TAC) (a downstream mediator) were elevated in the substantia nigra of DJ-1 KO mice and in microglia cells with DJ-1 deficiency, and the release of cytokine/chemokine was greatly enhanced following LPS administration in the DJ-1 deficient conditions. In addition, direct intranigral LPS challenge caused a greater loss of nigrostriatal dopaminergic neurons and striatal dopamine content in DJ-1 KO mice than in WT mice. Furthermore, the sensitization of microglia cells to LPS challenge to release IFN-γ and I-TAC was via the enhancement of NF-κB signaling, which was antagonized by NF-κB inhibitors. LPS-induced increase in neuronal death in the neuron-glia co-culture was enhanced by DJ-1 deficiency in microglia, which was antagonized by the neutralizing antibodies against IFN-γ or I-TAC. These results indicate that DJ-1 deficiency sensitizes microglia cells to release IFN-γ and I-TAC and causes inflammatory damage to dopaminergic neurons. The interaction between the genetic defect (i.e. DJ-1) and inflammatory factors (e.g. LPS) may contribute to the development of PD. PMID:26982707

  1. The brain dopaminergic system. Pharmacological, behavioural and electrophysiological studies.

    PubMed

    Glenthøj, B Y

    1995-02-01

    The kindling phenomenon is a good example of the effect of multiplicity on response increment processes in the nervous system. The electrical potentiation resembles pharmacological sensitization. An intermittent regimen is essential for a progressive augmentation of the behavioural response in both conditions. Nigro-striatal dopaminergic sensitization by on and off anti-dopaminergic drugs has been suggested as a model for development of tardive dyskinesia (TD) and sensitization of the meso-limbic dopaminergic system either by repeated stimulation with agonists or by environmental stressors has been proposed to model psychotic development in schizophrenia. The present thesis addresses the implications of intermittent influences on the brain dopaminergic systems for the development of pathological behaviours. For this purpose new rat models have been developed both for studying the effects of the treatment schedule of neuroleptics on the development of oral hyperactivity and for studying the effects of intermittent electrical stimulations of the ventral tegmental area (VTA) housing the meso-limbic dopamine (DA) cells. A long-lasting/permanent kindling-like sensitization to the dyskinetic inducing side-effects of classical neuroleptic drugs following intermittent opposed to continuous treatment has been demonstrated. This sensitization is proposed to represent an animal model for TD. The significance of receptor profiles, the effects of pharmacological interventions and the possible relation to the GABAergic and cholinergic systems are discussed. Intermittent electrical activation of the cells in the VTA resulted in a syndrome characterized by a hypersensitive response to electrical or pharmacological dopaminergic provocation combined with abnormal social interactions. This new animal model may have implications for the understanding of the pathogenesis of schizophrenia. Hypotheses are proposed for the meaning of dopaminergic sensitization both in the development of

  2. The role of dopaminergic imaging in patients with symptoms of dopaminergic system neurodegeneration.

    PubMed

    Cummings, Jeffrey L; Henchcliffe, Claire; Schaier, Sharon; Simuni, Tanya; Waxman, Alan; Kemp, Paul

    2011-11-01

    Diagnosis of neurological and psychiatric conditions associated with disturbances of dopaminergic functioning can be challenging, especially in the early stages, and may be assisted with biomarkers such as dopamine system imaging. Distinguishing between Alzheimer's disease and dementia with Lewy bodies is a major diagnostic challenge. Clinical diagnosis of Parkinson's disease is straightforward with classic presentation, but accurate distinction among Parkinsonian variants may be difficult; non-Parkinson's disease conditions are commonly misdiagnosed as Parkinson's disease, and ~20% of patients with Parkinson's disease are not clinically diagnosed despite coming to medical attention. Early and accurate diagnosis is desirable to improve management. Imaging of the dopamine transporter using single-photon emission computed tomography may be of particular utility in this regard. Abnormal imaging indicates underlying nigrostriatal neurodegeneration, supportive of a diagnosis of Parkinson's disease, atypical parkinsonism or dementia with Lewy bodies, and identifies patient groups in whom dopaminergic therapy may be beneficial. Normal imaging supports diagnosis of a condition not involving nigrostriatal neurodegeneration such as Alzheimer's disease, essential tremor or drug-induced parkinsonism and hence a different therapeutic approach. In patients in whom there was diagnostic uncertainty between degenerative parkinsonism and non-degenerative tremor disorders, baseline imaging with the dopamine transporter ligand [(123)I]ioflupane (DaTscan™) has shown 78% sensitivity and 97% specificity with reference to clinical diagnosis at 3 years, versus 93% and 46%, respectively, for baseline clinical diagnosis. In a Phase III trial of [(123)I]ioflupane in patients with initial clinical diagnosis of probable or possible dementia with Lewy bodies or non-Lewy body dementia, mean specificity for excluding non-Lewy body dementia (predominantly Alzheimer's disease) was 90.4%. Using

  3. GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson’s disease

    PubMed Central

    d’Anglemont de Tassigny, Xavier; Pascual, Alberto; López-Barneo, José

    2015-01-01

    The glial cell line-derived neurotrophic factor (GDNF) is a well-established trophic agent for dopaminergic (DA) neurons in vitro and in vivo. GDNF is necessary for maintenance of neuronal morphological and neurochemical phenotype and protects DA neurons from toxic damage. Numerous studies on animal models of Parkinson’s disease (PD) have reported beneficial effects of GDNF on nigrostriatal DA neuron survival. However, translation of these observations to the clinical setting has been hampered so far by side effects associated with the chronic continuous intra-striatal infusion of recombinant GDNF. In addition, double blind and placebo-controlled clinical trials have not reported any clinically relevant effect of GDNF on PD patients. In the past few years, experiments with conditional Gdnf knockout mice have suggested that GDNF is necessary for maintenance of DA neurons in adulthood. In parallel, new methodologies for exogenous GDNF delivery have been developed. Recently, it has been shown that a small population of scattered, electrically interconnected, parvalbumin positive (PV+) GABAergic interneurons is responsible for most of the GDNF produced in the rodent striatum. In addition, cholinergic striatal interneurons appear to be also involved in the modulation of striatal GDNF. In this review, we summarize current knowledge on brain GDNF delivery, homeostasis, and its effects on nigrostriatal DA neurons. Special attention is paid to the therapeutic potential of endogenous GDNF stimulation in PD. PMID:25762899

  4. Inflammation and B-cell Lymphoma-2 Associated X Protein Regulate Zinc-Induced Apoptotic Degeneration of Rat Nigrostriatal Dopaminergic Neurons.

    PubMed

    Chauhan, Amit Kumar; Mittra, Namrata; Kumar, Vinod; Patel, Devendra Kumar; Singh, Chetna

    2016-10-01

    Clinical evidences showing zinc (Zn) accumulation in the post-mortem brain of Parkinson's disease (PD) patients and experimental studies on rodents chronically exposed to Zn suggested its role in PD. While oxidative stress is implicated in Zn-induced neurodegeneration, roles of inflammation and apoptosis in degeneration of the nigrostriatal dopaminergic neurons have yet been elusive. The present study investigated the contribution of the nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and B-cell lymphoma 2 (Bcl-2) family proteins in Zn-induced Parkinsonism. Male Wistar rats were treated with/without zinc sulfate (Zn; 20 mg/kg, intraperitoneally), twice a week, for 2-12 weeks. In a few sets, animals were treated intraperitoneally with a NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC; 100 mg/kg), a TNF-α inhibitor, pentoxyfylline (PTX; 50 mg/kg), and an anti-inflammatory agent, dexamethasone (DEX; 5 mg/kg), prior to Zn exposure along with respective controls. Zn caused neurobehavioral impairments and reduction in dopamine and its metabolites, tyrosine hydroxylase (TH)-positive neurons, catalase activity, and expression of TH, Bcl-2, and NOXA. On the contrary, Zn augmented lipid peroxidation, activity of superoxide dismutase, expression of TNF-α, IL-1β, Bcl-xl, and p53-upregulated modulator of apoptosis (PUMA), and translocation of NF-κB and Bax from the cytosol to the nucleus and mitochondria, respectively, with concomitant increase in the mitochondrial cytochrome c release and activation of procaspase-3 and -9. Pre-treatment with PTX, DEX, or PDTC invariably ameliorated Zn-induced changes in behavioral and neurodegenerative indexes, inflammatory mediators, and apoptosis. Results demonstrate that inflammation regulates Bax expression that subsequently contributes to the nigrostriatal dopaminergic neurodegeneration.

  5. Effects of L-DOPA/benserazide co-treatment on colonic excitatory cholinergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration.

    PubMed

    Pellegrini, C; Antonioli, L; Colucci, R; Tirotta, E; Gentile, D; Ippolito, C; Segnani, C; Levandis, G; Cerri, S; Blandini, F; Barocelli, E; Ballabeni, V; Bernardini, N; Blandizzi, C; Fornai, M

    2017-09-01

    The mainstay therapy for Parkinson's disease (PD) relies on L-3,4-dihydroxyphenylalanine (L-DOPA) plus a DOPA-decarboxylase inhibitor. However, their effects on colonic dysmotility and inflammation observed in PD are undetermined. This study examined the effects of L-DOPA plus benserazide (BE) on colonic motility and inflammation in rats with central nigrostriatal dopaminergic denervation. Neurodegeneration was induced by 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). 6-OHDA animals were treated orally with L-DOPA/BE for 28 days, starting 28 days after 6-OHDA injection. At the end of treatment, in vivo colonic transit was evaluated by a radiologic assay. Electrically stimulated (ES) cholinergic contractions were recorded in vitro from colonic preparations, while acetylcholine release was measured in the incubation medium. Choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) expression as well as eosinophil and mast cell density were examined in the colonic wall by immunohistochemistry. Colonic TNF and IL-1β levels were also assayed. 6-OHDA animals displayed: 1) decrease in in vivo colonic transit; 2) impairment of ES-stimulated cholinergic contractions; 3) decreased acetylcholine release from myenteric nerves; 4) decrease in ChAT and increase in GFAP myenteric immunopositivity; 5) increase in eosinophil and mast cell density; 6) increase in TNF and IL-1β levels. Treatment with L-DOPA/BE elicited an improvement of in vivo and in vitro colonic motor activity, a normalization of acetylcholine release, ChAT immunopositivity, as well as pro-inflammatory cytokine patterns, ganglionic GFAP levels, eosinophil and mast cell density. Under dopaminergic nigrostriatal denervation, treatment with L-DOPA/BE ameliorated colonic motility through a normalization of myenteric cholinergic neurotransmission, along with an improvement of colonic inflammation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: role of dopamine handling in neurotoxicity.

    PubMed

    Bradner, Joshua M; Suragh, Tiffany A; Wilson, W Wyatt; Lazo, Carlos R; Stout, Kristen A; Kim, Hye Mi; Wang, Min Z; Walker, Douglas I; Pennell, Kurt D; Richardson, Jason R; Miller, Gary W; Caudle, W Michael

    2013-03-01

    In the last several decades polybrominated diphenyl ethers (PBDEs) have replaced the previously banned polychlorinated biphenyls (PCBs) in multiple flame retardant utilities. As epidemiological and laboratory studies have suggested PCBs as a risk factor for Parkinson's disease (PD), the similarities between PBDEs and PCBs suggest that PBDEs have the potential to be neurotoxic to the dopamine system. The purpose of this study was to evaluate the neurotoxic effects of the PBDE mixture, DE-71, on the nigrostriatal dopamine system and address the role of altered dopamine handling in mediating this neurotoxicity. Using an in vitro model system we found DE-71 effectively caused cell death in a dopaminergic cell line as well as reducing the number of TH+ neurons isolated from VMAT2 WT and LO animals. Assessment of DE-71 neurotoxicity in vivo demonstrated significant deposition of PBDE congeners in the brains of mice, leading to reductions in striatal dopamine and dopamine handling, as well as reductions in the striatal dopamine transporter (DAT) and VMAT2. Additionally, DE-71 elicited a significant locomotor deficit in the VMAT2 WT and LO mice. However, no change was seen in TH expression in dopamine terminal or in the number of dopamine neurons in the substantia nigra pars compacta (SNpc). To date, these are the first data to demonstrate that exposure to PBDEs disrupts the nigrostriatal dopamine system. Given their similarities to PCBs, additional laboratory and epidemiological research should be considered to assess PBDEs as a potential risk factor for PD and other neurological disorders.

  7. Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons

    PubMed Central

    Aguirre, Pabla; Mena, Natalia P.; Carrasco, Carlos M.; Muñoz, Yorka; Pérez-Henríquez, Patricio; Morales, Rodrigo A.; Cassels, Bruce K.; Méndez-Gálvez, Carolina; García-Beltrán, Olimpo; González-Billault, Christian; Núñez, Marco T.

    2015-01-01

    Neuronal death in Parkinson’s disease (PD) is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2’-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH)-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death. PMID:26658949

  8. Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons.

    PubMed

    Aguirre, Pabla; Mena, Natalia P; Carrasco, Carlos M; Muñoz, Yorka; Pérez-Henríquez, Patricio; Morales, Rodrigo A; Cassels, Bruce K; Méndez-Gálvez, Carolina; García-Beltrán, Olimpo; González-Billault, Christian; Núñez, Marco T

    2015-01-01

    Neuronal death in Parkinson's disease (PD) is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2'-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH)-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death.

  9. Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration.

    PubMed

    Mathur, Brian N; Neely, M Diana; Dyllick-Brenzinger, Melanie; Tandon, Anurag; Deutch, Ariel Y

    2007-09-07

    Proteasomal dysfunction has been suggested to contribute to the degeneration of nigrostriatal dopamine neurons in Parkinson's disease. A recent study reported that systemic treatment of rats with the proteasome inhibitor Z-lle-Glu(OtBu)-Ala-Leu-al (PSI) causes a slowly progressive degeneration of nigrostriatal dopamine neurons, the presence of inclusion bodies in dopamine neurons, and motor impairment. We examined in vitro and in vivo the effects of PSI on nigrostriatal dopamine neurons. Mass spectrometric analysis was employed to verify the authenticity of the PSI compound. PSI was non-specifically toxic to neurons in ventral mesencephalic organotypic slice cultures, indicating that impairment of proteasome function in vitro is toxic. Moreover, systemic administration of PSI transiently decreased brain proteasome activity. Systemic treatment of rats with PSI did not, however, result in any biochemical or anatomical evidence of lesions of nigrostriatal dopamine neurons, nor were any changes in locomotor activity observed. These data suggest that systemic administration of proteasome inhibitors to normal adult rats does not reliably cause an animal model of parkinsonism.

  10. Exposure to the Polybrominated Diphenyl Ether Mixture DE-71 Damages the Nigrostriatal Dopamine System: Role of Dopamine Handling in Neurotoxicity

    PubMed Central

    Bradner, Joshua M.; Suragh, Tiffany A.; Wilson, W. Wyatt; Lazo, Carlos R.; Stout, Kristen A.; Kim, Hye Mi; Wang, Min Z.; Walker, Douglas I.; Pennell, Kurt D.; Richardson, Jason R.; Miller, Gary W.; Caudle, W. Michael

    2013-01-01

    In the last several decades polybrominated diphenyl ethers (PBDEs) have replaced the previously banned polychlorinated biphenyls (PCBs) in multiple flame retardant utilities. As epidemiological and laboratory studies have suggested PCBs as a risk factor for Parkinson’s disease (PD), the similarities between PBDEs and PCBs suggest that PBDEs have the potential to be neurotoxic to the dopamine system. The purpose of this study was to evaluate the neurotoxic effects of the PBDE mixture, DE-71, on the nigrostriatal dopamine system and address the role of altered dopamine handling in mediating this neurotoxicity. Using an in vitro model system we found DE-71 effectively caused cell death in a dopaminergic cell line as well as reducing the number of TH+ neurons isolated from VMAT2 WT and LO animals. Assessment of DE-71 neurotoxicity in vivo demonstrated significant deposition of PBDE congeners in the brains of mice, leading to reductions in striatal dopamine and dopamine handling, as well as reductions in the striatal dopamine transporter (DAT) and VMAT2. Additionally, DE-71 elicited a significant locomotor deficit in the VMAT2 WT and LO mice. However, no change was seen in TH expression in dopamine terminal or in the number of dopamine neurons in the substantia nigra pars compacta (SNpc). To date, these are the first data to demonstrate that exposure to PBDEs disrupts the nigrostriatal dopamine system. Given their similarities to PCBs, additional laboratory and epidemiological research should be considered to assess PBDEs as a potential risk factor for PD and other neurological disorders. PMID:23287494

  11. Cholinergic and Dopaminergic Alterations in Nigrostriatal Neurons Are Involved in Environmental Enrichment Motor Protection in a Mouse Model of Parkinson's Disease.

    PubMed

    Hilario, Willyan Franco; Herlinger, Alice Laschuk; Areal, Lorena Bianchine; de Moraes, Lívia Silveira; Ferreira, Tamara Andrea Alarcon; Andrade, Tassiane Emanuelle Servane; Martins-Silva, Cristina; Pires, Rita Gomes Wanderley

    2016-12-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, being characterized by dopaminergic neurodegeneration of substantia nigra pars compacta. PD pharmacotherapy has been based on dopamine replacement in the striatum with the dopaminergic precursor 3,4-dihydroxyphenylalanine (L-DOPA) and/or with dopaminergic agonists, alongside anticholinergic drugs in order to mitigate the motor abnormalities. However, these practices neither prevent nor stop the progression of the disease. Environmental enrichment (EE) has effectively prevented several neurodegenerative processes, mainly in preclinical trials. Several studies have demonstrated that EE induces biological changes, bearing on cognitive enhancement, neuroprotection, and on the attenuation of the effects of stress, anxiety, and depression. Herein, we investigated whether EE could prevent the motor, biochemical, and molecular abnormalities in a murine model of PD induced by 1-methyl-4-phenyl-2,3-dihydropyridine (MPTP). Our results show that EE does not prevent the dopaminergic striatal depletion induced by MPTP, despite having averted the MPTP-induced hyperlocomotion. However, it was able to slow down and avoid, respectively, the 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion. Analysis of dopaminergic mRNA alterations in the midbrain showed that D1R expression was increased by MPTP, while the normal expression level of this receptor was restored by EE. As for the cholinergic system, MPTP led to a decrease in the ChAT gene expression while increasing the expression of both AChE and M1R. EE attenuated and prevented-respectively-ChAT and M1R gene expression alterations triggered by MPTP in the midbrain. Overall, our data brings new evidence supporting the neuroprotective potential of EE in PD, focusing on the interaction between dopaminergic and cholinergic systems.

  12. Suppression of endogenous PPARγ increases vulnerability to methamphetamine –induced injury in mouse nigrostriatal dopaminergic pathway

    PubMed Central

    Yu, Seong-Jin; Airavaara, Mikko; Shen, Hui; Chou, Jenny; Harvey, Brandon K.; Wang, Yun

    2012-01-01

    Rationale Methamphetamine is a commonly abused drug and dopaminergic neurotoxin. Repeated administration of high doses of methamphetamine induces programmed cell death, suppression of dopamine release, and reduction in locomotor activity. Previous studies have shown that pretreatment with Peroxisome Proliferator-Activated Receptor gamma (PPARγ) agonist reduced Methamphetamine -induced neurodegeneration. Objectives The purpose of this study was to examine the role of endogenous PPARγ in protecting against methamphetamine toxicity. Methods Adeno-associated virus (AAV) encoding the Cre recombinase gene was unilaterally injected into the left substantia nigra of loxP-PPARγ or control wild type mice. Animals were treated with high doses of methamphetamine 1-month after viral injection. Behavioral tests were examined using Rotarod and rotometer. In vivo voltammetry was used to examine dopamine release/clearance and at 2 months after methamphetamine injection. Results Administration of AAV-Cre selectively removed PPARγ in left nigra in loxP-PPARγ mice but not in the wild type mice. The loxP-PPARγ/AAV-Cre mice that received methamphetamine showed a significant reduction in time on the rotarod and exhibited increased ipislateral rotation using a rotometer. The peak of dopamine release induced by local application of KCl and the rate of dopamine clearance were significantly attenuated in the left striatum of loxP-PPARγ/AAV-Cre animals. Tyrosine hydroxylase immunoreactivity was reduced in the left, compared to right, nigra and dorsal striatum in loxP-PPARγ/AAV-Cre mice receiving high doses of methamphetamine. Conclusion A deficiency in PPARγ increases vulnerability to high doses of methamphetamine. Endogenous PPARγ may play an important role in reducing methamphetamine toxicity in vivo. PMID:22160138

  13. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environment, Metabolic and Oxidative Stress

    DTIC Science & Technology

    2000-07-01

    Degeneration of the nigrostriatal dopamine system is linked to the pathophysiology of Parkinson’s disease . Similarly, the psycho stimulant drug...throughout the U.S. However, the neurochemical underpinnings that mediate methamphetamine toxicity and Parkinson’s disease have escaped definition...We propose that several variables common to methamphetamine toxicity and Parkinson’s disease , each of which may be important but alone are insufficient

  14. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environment, Metabolic and Oxidative Stress

    DTIC Science & Technology

    2001-07-01

    Degeneration of the nigrostriatal dopamine system is linked to the pathophysiology of Parkinson’s disease . Similarly, the psychostimulant drug...throughout the U.S. However, the neurochemical underpinnings that mediate methamphetamine toxicity and Parkinson’s disease have escaped definition. We...propose that several variables common to methamphetamine toxicity and Parkinson’s disease , each of which may be important but alone are insufficient

  15. The systemic administration of oleoylethanolamide exerts neuroprotection of the nigrostriatal system in experimental Parkinsonism.

    PubMed

    Gonzalez-Aparicio, Ramiro; Blanco, Eduardo; Serrano, Antonia; Pavon, Francisco Javier; Parsons, Loren H; Maldonado, Rafael; Robledo, Patricia; Fernandez-Espejo, Emilio; de Fonseca, Fernando Rodriguez

    2014-03-01

    Oleoylethanolamide (OEA) is an agonist of the peroxisome proliferator-activated receptor α (PPARα) and has been described to exhibit neuroprotective properties when administered locally in animal models of several neurological disorder models, including stroke and Parkinson's disease. However, there is little information regarding the effectiveness of systemic administration of OEA on Parkinson's disease. In the present study, OEA-mediated neuroprotection has been tested on in vivo and in vitro models of 6-hydroxydopamine (6-OH-DA)-induced degeneration. The in vivo model was based on the intrastriatal infusion of the neurotoxin 6-OH-DA, which generates Parkinsonian symptoms. Rats were treated 2 h before and after the 6-OH-DA treatment with systemic OEA (0.5, 1, and 5 mg/kg). The Parkinsonian symptoms were evaluated at 1 and 4 wk after the development of lesions. The functional status of the nigrostriatal system was studied through tyrosine-hydroxylase (TH) and hemeoxygenase-1 (HO-1, oxidation marker) immunostaining as well as by monitoring the synaptophysin content. In vitro cell cultures were also treated with OEA and 6-OH-DA. As expected, our results revealed 6-OH-DA induced neurotoxicity and behavioural deficits; however, these alterations were less severe in the animals treated with the highest dose of OEA (5 mg/kg). 6-OH-DA administration significantly reduced the striatal TH-immunoreactivity (ir) density, synaptophysin expression, and the number of nigral TH-ir neurons. Moreover, 6-OH-DA enhanced striatal HO-1 content, which was blocked by OEA (5 mg/kg). In vitro, 0.5 and 1 μM of OEA exerted significant neuroprotection on cultured nigral neurons. These effects were abolished after blocking PPARα with the selective antagonist GW6471. In conclusion, systemic OEA protects the nigrostriatal circuit from 6-OH-DA-induced neurotoxicity through a PPARα-dependent mechanism.

  16. Targeting Dopaminergic System for Treating Nicotine Dependence.

    PubMed

    Abuhamdah, Sawsan; Khalil, Ashraf; Sari, Youssef

    2016-01-01

    Smoking is the world's leading cause of preventable death among populations. Cigarette smoking increases the risk of numerous health problems, including heart diseases, stroke, atherosclerosis and many types of cancer, including lung, stomach and bladder cancers. Many individuals find it difficult to stop smoking because of the addictive effects of nicotine and the presence of several monoamine oxidase (MAO) inhibitors in the tobacco smoke extract. The development of novel, safe and effective medications for smoking cessation is a high public health priority. The role of mesocorticolimbic dopaminergic pathways in withdrawal symptoms and general reinforcement processes clearly recommends dopaminergic system as a potential target for the treatment of nicotine addiction. This review article discusses the new pharmacological treatments of nicotine dependence, which are targeting dopaminergic neurotransmission. This includes blockade of dopamine transporter and inhibition of MAO as pharmacotherapy for the treatment of nicotine dependence.

  17. Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system

    PubMed Central

    Hatcher, Jaime M.; Richardson, Jason R.; Guillot, Thomas S.; McCormack, Alison L.; Di Monte, Donato A.; Jones, Dean P.; Pennell, Kurt D.; Miller, Gary W.

    2007-01-01

    Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson’s disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. α-Synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by 3H-WIN 35,428 binding and 3H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD. PMID:17291500

  18. Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system.

    PubMed

    Hatcher, Jaime M; Richardson, Jason R; Guillot, Thomas S; McCormack, Alison L; Di Monte, Donato A; Jones, Dean P; Pennell, Kurt D; Miller, Gary W

    2007-04-01

    Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson's disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. Alpha-synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by (3)H-WIN 35,428 binding and (3)H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD.

  19. Salience and dysregulation of the dopaminergic system.

    PubMed

    Lahera, Guillermo; Freund, Namdev; Sáiz-Ruiz, Jerónimo

    2013-01-01

    Psychosis is a subjective and experiential phenomenon of the mind, influenced by cognitive and socio-cultural patterns of the individual. The neurobiological correlate of this phenomenon is the dysfunction of brain dopaminergic pathways. This article reviews the scientific evidence on the theoretical approaches of the dopaminergic hypothesis of psychosis and its relationship with the reward and salience systems. The aberrant salience occurs when the dysregulation of dopamine transmission produces a mistaken interpretation of neutral or irrelevant stimuli as a source of reward or punishment. Advances in neuroscience achieved in the last decade have led to the conceptualization of the constructs of visual, social and emotional salience, to test the hypothesis of aberrant salience in psychosis. Psychosis appears, therefore, as a trans-nosological pathological process, relatively nonspecific, which alters the attribution system of reality. Copyright © 2012 SEP y SEPB. Published by Elsevier Espana. All rights reserved.

  20. Dopaminergic System Dysfunction in Recreational Dexamphetamine Users

    PubMed Central

    Schrantee, Anouk; Václavů, Lena; Heijtel, Dennis F R; Caan, Matthan W A; Gsell, Willy; Lucassen, Paul J; Nederveen, Aart J; Booij, Jan; Reneman, Liesbeth

    2015-01-01

    Dexamphetamine (dAMPH) is a stimulant drug that is widely used recreationally as well as for the treatment of attention-deficit hyperactivity disorder (ADHD). Although animal studies have shown neurotoxic effects of dAMPH on the dopaminergic system, little is known about such effects on the human brain. Here, we studied the dopaminergic system at multiple physiological levels in recreational dAMPH users and age, gender, and IQ-matched dAMPH-naïve healthy controls. We assessed baseline D2/3 receptor availability, in addition to changes in dopamine (DA) release using single-photon emission computed tomography and DA functionality using pharmacological magnetic resonance imaging, following a dAMPH challenge. Also, the subjective responses to the challenge were determined. dAMPH users displayed significantly lower striatal DA D2/3 receptor binding compared with healthy controls. In dAMPH users, we further observed a blunted DA release and DA functionality to an acute dAMPH challenge, as well as a blunted subjective response. Finally, the lower D2/3 availability, the more pleasant the dAMPH administration was experienced by control subjects, but not by dAMPH users. Thus, in agreement with preclinical studies, we show that the recreational use of dAMPH in human subjects is associated with dopaminergic system dysfunction. These findings warrant further (longitudinal) investigations and call for caution when using this drug recreationally and for ADHD. PMID:25394786

  1. Characterization of Fetal Antigen 1/Delta-Like 1 Homologue Expressing Cells in the Rat Nigrostriatal System: Effects of a Unilateral 6-Hydroxydopamine Lesion

    PubMed Central

    Liechti, Rémy; Ducray, Angélique D.; Jensen, Pia; Di Santo, Stefano; Seiler, Stefanie; Jensen, Charlotte H.; Meyer, Morten; Widmer, Hans Rudolf

    2015-01-01

    Fetal antigen 1/delta-like 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a non-canonical ligand for the Notch receptor. Interactions between Notch and its ligands are crucial for the development of various tissues. Moreover, FA1/dlk1 has been suggested as a potential supplementary marker of dopaminergic neurons. The present study aimed at investigating the distribution of FA1/dlk1-immunoreactive (-ir) cells in the early postnatal and adult midbrain as well as in the nigrostriatal system of 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata as compared to unlesioned controls. The higher number of FA1/dlk1-ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was up-regulated in intrinsic cells in response to the 6-OHDA-mediated loss of FA1/dlk1-expressing SNc dopaminergic neurons and/or due to the stab wound. Our findings hint to a significant role of FA1/dlk1 in the SNc during early postnatal development. The differential expression of FA1/dlk1 in the SNc and the striatum of dopamine-depleted rats could indicate a potential involvement of FA1/dlk1 in the cellular response to the degenerative processes. PMID:25723595

  2. Dopaminergic system in birdsong learning and maintenance.

    PubMed

    Kubikova, Lubica; Kostál, Lubor

    2010-03-01

    Dopamine function in birdsong has been studied extensively in recent years. Several song and auditory nuclei are innervated by midbrain dopaminergic fibers and contain neurons with various dopamine receptors. During sexually motivated singing, activity of midbrain dopaminergic neurons in the ventral tegmental area and dopamine release in the striatal Area X, involved in song learning and maintenance, are higher. In this review we provide an overview of the dopaminergic system and neurotransmission in songbirds and the outline of possible involvement of dopamine in control of song learning, production, and maintenance. Based on both behavioral and computational biology data, we describe several models of song learning and the proposed role of dopamine in them. Special attention is given to possible role of dopamine in incentive salience (wanting) and reward prediction error signaling during song learning and maintenance, as well as the role of dopamine-mediated synaptic plasticity in reward processing. Finally, the role of dopamine in determination of personality traits in relation to birdsong is discussed.

  3. Chronic atrazine exposure causes disruption of the spontaneous locomotor activity and alters the striatal dopaminergic system of the male Sprague-Dawley rat.

    PubMed

    Bardullas, Ulises; Giordano, Magda; Rodríguez, Verónica M

    2011-01-01

    The herbicide atrazine (ATR) is widely used around the world, and is a potential toxicant of the dopaminergic systems. Nigrostriatal and mesolimbic systems are the two major dopaminergic pathways of the central nervous system; they play key roles mediating a wide array of critical motor and cognitive functions. We evaluated the effects of exposing male rats for one year to 10 mg ATR/kg B.W. on these systems using motor and cognitive tasks and measuring monoamine content in the striatum, nucleus accumbens, prefrontal cortex, and hypothalamus. ATR administration resulted in impaired motor coordination and greater spontaneous locomotor activity only after 10 to 12 months of exposure. Chronic exposure to 10 mg ATR decreased striatal dopamine, but had no effect on accumbal, hypothalamic or cortical monoamine content. Chronic ATR exposure caused discrete changes in learning tasks that involve either the striatum or the nucleus accumbens. These results indicate that chronic exposure to ATR preferentially targets the nigrostriatal dopaminergic pathway, in comparison to the other dopaminergic pathways evaluated in this study, inducing behavioral and neurochemical alterations. In order to unveil the full extent of atrazine's effects on the nervous system, other neurochemical systems should be considered in future studies. Copyright © 2010 Elsevier Inc. All rights reserved.

  4. [Current views on the mechanisms of dopaminergic neuron death of the nigrostriatal system in Parkinson's disease].

    PubMed

    Bertrand, E; Lechowicz, W; Szpak, G M; Dymecki, J

    1997-01-01

    Current views on the pathogenesis of Parkinson's disease are presented. Studies, particularly those carried out during the last decade, highlight the significance of endogenic processes responsible for a cumulative production of neurotoxic substances, especially free oxygen radicals which exert chronic effect on neurons. In Parkinson's disease, overproduction of free radicals and concomitant failure of protective mechanisms are most likely. An excess of free radicals is cytotoxic because of their very high chemical activity and uncontrolled chain reactions with numerous organic compounds, especially those which are mostly responsible for vital functions of cells. Oxidative stress disturbs metabolism of the cell what finally leads to its death most probably due to damage of cell membrane. That results in increased plasma membrane permeability for calcium ions which activate several subcellular mechanisms and initiate the final phase of cell death. Nonprotein-bound "free" iron ions are the strongest and most dangerous generators of free oxygen radicals. It is thought that ferric (Fe-3+" iron bound to neuromelanin may play a profound role in the overproduction of especially cytotoxic hydroxyl radicals, derivatives of molecular oxygen. Both, oxygen stress inducing factor and the sequence of related biochemical disorders remain still unknown. However, the synergy of the excess of reactive oxygen metabolites (mainly free radicals), nitric oxide, "free" iron ions and neuromelanin may contribute considerably to the generation of oxygen stress.

  5. Reformation of the nigrostriatal pathway by fetal dopaminergic micrografts into the substantia nigra is critically dependent on the age of the host.

    PubMed

    Bentlage, C; Nikkhah, G; Cunningham, M G; Björklund, A

    1999-09-01

    The aim of this study was to determine whether the growth of axons along the nigrostriatal pathway from fetal dopamine cells, transplanted into the substantia nigra of young postnatal 6-OHDA-lesioned rats, is dependent on the age of the host brain. Neonatal rats were lesioned bilaterally by intraventricular injection of 6-OHDA at postnatal day 1 (P1) and received grafts of E14 ventral mesencephalon at day 3 (group P3), day 10 (group P10), or day 20 (group P20) into the right substantia nigra. One lesioned group was left untransplanted. Six months after surgery the animals were subjected to analysis of drug-induced rotation following injection of amphetamine, apomorphine, a D1 agonist (SKF38393), or a D2 agonist (Quinpirole). Animals transplanted intranigrally at day 3 and day 10 showed a strong amphetamine-induced rotational bias toward the side contralateral to the transplant. Animals transplanted into substantia nigra at P20, like the lesioned control animals, showed no rotational bias. Apomorphine and selective D1 and D2 agonists induced ipsilateral turning behavior in the P3 and P10 group, but not in the P20 or the lesion control groups. Immunofluorescence histochemistry in combination with retrograde axonal tracing, using FluoroGold injection into the ipsilateral caudate-putamen showed colocalization of tyrosine hydroxylase and FluoroGold in large numbers of transplanted neurons in the animals transplanted at postnatal day 3 and postnatal day 10, which was not observed in the group P20. The lesion control group showed a 90% complete lesion of the TH-positive cells in the substantia nigra while largely sparing the neurons in the ventral tegmental area. The results indicate that intranigral grafts can be placed accurately and survive well within the substantia nigra region at various time points during postnatal development. Furthermore, embryonic dopamine neurons have the ability to extend axons along the nigrostriatal pathway and reconnect with the dopamine

  6. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitoxicity and Environmental, Metabolic and Oxidative Stress

    DTIC Science & Technology

    2002-07-01

    Parkinson’s disease . Similarly, the psychostimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is a widespread problem and drug of abuse throughout the U.S. However, the neurochemical underpinnings that mediate methamphetamine toxicity and Parkinson’s disease are unknown. Several variables common to methamphetamine toxicity and Parkinson’s disease , each of which may be important but alone are insufficient, may account for the neurodegeneration of the

  7. Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family

    PubMed Central

    Anwar, Sabina; Peters, Owen; Millership, Steven; Ninkina, Natalia; Doig, Natalie; Connor-Robson, Natalie; Threlfell, Sarah; Kooner, Gurdeep; Deacon, Robert M.; Bannerman, David M.; Bolam, J. Paul; Chandra, Sreeganga S.; Cragg, Stephanie J.; Wade-Martins, Richard; Buchman, Vladimir L.

    2011-01-01

    The synucleins (α, β and γ) are highly homologous proteins thought to play a role in regulating neurotransmission and are found abundantly in presynaptic terminals. To overcome functional overlap between synuclein proteins and to understand their role in presynaptic signalling from mesostriatal dopaminergic neurons, we produced mice lacking all three members of the synuclein family. The effect on the mesostriatal system was assessed in adult (4-14 month old) animals using a combination of behavioural, biochemical, histological and electrochemical techniques. Adult triple synuclein null (TKO) mice displayed no overt phenotype, and no change in the number of midbrain dopaminergic neurons. TKO mice were hyperactive in novel environments and exhibited elevated evoked release of dopamine in the striatum detected with fast-scan cyclic voltammetry. Elevated dopamine release was specific to the dorsal not ventral striatum and was accompanied by a decrease of dopamine tissue content. We confirmed a normal synaptic ultrastructure and a normal abundance of SNARE protein complexes in the dorsal striatum. Treatment of TKO animals with drugs affecting dopamine metabolism revealed normal rate of synthesis, enhanced turnover and reduced presynaptic striatal dopamine stores. Our data uniquely reveal the importance of the synuclein proteins in regulating neurotransmitter release from specific populations of midbrain dopamine neurons through mechanisms which differ from those reported in other neurons. The finding that the complete loss of synucleins leads to changes in dopamine handling by presynaptic terminals specifically in those regions preferentially vulnerable in Parkinson’s disease (PD) may ultimately inform on the selectivity of the disease process. PMID:21593311

  8. Transduction Profiles of Recombinant Adeno-Associated Virus Vectors Derived from Serotypes 2 and 5 in the Nigrostriatal System of Rats

    PubMed Central

    Paterna, Jean-Charles; Feldon, Joram; Büeler, Hansruedi

    2004-01-01

    We compared the transduction efficiencies and tropisms of titer-matched recombinant adeno-associated viruses (rAAV) derived from serotypes 2 and 5 (rAAV-2 and rAAV-5, respectively) within the rat nigrostriatal system. The two serotypes (expressing enhanced green fluorescent protein [EGFP]) were delivered by stereotaxic surgery into the same animals but different hemispheres of the striatum (STR), the substantia nigra (SN), or the medial forebrain bundle (MFB). While both serotypes transduced neurons effectively within the STR, rAAV-5 resulted in a much larger EGFP-expressing area than did rAAV-2. However, neurons transduced with rAAV-2 vectors expressed higher levels of EGFP. Consistent with this result, EGFP-positive projections emanating from transduced striatal neurons covered a larger area of the SN pars reticulata (SNr) after striatal delivery of rAAV-5, but EGFP levels in fibers of the SNr were higher after striatal injection of rAAV-2. We also compared the potentials of the two vectors for retrograde transduction and found that striatal delivery of rAAV-5 resulted in significantly more transduced dopaminergic cell bodies within the SN pars compacta and ventral tegmental area. Similarly, EGFP-transduced striatal neurons were detected only after nigral delivery of rAAV-5. Furthermore, we demonstrate that after striatal AAV-5 vector delivery, the transduction profiles were stable for as long as 9 months. Finally, although we did not target the hippocampus directly, efficient and widespread transduction of hippocampal neurons was observed after delivery of rAAV-5, but not rAAV-2, into the MFB. PMID:15194756

  9. The melanoma-linked "redhead" MC1R influences dopaminergic neuron survival.

    PubMed

    Chen, Xiqun; Chen, Hongxiang; Cai, Waijiao; Maguire, Michael; Ya, Bailiu; Zuo, Fuxing; Logan, Robert; Li, Hui; Robinson, Katey; Vanderburg, Charles R; Yu, Yang; Wang, Yinsheng; Fisher, David E; Schwarzschild, Michael A

    2017-03-01

    Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss-of-function variants of MC1R have also been linked to increased risk of Parkinson disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo. Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures. MC1R(e/e) mice, which carry an inactivating mutation of MC1R and mimic the human redhead phenotype, have compromised nigrostriatal dopaminergic neuronal integrity, and they are more susceptible to dopaminergic neuron toxins 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, a selective MC1R agonist protects against MPTP-induced dopaminergic neurotoxicity. Our findings reveal a protective role of MC1R in the nigrostriatal dopaminergic system, and they provide a rationale for MC1R as a potential therapeutic target for Parkinson disease. Together with its established role in melanoma, MC1R may represent a common pathogenic pathway for melanoma and Parkinson disease. Ann Neurol 2017;81:395-406. © 2016 American Neurological Association.

  10. Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease.

    PubMed

    Caminiti, Silvia Paola; Presotto, Luca; Baroncini, Damiano; Garibotto, Valentina; Moresco, Rosa Maria; Gianolli, Luigi; Volonté, Maria Antonietta; Antonini, Angelo; Perani, Daniela

    2017-01-01

    A progressive loss of dopamine neurons in the substantia nigra (SN) is considered the main feature of idiopathic Parkinson's disease (PD). Recent neuropathological evidence however suggests that the axons of the nigrostriatal dopaminergic system are the earliest target of α-synuclein accumulation in PD, thus the principal site for vulnerability. Whether this applies to in vivo PD, and also to the mesolimbic system has not been investigated yet. We used [(11)C]FeCIT PET to measure presynaptic dopamine transporter (DAT) activity in both nigrostriatal and mesolimbic systems, in 36 early PD patients (mean disease duration in months ± SD 21.8 ± 10.7) and 14 healthy controls similar for age. We also performed anatomically-driven partial correlation analysis to evaluate possible changes in the connectivity within both the dopamine networks at an early clinical phase. In the nigrostriatal system, we found a severe DAT reduction in the afferents to the dorsal putamen (DPU) (η(2) = 0.84), whereas the SN was the less affected region (η(2) = 0.31). DAT activity in the ventral tegmental area (VTA) and the ventral striatum (VST) were also reduced in the patient group, but to a lesser degree (VST η(2) = 0.71 and VTA η(2) = 0.31). In the PD patients compared to the controls, there was a marked decrease in dopamine network connectivity between SN and DPU nodes, supporting the significant derangement in the nigrostriatal pathway. These results suggest that neurodegeneration in the dopamine pathways is initially more prominent in the afferent axons and more severe in the nigrostriatal system. Considering PD as a disconnection syndrome starting from the axons, it would justify neuroprotective interventions even if patients have already manifested clinical symptoms.

  11. The dopaminergic system and aggression in laying hens

    USDA-ARS?s Scientific Manuscript database

    The dopaminergic system regulates aggression in humans and other mammals. To investigate if birds with genetic propensity for high and low aggressiveness may exhibit distinctly different aggressive mediation via dopamine (DA) D1 and D2 receptor pathways, two high aggressive (DXL and LGPS) and one lo...

  12. A new dopaminergic nigro-olfactory projection.

    PubMed

    Höglinger, Günter U; Alvarez-Fischer, Daniel; Arias-Carrión, Oscar; Djufri, Miriam; Windolph, Andrea; Keber, Ursula; Borta, Andreas; Ries, Vincent; Schwarting, Rainer K W; Scheller, Dieter; Oertel, Wolfgang H

    2015-09-01

    Parkinson disease (PD) is a neurodegenerative disorder characterized by massive loss of midbrain dopaminergic neurons. Whereas onset of motor impairments reflects a rather advanced stage of the disorder, hyposmia often marks the beginning of the disease. Little is known about the role of the nigro-striatal system in olfaction under physiological conditions and the anatomical basis of hyposmia in PD. Yet, the early occurrence of olfactory dysfunction implies that pathogens such as environmental toxins could incite the disease via the olfactory system. In the present study, we demonstrate a dopaminergic innervation from neurons in the substantia nigra to the olfactory bulb by axonal tracing studies. Injection of two dopaminergic neurotoxins-1-methyl-4-phenylpyridinium and 6-hydroxydopamine-into the olfactory bulb induced a decrease in the number of dopaminergic neurons in the substantia nigra. In turn, ablation of the nigral projection led to impaired olfactory perception. Hyposmia following dopaminergic deafferentation was reversed by treatment with the D1/D2/D3 dopamine receptor agonist rotigotine. Hence, we demonstrate for the first time the existence of a direct dopaminergic projection into the olfactory bulb and identify its origin in the substantia nigra in rats. These observations may provide a neuroanatomical basis for invasion of environmental toxins into the basal ganglia and for hyposmia as frequent symptom in PD.

  13. Effect of monocrotophos, an organophosphorus insecticide, on the striatal dopaminergic system in a mouse model of Parkinson's disease.

    PubMed

    Ali, Shaheen Jafri; Rajini, Padmanabhan Sharda

    2016-07-01

    Our earlier study had shown that low concentrations of monocrotophos (MCP) elicited dopaminergic features of Parkinson's disease (PD) in the nematode Caenorhabditis elegans In the present study, the effect of low doses of MCP on the striatal dopaminergic neurons was investigated using the mouse model system. MCP was initially screened for its ability to cause any neurobehavioral deficits and alterations in the dopaminergic system in Swiss albino mice, aged 8 weeks and weighing 25-30 g, with repeated doses at 0.3 and 0.6 mg/kg body weight (b.w.)/day for 7 days and 30 days. Mice were treated with four intraperitoneal injections for every 2 h with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at the dosage of 14 mg/kg b.w. MCP was administered to these mice at the above-mentioned doses for 7 days. Mice administered with MCP alone revealed a significant (p < 0.05) reduction in the dopamine (DA) content at both 7 and 30 days and showed a significant (p < 0.05) increase in neurobehavioral deficits. Interestingly, when MCP was administered for 7 days to MPTP-treated mice, further significant decrease in both DA content and increase in neurobehavioral deficits were apparent. The extent of reactive oxygen species and lipid peroxidation were markedly increased, while the ratio of reduced to oxidized glutathione levels were significantly decreased (p < 0.05) in the treated mice as compared to the control. Significant histopathological alterations and a marked reduction in the number of tyrosine hydroxylase positive cells were evident in striatum of mice treated with higher doses of MCP. These changes were comparable to that seen in mice treated with MPTP and post-administered lower doses of MCP. Our findings suggest that MCP per se has the propensity to induce pathological changes in the dopaminergic neurons as well as augment the degeneration in a compromised nigrostriatal system such as that in PD. © The Author(s) 2014.

  14. Full Anatomical Recovery of the Dopaminergic System after a Complete Spinal Cord Injury in Lampreys

    PubMed Central

    Fernández-López, Blanca; Romaus-Sanjurjo, Daniel; Cornide-Petronio, María Eugenia; Gómez-Fernández, Sonia; Barreiro-Iglesias, Antón; Rodicio, María Celina

    2015-01-01

    Following a spinal injury, lampreys at first are paralyzed below the level of transection. However, they recover locomotion after several weeks, and this is accompanied by the regeneration of descending axons from the brain and the production of new neurons in the spinal cord. Here, we aimed to analyse the changes in the dopaminergic system of the sea lamprey after a complete spinal transection by studying the changes in dopaminergic cell numbers and dopaminergic innervation in the spinal cord. Changes in the expression of the D2 receptor were also studied. We report the full anatomical regeneration of the dopaminergic system after an initial decrease in the number of dopaminergic cells and fibres. Numbers of dopaminergic cells were recovered rostrally and caudally to the site of injury. Quantification of dopaminergic profiles revealed the full recovery of the dopaminergic innervation of the spinal cord rostral and caudal to the site of injury. Interestingly, no changes in the expression of the D2 receptor were observed at time points in which a reduced dopaminergic innervation of the spinal cord was observed. Our observations reveal that in lampreys a spinal cord injury is followed by the full anatomical recovery of the dopaminergic system. PMID:25861481

  15. Long-term effects of irradiation with iron-56 particles on the nigrostriatal dopamine system.

    PubMed

    Rice, Onarae V; Grande, Alicia V; Dehktyar, Natasha; Bruneus, Magalie; Robinson, John K; Gatley, Samuel J

    2009-04-01

    Exposure to heavy ions during a Mars mission might damage the brain, thus compromising mission success and the quality of life of returning astronauts. Several workers have suggested that the dopamine system is particularly sensitive to heavy ion radiation, but direct evidence for this notion is lacking. We examined measures of brain dopamine viability at times up to 15 months after acute exposure of rats to (56)Fe (1.2-2.4 Gy). No effects were seen in brain sections stained for tyrosine hydroxylase, the classical marker for dopamine cells and nerve terminals. Locomotion stimulated by cocaine, which directly activates the dopamine system, was reduced at 6 months but not at 12 months. Furthermore, in a visually cued lever-pressing test, reaction times, which are prolonged by dopamine system damage, were identical in irradiated and control animals. However, learning times were increased by irradiation. Our data suggest that the midbrain dopamine system is not especially sensitive to damage by (56)Fe particles at doses much higher than would be associated with travel to and from Mars.

  16. Reelin and CXCL12 regulate distinct migratory behaviors during the development of the dopaminergic system.

    PubMed

    Bodea, Gabriela Oana; Spille, Jan-Hendrik; Abe, Philipp; Andersson, Aycan Senturk; Acker-Palmer, Amparo; Stumm, Ralf; Kubitscheck, Ulrich; Blaess, Sandra

    2014-02-01

    The proper functioning of the dopaminergic system requires the coordinated formation of projections extending from dopaminergic neurons in the substantia nigra (SN), ventral tegmental area (VTA) and retrorubral field to a wide array of forebrain targets including the striatum, nucleus accumbens and prefrontal cortex. The mechanisms controlling the assembly of these distinct dopaminergic cell clusters are not well understood. Here, we have investigated in detail the migratory behavior of dopaminergic neurons giving rise to either the SN or the medial VTA using genetic inducible fate mapping, ultramicroscopy, time-lapse imaging, slice culture and analysis of mouse mutants. We demonstrate that neurons destined for the SN migrate first radially and then tangentially, whereas neurons destined for the medial VTA undergo primarily radial migration. We show that tangentially migrating dopaminergic neurons express the components of the reelin signaling pathway, whereas dopaminergic neurons in their initial, radial migration phase express CXC chemokine receptor 4 (CXCR4), the receptor for the chemokine CXC motif ligand 12 (CXCL12). Perturbation of reelin signaling interferes with the speed and orientation of tangentially, but not radially, migrating dopaminergic neurons and results in severe defects in the formation of the SN. By contrast, CXCR4/CXCL12 signaling modulates the initial migration of dopaminergic neurons. With this study, we provide the first molecular and functional characterization of the distinct migratory pathways taken by dopaminergic neurons destined for SN and VTA, and uncover mechanisms that regulate different migratory behaviors of dopaminergic neurons.

  17. Effects of early and delayed treatment with an mGluR5 antagonist on motor impairment, nigrostriatal damage and neuroinflammation in a rodent model of Parkinson's disease.

    PubMed

    Ambrosi, G; Armentero, M-T; Levandis, G; Bramanti, P; Nappi, G; Blandini, F

    2010-04-29

    The loss of nigrostriatal dopaminergic neurons that characterizes Parkinson's disease (PD) causes complex functional alterations in the basal ganglia circuit. Increased glutamatergic activity at crucial points of the circuit may be central to these alterations, thereby contributing to the onset of PD motor symptoms. Signs of neuroinflammation accompanying the neuronal loss have also been observed; also in this case, glutamate-mediated mechanisms may be involved. Glutamate may therefore intervene at multiple levels in PD pathophysiology, possibly through the modulation of metabotropic receptors. To address this issue, we evaluated the effects of systemic treatment with MPEP (2-methyl-6-(phenylethynyl)-pyridine), an antagonist of metabotropic receptor mGluR5, in a rodent model of progressive nigrostriatal degeneration based on the intrastriatal injection of 6-hydroxydopamine (6-OHDA). Following 6-OHDA injection, Sprague-Dawley rats underwent a 4-week, daily treatment with MPEP (1.5mg/kg, i.p.). To investigate whether the effects varied with the progression of the lesion, subgroups of lesioned animals started the treatment at different time-points: (1) immediately, (2) 1 week, or (3) 4 weeks after the neurotoxin injection. Akinesia, dopaminergic nigrostriatal damage and neuroinflammatory response (microglial and astroglial activation) were investigated. MPEP prompted immediate amelioration of 6-OHDA-induced akinesia, as measured by the Adjusting step test, in all subgroups, regardless of the degree of nigrostriatal damage. Conversely, MPEP did not modify neuronal survival or neuroinflammatory response in the nigrostriatal pathway. In conclusion, chronic treatment with MPEP exerted a pure symptomatic effect, further supporting that mGluR5 modulation may be a viable strategy to counteract the basal ganglia functional modifications underlying PD motor symptoms. Copyright 2010 Elsevier Inc. All rights reserved.

  18. Renal dopaminergic system: Pathophysiological implications and clinical perspectives

    PubMed Central

    Choi, Marcelo Roberto; Kouyoumdzian, Nicolás Martín; Rukavina Mikusic, Natalia Lucía; Kravetz, María Cecilia; Rosón, María Inés; Rodríguez Fermepin, Martín; Fernández, Belisario Enrique

    2015-01-01

    Fluid homeostasis, blood pressure and redox balance in the kidney are regulated by an intricate interaction between local and systemic anti-natriuretic and natriuretic systems. Intrarenal dopamine plays a central role on this interactive network. By activating specific receptors, dopamine promotes sodium excretion and stimulates anti-oxidant and anti-inflammatory pathways. Different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome, hypertension and renal inflammation, can be associated with impaired action of renal dopamine including alteration in biosynthesis, dopamine receptor expression and signal transduction. Given its properties on the regulation of renal blood flow and sodium excretion, exogenous dopamine has been postulated as a potential therapeutic strategy to prevent renal failure in critically ill patients. The aim of this review is to update and discuss on the most recent findings about renal dopaminergic system and its role in several diseases involving the kidneys and the potential use of dopamine as a nephroprotective agent. PMID:25949933

  19. The dopaminergic projection system, basal forebrain macrosystems, and conditioned stimuli

    PubMed Central

    Zahm, Daniel S.

    2011-01-01

    This review begins with a description of some problems that in recent years have beset an influential circuit model of fear-conditioning and goes on to look at neuroanatomy that might subserve conditioning viewed in a broader perspective, including not only fear, but also appetitive, conditioning. The paper then focuses on basal forebrain functional-anatomical systems, or macrosystems, as they have come to be called, which Lennart Heimer and colleagues described beginning in the 1970’s. Yet more specific attention is then given to the relationships of the dorsal and ventral striatopallidal systems and extended amygdala with the dopaminergic mesotelencephalic projection systems, culminating with the hypothesis that all macrosystems contribute to behavioral conditioning. PMID:18204412

  20. Regulation of human GDNF gene expression in nigral dopaminergic neurons using a new doxycycline-regulated NTS-polyplex nanoparticle system.

    PubMed

    Espadas-Alvarez, Armando J; Bannon, Michael J; Orozco-Barrios, Carlos E; Escobedo-Sanchez, Lourdes; Ayala-Davila, Jose; Reyes-Corona, David; Soto-Rodriguez, Guadalupe; Escamilla-Rivera, Vicente; De Vizcaya-Ruiz, Andrea; Eugenia Gutierrez-Castillo, M; Padilla-Viveros, America; Martinez-Fong, Daniel

    2017-02-17

    The human glial-cell derived neurotrophic factor (hGDNF) gene transfer by neurotensin (NTS)-polyplex nanoparticles functionally restores the dopamine nigrostriatal system in experimental Parkinson's disease models. However, high levels of sustained expression of GDNF eventually can cause harmful effects. Herein, we report an improved NTS-polyplex nanoparticle system that enables regulation of hGDNF expression within dopaminergic neurons. We constructed NTS-polyplex nanoparticles containing a single bifunctional plasmid that codes for the reverse tetracycline-controlled transactivator advanced (rtTA-Adv) under the control of NBRE3x promoter, and for hGDNF under the control of tetracycline-response element (TRE). Another bifunctional plasmid contained the enhanced green fluorescent protein (GFP) gene. Transient transfection experiments in N1E-115-Nurr1 cells showed that doxycycline (100 ng/mL) activates hGDNF and GFP expression. Doxycycline (5 mg/kg, i.p.) administration in rats activated hGDNF expression only in transfected dopaminergic neurons, whereas doxycycline withdrawal silenced transgene expression. Our results offer a specific doxycycline-regulated system suitable for nanomedicine-based treatment of Parkinson's disease.

  1. Differential expression of Fos and Zif268 in the nigrostriatal system after methamphetamine administration in a rat model of Parkinson's disease.

    PubMed

    Ishida, Yasushi; Kawai, Keiichi; Magata, Yasuhiro; Ebihara, Kosuke; Takeda, Ryuichiro; Abe, Hiroshi; Yoshimoto, Mitsuyoshi; Hashiguchi, Hiroyuki; Odagiri, Kei; Matsuo, Hisae; Nishimori, Toshikazu

    2008-12-01

    The goal of this study was to examine the topological specificity of methamphetamine-induced activation of the immediate-early gene proteins, Fos and Zif268, in the nigrostriatal system in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease with or without intrastriatal grafts of fetal ventral mesencephalon. Methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) dominantly in the striatum and the globus pallidus (GP) on the intact side as well as in the substantia nigra pars reticulata (SNr) on the lesioned side in the 6-OHDA rats. Lower levels of methamphetamine-induced FLI in the striatum and GP on the lesioned side were restored by intrastriatal grafts which could completely suppress the methamphetamine-induced rotation. In the striatum, a similar tendency could be observed between Fos and Zif268 immunoreactivity following methamphetamine. However, sparse immunoreactivity of Zif268 could be detected in the GP and SNr on both sides in the 6-OHDA rats. Intrastriatal grafts had little influence on Zif268 expression in these two regions. The differential expression of Fos and Zif268 was observed among the three regions of the nigrostriatal system following methamphetamine in the 6-OHDA rats. This may suggest that Fos and Zif268 therefore possess gene-specific and region-specific functions in the basal ganglia nuclei.

  2. Evolution of the dopaminergic system and its relationships with the psychopathology of pleasure.

    PubMed

    Pani, L; Gessa, G L

    1997-01-01

    This paper summarizes the fundamental steps in the evolution of the dopaminergic system. A rudimentary dopaminergic system is present in primitive creatures, already able to select information processing, modulate "emotional" behaviours and react to perturbations in environmental conditions. Pharmacological manipulations of the dopaminergic transmission are able to modify basic behaviours present in all animals from fishes to lizards to mammals. The ability to put the organism in motion and the hedonic capacity of giving pleasure, would justify the conservation through evolution of such a neuronal system. The fact however that the dopaminergic system has remained identical for the last several centuries, while many external conditions which interfere with its physiology have dramatically changed, may contribute to explain the transition from the original vital advantages of the dopaminergic system to its crucial role in the psychopathology of pleasure.

  3. Evolutionarily conserved organization of the dopaminergic system in lamprey: SNc/VTA afferent and efferent connectivity and D2 receptor expression.

    PubMed

    Pérez-Fernández, Juan; Stephenson-Jones, Marcus; Suryanarayana, Shreyas M; Robertson, Brita; Grillner, Sten

    2014-12-01

    The dopaminergic system influences motor behavior, signals reward and novelty, and is an essential component of the basal ganglia in all vertebrates including the lamprey, one of the phylogenetically oldest vertebrates. The intrinsic organization and function of the lamprey basal ganglia is highly conserved. For instance, the direct and indirect pathways are modulated through dopamine D1 and D2 receptors in lamprey and in mammals. The nucleus of the tuberculum posterior, a homologue of the substantia nigra pars compacta (SNc)/ventral tegmental area (VTA) is present in lamprey, but only scarce data exist about its connectivity. Likewise, the D2 receptor is expressed in the striatum, but little is known about its localization in other brain areas. We used in situ hybridization and tracer injections, both in combination with tyrosine hydroxylase immunohistochemistry, to characterize the SNc/VTA efferent and afferent connectivity, and to relate its projection pattern with D2 receptor expression in particular. We show that most features of the dopaminergic system are highly conserved. As in mammals, the direct pallial (cortex in mammals) input and the basal ganglia connectivity with the SNc/VTA are present as part of the evaluation system, as well as input from the tectum as the evolutionary basis for salience/novelty detection. Moreover, the SNc/VTA receives sensory information from the olfactory bulbs, optic tectum, octavolateral area, and dorsal column nucleus, and it innervates, apart from the nigrostriatal pathway, several motor-related areas. This suggests that the dopaminergic system also contributes to the control of different motor centers at the brainstem level.

  4. Gestational restraint stress and the developing dopaminergic system: an overview.

    PubMed

    Baier, Carlos J; Katunar, María R; Adrover, Ezequiela; Pallarés, María Eugenia; Antonelli, Marta C

    2012-07-01

    Prenatal stress exerts a strong impact on fetal brain development in rats impairing adaptation to stressful conditions, subsequent vulnerability to anxiety, altered sexual function, and enhanced propensity to self-administer drugs. Most of these alterations have been attributed to changes in the neurotransmitter dopamine (DA). In humans; dysfunction of dopaminergic system is associated with development of several neurological disorders, such as Parkinson disease, schizophrenia, attention-deficit hyperactivity disorder, and depression. Evidences provided by animal research, as well as retrospective studies in humans, pointed out that exposure to adverse events in early life can alter adult behaviors and neurochemical indicators of midbrain DA activity, suggesting that the development of the DA system is sensitive to disruption by exposure to early stressors. The purpose of this article is to provide a general overview of published studies and our own study related to the effect of prenatal insults on the development of DA metabolism and biology, focusing mainly in articles involving prenatal-restraint stress protocols in rats. We will also attempt to make a correlation between theses alterations and DA-related pathological processes in humans.

  5. The Amygdalo-Nigrostriatal Network Is Critical for an Optimal Temporal Performance

    ERIC Educational Resources Information Center

    Es-seddiqi, Mouna; El Massioui, Nicole; Samson, Nathalie; Brown, Bruce L.; Doyère, Valérie

    2016-01-01

    The amygdalo-nigrostriatal (ANS) network plays an essential role in enhanced attention to significant events. Interval timing requires attention to temporal cues. We assessed rats having a disconnected ANS network, due to contralateral lesions of the medial central nucleus of the amygdala (CEm) and dopaminergic afferents to the lateral striatum,…

  6. The Amygdalo-Nigrostriatal Network Is Critical for an Optimal Temporal Performance

    ERIC Educational Resources Information Center

    Es-seddiqi, Mouna; El Massioui, Nicole; Samson, Nathalie; Brown, Bruce L.; Doyère, Valérie

    2016-01-01

    The amygdalo-nigrostriatal (ANS) network plays an essential role in enhanced attention to significant events. Interval timing requires attention to temporal cues. We assessed rats having a disconnected ANS network, due to contralateral lesions of the medial central nucleus of the amygdala (CEm) and dopaminergic afferents to the lateral striatum,…

  7. Insulin resistance impairs nigrostriatal dopamine function.

    PubMed

    Morris, J K; Bomhoff, G L; Gorres, B K; Davis, V A; Kim, J; Lee, P-P; Brooks, W M; Gerhardt, G A; Geiger, P C; Stanford, J A

    2011-09-01

    Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. The Dopaminergic System in the Aging Brain of Drosophila

    PubMed Central

    White, Katherine E.; Humphrey, Dickon M.; Hirth, Frank

    2010-01-01

    Drosophila models of Parkinson's disease are characterized by two principal phenotypes: the specific loss of dopaminergic (DA) neurons in the aging brain and defects in motor behavior. However, an age-related analysis of these baseline parameters in wildtype Drosophila is lacking. Here we analyzed the DA system and motor behavior in aging Drosophila. DA neurons in the adult brain can be grouped into bilateral symmetric clusters, each comprising a stereotypical number of cells. Analysis of TH > mCD8::GFP and cell type-specific MARCM clones revealed that DA neurons show cluster-specific, stereotypical projection patterns with terminal arborization in target regions that represent distinct functional areas of the adult brain. Target areas include the mushroom bodies, involved in memory formation and motivation, and the central complex, involved in the control of motor behavior, indicating that similar to the mammalian brain, DA neurons in the fly brain are involved in the regulation of specific behaviors. Behavioral analysis revealed that Drosophila show an age-related decline in startle-induced locomotion and negative geotaxis. Motion tracking however, revealed that walking activity, and exploration behavior, but not centrophobism increase at late stages of life. Analysis of TH > Dcr2, mCD8::GFP revealed a specific effect of Dcr2 expression on walking activity but not on exploratory or centrophobic behavior, indicating that the siRNA pathway may modulate distinct DA behaviors in Drosophila. Moreover, DA neurons were maintained between early- and late life, as quantified by TH > mCD8::GFP and anti-TH labeling, indicating that adult onset, age-related degeneration of DA neurons does not occur in the aging brain of Drosophila. Taken together, our data establish baseline parameters in Drosophila for the study of Parkinson's disease as well as other disorders affecting DA neurons and movement control. PMID:21165178

  9. Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intraventricular and intranigral delivery.

    PubMed

    Lapchak, P A; Miller, P J; Collins, F; Jiao, S

    1997-05-01

    -enkephalin or substance P levels nor striatal dopamine levels. In lesioned rats with intraventricular injections of glial cell line-derived neurotrophic factor, tyrosine hydroxylase ispilateral to the lesion was increased in the substantia nigra, but not in the striatum. Intraventricularly-administered glial cell line-derived neurotrophic factor did not reverse lesion-induced increases in nigral dynorphin A or met-enkephalin levels nor did glial cell line-derived neurotrophic factor affect substance P levels in the striatum. These results suggest that in an animal model of Parkinson's disease, the neurotrophic factor glial cell line-derived neurotrophic factor reverses behavioural consequences of 6-hydroxydopamine administration, an effect that may involve both dopaminergic and peptidergic neurotransmission.

  10. The dopaminergic system and aggression in laying hens.

    PubMed

    Dennis, R L; Cheng, H W

    2011-11-01

    The dopaminergic system is involved in the regulation of aggression in many species, especially via dopamine (DA) D1 and D2 receptor pathways. To investigate heritable differences in this regulation, 2 high aggressive strains [Dekalb XL (DXL) and low group egg productivity and survivability (LGPS)] and one low aggressive strain (low group egg productivity and survivability; HGPS) of laying hens were used in the study. The HGPS and LGPS lines were diversely selected using group selection for high and low group production and survivability. The DXL line is a commercial line selected through individual selection based on egg production. Heritable differences in aggressive propensity between the strains have been previously assessed. The birds were pair housed within the same strain and labeled as dominant or subordinate based on behavioral observation. For both experiments 1 and 2, behavioral analysis was performed on all 3 strains whereas neurotransmitter analysis was performed only on the most aggressive (DXL) and least aggressive (HGPS) strains. In experiment 1, the subordinate birds were treated with D1 agonist, D2 agonist, or saline controls (n = 12). In experiment 2, the dominant birds from a separate flock were treated with D1 antagonist, D2 antagonist, or saline controls (n = 12). Treatment-associated changes in aggressive behaviors and central neurotransmitters were measured. Aggression was increased in all strains in response to D1 agonism but increased only in the less aggressive HGPS birds with D2 agonism. Aggression was decreased and hypothalamic serotonin and epinephrine were increased in birds from all strains treated with D2 receptor antagonist. The D1 receptor antagonism elicited different behavioral and neurotransmitter responses based on the aggressive phenotype of the genetic strains. Aggressive strains DXL and LGPS but not the HGPS strain decreased aggressiveness following antagonism of the D1 receptor. The data show evidence for distinct

  11. The dopaminergic system dynamic in the time perception: A review of the evidence.

    PubMed

    Marinho, Victor; Oliveira, Thomaz; Rocha, Kaline; Ribeiro, Jéssica; Magalhães, Francisco; Bento, Thalys; Pinto, Giovanny R; Velasques, Bruna; Ribeiro, Pedro; Di Giorgio, Luiza; Orsini, Marco; Gupta, Daya S; Bittencourt, Juliana; Bastos, Victor Hugo; Teixeira, Silmar

    2017-09-26

    Dopaminergic system plays a key role in perception, which is an important executive function of the brain. Modulation in dopaminergic system forms an important biochemical underpinning of neural mechanisms of time perception in a very wide range, from milliseconds to seconds to longer daily rhythms. Distinct types of temporal experience are poorly understood, and the relationship between processing of different intervals by the brain has received little attention. A comprehensive understanding of interval timing functions should be sought within a wider context of temporal processing, involving genetic aspects, pharmacological models, cognitive aspects, motor control and the neurological diseases with impaired dopaminergic system. Particularly, an unexplored question is whether the role of dopamine in interval timing can be integrated the role of dopamine in non-interval timing temporal components. In this review, we explore a wider perspective of dopaminergic system, involving genetic polymorphisms, pharmacological models, executive functions and neurological diseases on the time perception. We conclude that the dopaminergic system has great participation in impact on time perception and neurobiological basis of the executive functions and neurological diseases.

  12. Differential activation of dopaminergic systems in rat brain basal ganglia by morphine and methamphetamine.

    PubMed

    Mori, T; Iwase, Y; Saeki, T; Iwata, N; Murata, A; Masukawa, D; Suzuki, T

    2016-05-13

    Typical abused drug-induced behavioral changes are ordinarily mediated by the mesolimbic dopaminergic system and even the phenotypes of behavior are different from each other. However, the mechanisms that underlie the behavioral changes induced by these abused drugs have not yet been elucidated. The present study was designed to investigate the mechanisms that underlie how abused drugs induce distinct behavioral changes using neurochemical as well as behavioral techniques in rats. Methamphetamine (2mg/kg) more potently increased dopamine release from the striatum more than that from the nucleus accumbens. In contrast, the administration of morphine (10mg/kg) produced a significant increase in the release of dopamine from the nucleus accumbens, but not the striatum, which is accompanied by a decrease in the release of GABA in the ventral tegmental area. These findings indicate that morphine and methamphetamine differentially regulate dopaminergic systems to produce behavioral changes, even though both drugs have abuse potential through activation of the mesolimbic dopaminergic system.

  13. Enhancing effect of taurine in the rat caudate spindle. II. Effect of bilateral 6-hydroxydopamine lesions of the nigro-striatal dopamine system.

    PubMed

    Hashimoto-Kitsukawa, S; Okuyama, S; Aihara, H

    1988-10-01

    Bilateral injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats resulted in destruction of dopamine (DA) nerve terminals in the striatum. DA contents decreased to 16.8, 15.0 and 13.7% of control values on 3, 5 and 7 days after the lesions, respectively. The time course of the effect of 6-OHDA lesions on apomorphine (0.5 mg/kg, IV)-induced stereotypy was investigated as the index of the development of supersensitivity. Stereotypy was unchanged on 3 days, but was enhanced 5 and 7 days after 6-OHDA lesions. Therefore, the sensitivity of postsynaptic DA receptors for apomorphine did not change 3 days after 6-OHDA lesions, although the striatal DA was depleted. The effects of bilateral injections of taurine into the striatum on the rat caudate spindle were determined 3 days after 6-OHDA lesions. Taurine, at a dose of 30 micrograms, enhanced the spindle in sham-operated rats, but this enhancement was not seen after 6-OHDA lesions. Intravenous administration of apomorphine (0.5 mg/kg) to lesioned rats suppressed the spindle, and this effect was prevented by a lower dose (3 micrograms) of taurine. These results provide further evidence that taurine enhances the spindle, possibly by decreasing the activity of the nigro-striatal DA system at the pre- and postsynaptic sites.

  14. Nicotine-induced acute hyperactivity is mediated by dopaminergic system in a sexually dimorphic manner.

    PubMed

    Zhang, Yunpeng; Guo, Jing; Guo, Aike; Li, Yan

    2016-09-22

    Short-term exposure to nicotine induces positive effects in mice, monkeys and humans, including mild euphoria, hyperactivity, and enhanced cognition. However, the underlying neural basis and molecular mechanisms for these effects remain poorly understood. Here, using a video recording system, we find that acute nicotine administration induces locomotor hyperactivity in Drosophila, similar to observations made in higher model organisms. Suppressing dopaminergic neurons or down-regulating dopamine 1-like receptor (DopR) abolishes this acute nicotine response, but surprisingly, does so only in male flies. Using a GFP reconstitution across synaptic partners (GRASP) approach, we show that dopaminergic neurons possess potential synaptic connections with acetylcholinergic neurons in wide regions of the brain. Furthermore, dopaminergic neurons are widely activated upon nicotine perfusion in both sexes, while the response curve differs significantly between the sexes. Moreover, knockdown of the β1 nicotine acetylcholine receptor (nAChR) in dopaminergic neurons abolishes the acute nicotine response only in male flies, while panneural knock-down occurs in both sexes. Taken together, our results reveal that in fruit flies, dopaminergic neurons mediate nicotine-induced acute locomotor hyperactivity in a sexually dimorphic manner, and Drosophila β1 nAChR subunit plays a crucial role in this nicotine response. These findings provide important insights into the molecular and neural basis of acute nicotine effects, and the underlying mechanisms may play conserved roles across species. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Differential sensitivity of cranial and limb motor function to nigrostriatal dopamine depletion.

    PubMed

    Plowman, Emily K; Maling, Nicholas; Rivera, Benjamin J; Larson, Krista; Thomas, Nagheme J; Fowler, Stephen C; Manfredsson, Fredric P; Shrivastav, Rahul; Kleim, Jeffrey A

    2013-01-15

    The present study determined the differential effects of unilateral striatal dopamine depletion on cranial motor versus limb motor function. Forty male Long Evans rats were first trained on a comprehensive motor testing battery that dissociated cranial versus limb motor function and included: cylinder forepaw placement, single pellet reaching, vermicelli pasta handling; sunflower seed opening, pasta biting acoustics, and a licking task. Following baseline testing, animals were randomized to either a 6-hydroxydopamine (6-OHDA) (n=20) or control (n=20) group. Animals in the 6-OHDA group received unilateral intrastriatal 6-OHDA infusions to induce striatal dopamine depletion. Six-weeks following infusion, all animals were re-tested on the same battery of motor tests. Near infrared densitometry was performed on sections taken through the striatum that were immunohistochemically stained for tyrosine hydroxylase (TH). Animals in the 6-OHDA condition showed a mean reduction in TH staining of 88.27%. Although 6-OHDA animals were significantly impaired on all motor tasks, limb motor deficits were more severe than cranial motor impairments. Further, performance on limb motor tasks was correlated with degree of TH depletion while performance on cranial motor impairments showed no significant correlation. These results suggest that limb motor function may be more sensitive to striatal dopaminergic depletion than cranial motor function and is consistent with the clinical observation that therapies targeting the nigrostriatal dopaminergic system in Parkinson's disease are more effective for limb motor symptoms than cranial motor impairments. Published by Elsevier B.V.

  16. A combinatorial regulatory signature controls terminal differentiation of the dopaminergic nervous system in C. elegans

    PubMed Central

    Doitsidou, Maria; Flames, Nuria; Topalidou, Irini; Abe, Namiko; Felton, Terry; Remesal, Laura; Popovitchenko, Tatiana; Mann, Richard; Chalfie, Martin; Hobert, Oliver

    2013-01-01

    Terminal differentiation programs in the nervous system are encoded by cis-regulatory elements that control the expression of terminal features of individual neuron types. We decoded the regulatory information that controls the expression of five enzymes and transporters that define the terminal identity of all eight dopaminergic neurons in the nervous system of the Caenorhabditis elegans hermaphrodite. We show that the tightly coordinated, robust expression of these dopaminergic enzymes and transporters (“dopamine pathway”) is ensured through a combinatorial cis-regulatory signature that is shared by all dopamine pathway genes. This signature is composed of an Ets domain-binding site, recognized by the previously described AST-1 Ets domain factor, and two distinct types of homeodomain-binding sites that act in a partially redundant manner. Through genetic screens, we identified the sole C. elegans Distalless/Dlx ortholog, ceh-43, as a factor that acts through one of the homeodomain sites to control both induction and maintenance of terminal dopaminergic fate. The second type of homeodomain site is a Pbx-type site, which is recognized in a partially redundant and neuron subtype-specific manner by two Pbx factors, ceh-20 and ceh-40, revealing novel roles of Pbx factors in the context of terminal neuron differentiation. Taken together, we revealed a specific regulatory signature and cognate, terminal selector-type transcription factors that define the entire dopaminergic nervous system of an animal. Dopaminergic neurons in the mouse olfactory bulb express a similar combinatorial transcription factor collective of Ets/Dlx/Pbx factors, suggesting deep phylogenetic conservation of dopaminergic regulatory programs. PMID:23788625

  17. Medications acting on the dopaminergic system in the treatment of alcoholic patients.

    PubMed

    Swift, Robert

    2010-01-01

    An extensive literature supports the role of dopamine in the development and maintenance of alcohol dependence. Yet the organization of brain dopamine is complex, with multiple dopamine receptor subtypes and distinct effects on reinforcement, craving, motivation and behavior. Several modestly effective pharmacological treatments for alcoholism, including naltrexone, baclofen and ondansetron, affect dopaminergic systems indirectly. Direct dopamine antagonists, including tiapride, quetiapine, ondansetron and clozapine have been shown to be somewhat effective in reducing alcohol consumption in controlled clinical trials. The partial dopamine agonist, aripiprazole has shown mixed efficacy. Dopaminergic medications can have significant side effects. A better understanding of how dopamine affects the various aspects of addictive behavior may lead to more effective medications.

  18. Cannabinoid modulation of the dopaminergic circuitry: Implications for limbic and striatal output

    PubMed Central

    Fitzgerald, Megan L.; Shobin, Eli; Pickel, Virginia M.

    2012-01-01

    Cannabinoid modulation of dopaminergic transmission is suggested by the ability of delta9-tetrahydrocanabinoid to affect motor and motivated behaviors in a manner similar to that produced by pharmacological manipulation of the nigrostriatal and mesocorticolimbic dopamine systems. These behavioral effects as well as analogous effects of endocannabinoids are largely mediated through the cannabinoid type 1 receptor (CB1R). This receptor is located within the substantia nigra and ventral tegmental area, which respectively house the somata of nigrostriatal and mesocorticolimbic dopaminergic neurons. The CB1R is also abundantly expressed in brain regions targeted by the efferent terminals of these dopaminergic neurons. In this review we present the accumulating anatomical and electrophysiological evidence indicating that in each of these systems cannabinoids modulate dopamine transmission largely if not exclusively through indirect mechanisms. The summarized mechanisms include presynaptic release of amino acid transmitters onto midbrain dopamine neurons and onto both cortical and striatal neurons that express dopamine D1-like or D2-like receptors functionally affiliated with the CB1 receptor. The review concludes with a consideration of the psychiatric and neurological implications of cannabinoid modulation of dopamine transmission within these networks. PMID:22265889

  19. Exposure to atrazine alters behaviour and disrupts the dopaminergic system in Drosophila melanogaster.

    PubMed

    Figueira, Fernanda Hernandes; de Quadros Oliveira, Natália; de Aguiar, Lais Mattos; Escarrone, Ana Laura; Primel, Ednei Gilberto; Barros, Daniela Martí; da Rosa, Carlos Eduardo

    2017-08-26

    Atrazine is an extensively used herbicide, and has become a common environmental contaminant. Effects on dopaminergic neurotransmission in mammals following exposure to atrazine have been previously demonstrated. Here, the effects of atrazine regarding behavioural and dopaminergic neurotransmission parameters were assessed in the fruit fly D. melanogaster, exposed during embryonic and larval development. Embryos (newly fertilized eggs) were exposed to two atrazine concentrations (10μM and 100μM) in the diet until the adult fly emerged. Negative geotaxis assay, as well as exploratory behaviour, immobility time and number of grooming episodes in an open field system were assessed. Tyrosine hydroxylase (TH) activity and gene expression of the dopaminergic system were also evaluated in newly emerged male and female flies. All analyzed parameters in male flies were not significantly affected by atrazine exposure. However female flies exposed to atrazine at 10μM presented an increase in immobility time and a reduction in exploratory activity in the open field test, which was offset by an increase in the number of grooming episodes. Also, female flies exposed to 100μM of atrazine presented an increase in immobility time. Gene expression of DOPA decarboxylase and dopamine (DA) receptors were also increased only in females. The behavioural effects of atrazine exposure observed in female flies were due to a disturbance in the dopaminergic system. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Malfunctioning DNA damage response (DDR) leads to the degeneration of nigro-striatal pathway in mouse brain.

    PubMed

    Kirshner, Michal; Galron, Ronit; Frenkel, Dan; Mandelbaum, Gil; Shiloh, Yosef; Wang, Zhao-Qi; Barzilai, Ari

    2012-03-01

    Pronounced neuropathology is a feature of ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS), which are both genomic instability syndromes. The Nbs1 protein, which is defective in NBS, is a component of the Mre11/RAD50/NBS1 (MRN) complex. This complex plays a major role in the early phase of the cellular response to double strand breaks (DSBs) in the DNA. Among others, MRN is required for timely activation of the protein kinase ATM (A-T mutated), which is disrupted in patients with A-T. Earlier reports show that Atm-deficient mice exhibit severe degeneration of tyrosine hydroxylase (TH)-positive dopaminergic nigro-striatal neurons and their terminals in the striatum. This cell loss is accompanied by a large reduction in immunoreactivity for the dopamine transporter protein (DAT) in the striatum. To test whether Nbs1 inactivation also affects the integrity of the nigro-striatal pathway, we examined this pathway in a murine model with conditional inactivation of the Nbs1 gene in central nervous system (Nbs1-CNS-Δ). We report that this model has a reduction in TH-positive cells in the substantia nigra. This phenomenon was seen at very early age, while Atm-/- mice showed a progressive age-dependent reduction. Furthermore, we observed an age-dependent increase in the level of TH in the striatum of Atm-/- and Nbs1-CNS-Δ mice. In addition to the altered expression of TH, we also found a reduction of DAT in the striatum of both Atm-/- and Nbs1-CNS-Δ mice at 60 days of age. Finally, microglial recruitment and alterations in the levels of various neurotrophic factors were also observed. These results indicate that malfunctioning DNA damage response severely affects the integrity of the nigro-striatal pathway and suggest a new neurodegenerative pathway in Parkinsonian syndromes.

  1. [Morphological signs of ethanol poisoning, alcohol abstinence and chronic alcoholic intoxication in the mesocorticolimbic dopaminergic system].

    PubMed

    Droblenkov, A V

    2011-01-01

    Forensic medical diagnostics of ethanol poisoning, alcohol abstinence, and chronic alcoholic intoxication of the mesocorticolimbic dopaminergic system remains an unresolved problem and encounters difficulties. This situation is due not only to the marked vulnerability of the neurons of the dopaminergic system but also to the fact that its mechanisms are poorly understood. The objective of the present work was to substantiate and develop diagnostic criteria for ethanol poisoning, alcohol abstinence, and chronic alcoholic intoxication of the neurons both in the mesocorticolimbic dopaminergic system and in other brain regions. The object of the study was the brain of healthy adult subjects who died from alcohol intoxication (in the period of ethanol resorption) and under conditions of alcohol abstinence (completion of the abstinence course). The purpose of the study was to elucidate factors responsible for the different degree of damage to the neurons of various identification groups (intact, hypochromic, picnomorphic, shadow) and macrogliocytes. The cells of all these types were counted at an area of 0.25 sq. mm within 4 squares each having a side of 250 mcm in length. The absolute and relative number of neurons in each group as well as the number of polyneuronal satellite cells per one intact neuron was determined. It was shown that alcohol intoxication is associated with acute swelling of and severe damage to brain neurons caused by the combination of such factors as toxic effect of ethanol, excessive production of catecholamines, and functional overstrain of dopaminergic neurons. The severity of acute alcohol damage to the neurons decreased with the distance from the mid-brain dopaminergic nuclei. Restoration of neurons during alcohol abstinence was due to compensatory activation of interactions between neurons and glial cells. It decreased in the sequence from the paranigral nucleus of the ventral portion of mesencephalic tegumentum to the medial portion of the

  2. MODELING NIGROSTRIATAL DEGENERATION IN ORGANOTYPIC CULTURES, A NEW EX VIVO MODEL OF PARKINSON’S DISEASE

    PubMed Central

    DAVIAUD, N.; GARBAYO, E.; LAUTRAM, N.; FRANCONI, F.; LEMAIRE, L.; PEREZ-PINZON, M.; MONTERO-MENEI, C. N.

    2014-01-01

    Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder afflicting 2% of the population older than 65 years worldwide. Recently, brain organotypic slices have been used to model neurodegenerative disorders, including PD. They conserve brain three-dimensional architecture, synaptic connectivity and its microenvironment. This model has allowed researchers a simple and rapid method to observe cellular interactions and mechanisms. In the present study, we developed an organotypic PD model from rat brains that includes all the areas involved in the nigrostriatal pathway in a single slice preparation, without using neurotoxins to induce the dopaminergic lesion. The mechanical transection of the nigrostriatal pathway obtained during slice preparation induced PD-like histopathology. Progressive nigrostriatal degeneration was monitored combining innovative approaches, such as diffusion tensor magnetic resonance imaging (DT-RMI) to follow fiber degeneration and mass spectrometry to quantify striatal dopamine content, together with bright-field and fluorescence microscopy imaging. A substantia nigra dopaminergic cell number decrease was observed by immunohistochemistry against rat tyrosine hydroxylase (TH) reaching 80% after 2 days in culture associated with a 30% decrease of striatal TH-positive fiber density, a 15% loss of striatal dopamine content quantified by mass spectrometry and a 70% reduction of nigrostriatal fiber fractional anisotropy quantified by DT-RMI. In addition, a significant decline of medium spiny neuron density was observed from days 7 to 16. These sagittal organotypic slices could be used to study the early stage of PD, namely dopaminergic degeneration, and the late stage of the pathology with dopaminergic and GABAergic neuron loss. This novel model might improve the understanding of PD and may represent a promising tool to refine the evaluation of new therapeutic approaches. PMID:24161279

  3. The amygdalo-nigrostriatal network is critical for an optimal temporal performance

    PubMed Central

    Es-seddiqi, Mouna; El Massioui, Nicole; Samson, Nathalie; Brown, Bruce L.

    2016-01-01

    The amygdalo-nigrostriatal (ANS) network plays an essential role in enhanced attention to significant events. Interval timing requires attention to temporal cues. We assessed rats having a disconnected ANS network, due to contralateral lesions of the medial central nucleus of the amygdala (CEm) and dopaminergic afferents to the lateral striatum, as compared to controls (sham and ipsilateral lesions of CEm and dopaminergic afferents to LS) in a temporal bisection task. ANS disconnection induced poorer temporal precision and increased response latencies to a short duration. The present results reveal a role of the ANS network in temporal processing. PMID:26884227

  4. HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity.

    PubMed

    Samikkannu, Thangavel; Rao, Kurapati V K; Salam, Abdul Ajees Abdul; Atluri, Venkata S R; Kaftanovskaya, Elena M; Agudelo, Marisela; Perez, Suray; Yoo, Changwon; Raymond, Andrea D; Ding, Hong; Nair, Madhavan P N

    2015-06-09

    HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, α -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity.

  5. Perturbation of transcription factor Nur77 expression mediated by myocyte enhancer factor 2D (MEF2D) regulates dopaminergic neuron loss in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

    PubMed

    Mount, Matthew P; Zhang, Yi; Amini, Mandana; Callaghan, Steve; Kulczycki, Jerzy; Mao, Zixu; Slack, Ruth S; Anisman, Hymie; Park, David S

    2013-05-17

    We have earlier reported the critical nature of calpain-CDK5-MEF2 signaling in governing dopaminergic neuronal loss in vivo. CDK5 mediates phosphorylation of the neuronal survival factor myocyte enhancer factor 2 (MEF2) leading to its inactivation and loss. However, the downstream factors that mediate MEF2-regulated survival are unknown. Presently, we define Nur77 as one such critical downstream survival effector. Following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo, Nur77 expression in the nigrostriatal region is dramatically reduced. This loss is attenuated by expression of MEF2. Importantly, MEF2 constitutively binds to the Nur77 promoter in neurons under basal conditions. This binding is lost following 1-methyl-4-phenylpyridinium treatment. Nur77 deficiency results in significant sensitization to dopaminergic loss following 1-methyl-4-phenylpyridinium/MPTP treatment, in vitro and in vivo. Furthermore, Nur77-deficient MPTP-treated mice displayed significantly reduced levels of dopamine and 3,4-Dihydroxyphenylacetic acid in the striatum as well as elevated post synaptic FosB activity, indicative of increased nigrostriatal damage when compared with WT MPTP-treated controls. Importantly, this sensitization in Nur77-deficient mice was rescued with ectopic Nur77 expression in the nigrostriatal system. These results indicate that the inactivation of Nur77, induced by loss of MEF2 activity, plays a critical role in nigrostriatal degeneration in vivo.

  6. Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypothesis.

    PubMed

    Pereira, Jose Carlos; Pradella-Hallinan, Marcia; Lins Pessoa, Hugo de

    2010-05-01

    Data collected from medical literature indicate that dopaminergic agonists alleviate Restless Legs Syndrome symptoms while dopaminergic agonists antagonists aggravate them. Dopaminergic agonists is a physiological regulator of thyroid-stimulating hormone. Dopaminergic agonists infusion diminishes the levels of thyroid hormones, which have the ability to provoke restlessness, hyperkinetic states, tremors, and insomnia. Conditions associated with higher levels of thyroid hormones, such as pregnancy or hyperthyroidism, have a higher prevalence of Restless Legs Syndrome symptoms. Low iron levels can cause secondary Restless Legs Syndrome or aggravate symptoms of primary disease as well as diminish enzymatic activities that are involved in dopaminergic agonists production and the degradation of thyroid hormones. Moreover, as a result of low iron levels, dopaminergic agonists diminishes and thyroid hormones increase. Iron therapy improves Restless Legs Syndrome symptoms in iron deprived patients. Medical hypothesis. To discuss the theory that thyroid hormones, when not counterbalanced by dopaminergic agonists, may precipitate the signs and symptoms underpinning Restless Legs Syndrome. The main cause of Restless Legs Syndrome might be an imbalance between the dopaminergic agonists system and thyroid hormones.

  7. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration.

    PubMed

    Mor, Danielle E; Tsika, Elpida; Mazzulli, Joseph R; Gould, Neal S; Kim, Hanna; Daniels, Malcolm J; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L; Tan, Victor X; Kalb, Robert G; Caldwell, Kim A; Caldwell, Guy A; Wolfe, John H; Ischiropoulos, Harry

    2017-09-18

    Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

  8. Regional analysis and genetic association of nigrostriatal degeneration in Lewy body disease.

    PubMed

    Kasanuki, Koji; Heckman, Michael G; Diehl, Nancy N; Murray, Melissa E; Koga, Shunsuke; Soto, Alexandra; Ross, Owen A; Dickson, Dennis W

    2017-09-26

    A number of genetic loci are associated with risk for Parkinson's disease (PD) based on genome-wide association studies; however, the relationship between genetic variants and nigrostriatal degeneration, which is the structural correlate of parkinsonism, has not been reported. We quantified nigrostriatal dopaminergic integrity with image analysis of putaminal tyrosine hydroxylase immunoreactivity in 492 brains with Lewy body disease and used this pathologic endophenotype to explore possible association with PD genetic variants. The study cases had Lewy-related pathology and variable degrees of nigrostriatal degeneration. They were assigned to one of the following clinical subgroups according to their predominant clinical syndrome: parkinsonism-predominant, parkinsonism+dementia, and dementia-predominant. In addition to putaminal tyrosine hydroxylase immunoreactivity, semiquantitative scoring was used to assess substantia nigra neuronal loss. A total of 29 PD genetic risk variants were genotyped on each case. When compared with controls, tyrosine hydroxylase immunoreactivity was reduced in Lewy body cases in the dorsolateral (79%) and ventromedial (57%) putamen. The dorsolateral region was better preserved in dementia-predominant cases than in cases with parkinsonism. Dorsolateral putaminal tyrosine hydroxylase immunoreactivity correlated with neuronal loss in the ventrolateral substantia nigra. Genetic analyses showed no significant association of PD risk variants with putaminal tyrosine hydroxylase immunoreactivity. The results confirm regional differences in putaminal dopaminergic degeneration and vulnerability of nigrostriatal pathway in Lewy body disorders with parkinsonism. The lack of association with PD genetic risk variants suggests that they may not be associated with quantitative endophenotypes of nigrostriatal degeneration, but more likely related to the risk of disease per se. © 2017 International Parkinson and Movement Disorder Society. © 2017

  9. Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation

    PubMed Central

    Meyer, Michael F.; Krasnianski, Michael

    2010-01-01

    The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders. PMID:21076988

  10. Roles for nigrostriatal--not just mesocorticolimbic--dopamine in reward and addiction.

    PubMed

    Wise, Roy A

    2009-10-01

    Forebrain dopamine circuitry has traditionally been studied by two largely independent specialist groups: students of Parkinson's disease who study the nigrostriatal dopamine system that originates in the substantia nigra (SN), and students of motivation and addiction who study the role of the mesolimbic and mesocortical dopamine systems that originate in the ventral tegmental area (VTA). The anatomical evidence for independent nigrostriatal and mesolimbic dopamine systems has, however, long been obsolete. There is now compelling evidence that both nominal "systems" participate in reward function and addiction. Electrical stimulation of both SN and VTA is rewarding, blockade of glutamatergic or cholinergic input to either SN or VTA attenuates the habit-forming effects of intravenous cocaine, and dopamine in both nigrostriatal and mesocorticolimbic terminal fields participates in the defining property of rewarding events: the reinforcement of memory consolidation. Thus, the similarities between nigrostriatal and mesolimbic dopamine systems can be as important as their differences.

  11. Dopamine-Dependent Compensation Maintains Motor Behavior in Mice with Developmental Ablation of Dopaminergic Neurons

    PubMed Central

    DeMaro, Joseph A.; Knoten, Amanda; Hoshi, Masato; Pehek, Elizabeth; Johnson, Eugene M.; Gereau, Robert W.

    2013-01-01

    The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and consequent depletion of striatal dopamine are known to underlie the motor deficits observed in Parkinson's disease (PD). Adaptive changes in dopaminergic terminals and in postsynaptic striatal neurons can compensate for significant losses of striatal dopamine, resulting in preservation of motor behavior. In addition, compensatory changes independent of striatal dopamine have been proposed based on PD therapies that modulate nondopaminergic circuits within the basal ganglia. We used a genetic strategy to selectively destroy dopaminergic neurons in mice during development to determine the necessity of these neurons for the maintenance of normal motor behavior in adult and aged mice. We find that loss of 90% of SNc dopaminergic neurons and consequent depletion of >95% of striatal dopamine does not result in changes in motor behavior in young-adult or aged mice as evaluated by an extensive array of motor behavior tests. Treatment of aged mutant mice with the dopamine receptor antagonist haloperidol precipitated motor behavior deficits in aged mutant mice, indicating that <5% of striatal dopamine is sufficient to maintain motor function in these mice. We also found that mutant mice exhibit an exaggerated response to l-DOPA compared with control mice, suggesting that preservation of motor function involves sensitization of striatal dopamine receptors. Our results indicate that congenital loss of dopaminergic neurons induces remarkable adaptions in the nigrostriatal system where limited amounts of dopamine in the dorsal striatum can maintain normal motor function. PMID:24155314

  12. Creative cognition and dopaminergic modulation of fronto-striatal networks: Integrative review and research agenda.

    PubMed

    Boot, Nathalie; Baas, Matthijs; van Gaal, Simon; Cools, Roshan; De Dreu, Carsten K W

    2017-07-01

    Creative cognition is key to human functioning yet the underlying neurobiological mechanisms are sparsely addressed and poorly understood. Here we address the possibility that creative cognition is a function of dopaminergic modulation in fronto-striatal brain circuitries. It is proposed that (i) creative cognition benefits from both flexible and persistent processing, (ii) striatal dopamine and the integrity of the nigrostriatal dopaminergic pathway is associated with flexible processing, while (iii) prefrontal dopamine and the integrity of the mesocortical dopaminergic pathway is associated with persistent processing. We examine this possibility in light of studies linking creative ideation, divergent thinking, and creative problem-solving to polymorphisms in dopamine receptor genes, indirect markers and manipulations of the dopaminergic system, and clinical populations with dysregulated dopaminergic activity. Combined, studies suggest a functional differentiation between striatal and prefrontal dopamine: moderate (but not low or high) levels of striatal dopamine benefit creative cognition by facilitating flexible processes, and moderate (but not low or high) levels of prefrontal dopamine enable persistence-driven creativity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Atrial Natriuretic Peptide and Renal Dopaminergic System: A Positive Friendly Relationship?

    PubMed Central

    Choi, Marcelo Roberto; Rukavina Mikusic, Natalia Lucía; Kouyoumdzian, Nicolás Martín; Kravetz, María Cecilia; Fernández, Belisario Enrique

    2014-01-01

    Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization) which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways. PMID:25013796

  14. Working memory training impacts the mean diffusivity in the dopaminergic system.

    PubMed

    Takeuchi, Hikaru; Taki, Yasuyuki; Nouchi, Rui; Hashizume, Hiroshi; Sekiguchi, Atsushi; Kotozaki, Yuka; Nakagawa, Seishu; Miyauchi, Carlos Makoto; Sassa, Yuko; Kawashima, Ryuta

    2015-11-01

    Dopaminergic transmission plays a critical role in working memory (WM). Mean diffusivity (MD) is a sensitive and unique neuroimaging tool for detecting microstructural differences particularly in the areas of the dopaminergic system. Despite previous investigation of the effects of WM training (WMT) on dopamine receptor binding potentials, the effects of WMT on MD remain unknown. In this study, we investigated these effects in young adult subjects who either underwent WMT or received no intervention for 4 weeks. Before and after the intervention or no-intervention periods, subjects underwent scanning sessions in diffusion-weighted imaging to measure MD. Compared with no intervention, WMT resulted in an increase in MD in the bilateral caudate, right putamen, left dorsolateral prefrontal cortex (DLPFC), right anterior cingulate cortex (ACC), right substantia nigra, and ventral tegmental area. Furthermore, the increase in performance on WMT tasks was significantly positively correlated with the mean increase in MD in the clusters of the left DLPFC and of the right ACC. These results suggest that WMT caused microstructural changes in the regions of the dopaminergic system in a way that is usually interpreted as a reduction in neural components.

  15. Pentadecapeptide BPC 157 interactions with adrenergic and dopaminergic systems in mucosal protection in stress.

    PubMed

    Sikirić, P; Mazul, B; Seiwerth, S; Grabarević, Z; Rucman, R; Petek, M; Jagić, V; Turković, B; Rotkvić, I; Mise, S; Zoricić, I; Jurina, L; Konjevoda, P; Hanzevacki, M; Gjurasin, M; Separović, J; Ljubanović, D; Artuković, B; Bratulić, M; Tisljar, M; Miklić, P; Sumajstorcić, J

    1997-03-01

    Since superior protection against different gastrointestinal and liver lesions and antiinflammatory and analgesic activities were noted for pentadecapeptide BPC (an essential fragment of an organoprotective gastric juice protein named BPC), the beneficial mechanism of BPC 157 and its likely interactions with other systems were studied. Hence its beneficial effects would be abolished by adrenal gland medullectomy, the influence of different agents affecting alpha, beta, and dopamine receptors on BPC 157 gastroprotection in 48 h restraint stress was further investigated. Animals were pretreated (1 hr before stress) with saline (controls) or BPC 157 (dissolved in saline) (10 microg or 10 ng/kg body wt intraperitoneally or intragastrically) applied either alone to establish basal conditions or, when manipulating the adrenergic or dopaminergic system, a simultaneous administration was carried out with various agents with specific effects on adrenergic or dopaminergic receptors [given in milligrams per kilogram intraperitoneally except for atenolol, which was given subcutaneously] phentolamine (10.0), prazosin (0.5), yohimbine (5.0), clonidine (0.1) (alpha-adrenergic domain), propranolol (1.0), atenolol (20.0) (beta-adrenergic domain), domperidone (5.0), and haloperidol (5.0) (peripheral/central dopamine system). Alternatively, agents stimulating adrenergic or dopaminergic systems--adrenaline (5.0) or bromocriptine (10.0)--were applied. A strong protection, noted following intragastric or intraperitoneal administration of BPC 157, was fully abolished by coadministration of phentolamine, clonidine, and haloperidol, and consistently not affected by prazosin, yohimbine, or domperidone. Atenolol abolished only intraperitoneal BPC 157 protection, whereas propranolol affected specifically intragastric BPC 157 protection. Interestingly, the severe course of lesion development obtained in basal conditions, unlike BPC 157 gastroprotection, was not influenced by the application of

  16. Splenectomy modifies hyperactive states of the dopaminergic system induced by morphine in C57BL/6J-bg(J)/bg(J) (beige-J) mice.

    PubMed

    Funada, Masahiko; Mori, Tomohisa; Maeda, Jun; Tsuda, Yuko; Komiya, Sachiko; Shimizu, Norifumi; Kamei, Junzo; Suzuki, Tsutomu

    2014-11-05

    Genetic factors affect the locomotor activity induced by morphine, which mainly depends on the activation of dopaminergic systems, and morphine has distinct pharmacological activities in C57BL/6J-bg(J)bg(J) (beige-J) mice, which have genetic deficiencies in immunological function. We previously showed that beige-J mice exhibited greater locomotor activity and dopamine turnover, whereas splenectomy reduced this hyperlocomotion and dopamine turnover, which suggests that beige-J mice could be an experimental animal model for investigating hyperactivation of the dopaminergic system, and that the spleen may contribute to the susceptibility to activation of the dopaminergic system. Furthermore, morphine can induce hyperlocomotion mediated by activation of the dopaminergic system. Therefore, we examined the effects of splenectomy on the hyperlocomotion and regulation of the dopaminergic system induced by morphine in beige-J mice. Morphine induced hyperlocomotion, which was accompanied by activation of the dopaminergic system, in beige-J mice. Furthermore, splenectomy enhanced the hyperlocomotion and activation of the mesolimbic dopaminergic system induced by morphine in beige-J mice. Our findings indicate that substances originating from the spleen may regulate both spontaneous activation of the mesolimbic dopaminergic system and the µ-opioidergic system-mediated activation of the mesolimbic dopaminergic system by morphine through different modes of action. These results imply that beige-J mice could be a practical animal model for investigating the interactions between immune-modulation and the µ-opioidergic system and/or dopaminergic system.

  17. Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.

    PubMed

    Nordströma, Ulrika; Beauvais, Geneviève; Ghosh, Anamitra; Pulikkaparambil Sasidharan, Baby Chakrapani; Lundblad, Martin; Fuchs, Julia; Joshi, Rajiv L; Lipton, Jack W; Roholt, Andrew; Medicetty, Satish; Feinstein, Timothy N; Steiner, Jennifer A; Escobar Galvis, Martha L; Prochiantz, Alain; Brundin, Patrik

    2015-01-01

    Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely

  18. Clinical Investigation of the Dopaminergic System with PET and FLUORINE-18-FLUORO-L-DOPA.

    NASA Astrophysics Data System (ADS)

    Oakes, Terrence Rayford

    1995-01-01

    Positron Emission Tomography (PET) is a tool that provides quantitative physiological information. It is valuable both in a clinical environment, where information is sought for an individual, and in a research environment, to answer more fundamental questions about physiology and disease states. PET is particularly attractive compared to other nuclear medicine imaging techniques in cases where the anatomical regions of interest are small or when true metabolic rate constants are required. One example with both of these requirements is the investigation of Parkinson's Disease, which is characterized as a presynaptic motor function deficit affecting the striatum. As dopaminergic neurons die, the ability of the striatum to affect motor function decreases. The extent of functional neuronal damage in the small sub-structures may be ascertained by measuring the ability of the caudate and putamen to trap and store dopamine, a neurotransmitter. PET is able to utilize a tracer of dopamine activity, ^ {18}F- scL-DOPA, to quantitate the viability of the striatum. This thesis work deals with implementing and optimizing the many different elements that compose a PET study of the dopaminergic system, including: radioisotope production; conversion of aqueous ^{18}F ^-into [^ {18}F]-F2; synthesis of ^{18}F- scL -DOPA; details of the PET scan itself; measurements to estimate the radiation dosimetry; accurate measurement of a plasma input function; and the quantitation of dopaminergic activity in normal human subjects as well as in Parkinson's Disease patients.

  19. Involvement of the dopaminergic system in the central orexin-induced antinociceptive action against colonic distension in conscious rats.

    PubMed

    Okumura, Toshikatsu; Nozu, Tsukasa; Kumei, Shima; Takakusaki, Kaoru; Miyagishi, Saori; Ohhira, Masumi

    2015-09-25

    We have recently demonstrated that orexin acts centrally in the brain to induce antinociceptive action against colonic distension through orexin 1 receptors in conscious rats. Although the dopaminergic system can induce antinociceptive action for somatic pain, the association between changes in the dopaminergic system and visceral pain perception has not been investigated. In the present study, we hypothesized that the dopaminergic system may be involved in visceral nociception, and if so, the dopaminergic system may mediate the orexin-induced visceral antinociception. Visceral sensation was evaluated using the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternal injection of D1 (SKF38398) or D2 (quinpirole) dopamine receptor agonist increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner. Pretreatment with either the D1 or D2 dopamine receptor antagonist (SCH23390 or sulpiride, respectively) potently blocked the centrally injected orexin-A-induced antinociceptive action against colonic distension. These results suggest for the first time that dopaminergic signaling via D1 and D2 dopamine receptors in the brain may induce visceral antinociception and that the dopaminergic signaling may be involved in the central orexin-induced antinociceptive action against colonic distension.

  20. Optimisation of murine organotypic slice culture preparation for a novel sagittal-frontal co-culture system.

    PubMed

    Joost, Sarah; Kobayashi, Kazuto; Wree, Andreas; Haas, Stefan Jean-Pierre

    2017-06-15

    The nigrostriatal pathway is of great importance for the execution of movements, especially in the context of Parkinson's disease. In research, analysis of this pathway often requires the application of severe animal experiments. Organotypic nigrostriatal slice cultures offer a resource-saving alternative to animal experiments for research on the nigrostriatal system. We have established a time-saving protocol for the preparation of murine sagittal nigrostriatal slice cultures by using a tissue chopper and agarose embedding instead of a vibratome. Furthermore, we developed the first murine co-culture model and the first co-culture utilising sagittal slices for modelling the nigrostriatal pathway. Sagittal nigrostriatal slice cultures show good overall tissue preservation and a high number of morphologically unimpaired dopaminergic neurons in the substantia nigra. Sagittal-frontal co-culture demonstrates massive outgrowth of dopaminergic fibres from the substantia nigra into co-cultured tissue. The use of a tissue chopper instead of a vibratome allows notable time-saving during culture preparation, therefore allowing optimisation of the preparation time. Sagittal co-cultures offer the opportunity to study dopaminergic fibres in their physiological environment and in co-cultured tissue from a different animal in the same culture system. We here present a possibility to optimise the slice culture preparation process with the simple means of using a tissue chopper and fast agarose embedding. Furthermore, our sagittal-frontal co-culture system is suitable for the observation of dopaminergic outgrowth in both co-cultured tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function.

    PubMed

    Abdallah, Luna; Bonasera, Stephen J; Hopf, F Woodward; O'Dell, Laura; Giorgetti, Marco; Jongsma, Minke; Carra, Scott; Pierucci, Massimo; Di Giovanni, Giuseppe; Esposito, Ennio; Parsons, Loren H; Bonci, Antonello; Tecott, Laurence H

    2009-06-24

    The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT(2C)R) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT(2C)Rs produces marked alterations in the activity and functional output of this pathway. 5-HT(2C)R mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of d-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D(1) receptor agonist SKF 81297. Differences in DSt D(1) or D(2) receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT(2C)Rs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.

  2. Impact of Serotonin 2C Receptor Null Mutation on Physiology and Behavior Associated with Nigrostriatal Dopamine Pathway Function

    PubMed Central

    Abdallah, Luna; Bonasera, Stephen J.; Hopf, F. Woodward; O’Dell, Laura; Giorgetti, Marco; Jongsma, Minke; Carra, Scott; Pierucci, Massimo; Di Giovanni, Giuseppe; Esposito, Ennio; Parsons, Loren H.; Bonci, Antonello; Tecott, Laurence H.

    2011-01-01

    The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT2CR) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT2CRs produces marked alterations in the activity and functional output of this pathway. 5-HT2CR mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of D-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D1 receptor agonist SKF 81297. Differences in DSt D1 or D2 receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT2CRs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt. PMID:19553455

  3. An update on the connections of the ventral mesencephalic dopaminergic complex

    PubMed Central

    Yetnikoff, Leora; Lavezzi, Heather N.; Reichard, Rhett A.; Zahm, Daniel S.

    2014-01-01

    This review covers the intrinsic organization and afferent and efferent connections of the midbrain dopaminergic complex, comprising the substantia nigra, ventral tegmental area and retrorubral field, which house, respectively, the A9, A10 and A8 groups of nigrostriatal, mesolimbic and mesocortical dopaminergic neurons. In addition, A10dc (dorsal, caudal) and A10rv (rostroventral) extensions into, respectively, the ventrolateral periaqueductal gray and supramammillary nucleus are discussed. Associated intrinsic and extrinsic connections of the midbrain dopaminergic complex that utilize gamma-aminobutyric acid (GABA), glutamate and neuropeptides and various co-expressed combinations of these compounds are considered in conjunction with the dopamine-containing systems. A framework is provided for understanding the organization of masssive afferent systems descending and ascending to the midbrain dopaminergic complex from the telencephalon and brainstem, respectively. Within the context of this framework, the basal ganglia direct and indirect output pathways are treated in some detail. Findings from rodent brain are briefly compared with those from primates, including human. Recent literature is emphasized, including traditional experimental neuroanatomical and modern gene transfer and optogenetic studies. An attempt was made to provide sufficient background and cite a representative sampling of earlier primary papers and reviews so that people new to the field may find this to be a relatively comprehensive treatment of the subject. PMID:24735820

  4. Recent Advances in Imaging of Dopaminergic Neurons for Evaluation of Neuropsychiatric Disorders

    PubMed Central

    Shen, Lie-Hang; Liao, Mei-Hsiu; Tseng, Yu-Chin

    2012-01-01

    Dopamine is the most intensely studied monoaminergic neurotransmitter. Dopaminergic neurotransmission plays an important role in regulating several aspects of basic brain function, including motor, behavior, motivation, and working memory. To date, there are numerous positron emission tomography (PET) and single photon emission computed tomography (SPECT) radiotracers available for targeting different steps in the process of dopaminergic neurotransmission, which permits us to quantify dopaminergic activity in the living human brain. Degeneration of the nigrostriatal dopamine system causes Parkinson's disease (PD) and related Parkinsonism. Dopamine is the neurotransmitter that has been classically associated with the reinforcing effects of drug abuse. Abnormalities within the dopamine system in the brain are involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Dopamine receptors play an important role in schizophrenia and the effect of neuroleptics is through blockage of dopamine D2 receptors. This review will concentrate on the radiotracers that have been developed for imaging dopaminergic neurons, describe the clinical aspects in the assessment of neuropsychiatric disorders, and suggest future directions in the diagnosis and management of such disorders. PMID:22570524

  5. The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans

    PubMed Central

    Eisner, Gilbert M.; Armando, Ines; Browning, Shaunagh; Pezzullo, John C.; Rhee, Lauren; Dajani, Mustafa; Carey, Robert M.; Jose, Pedro A.

    2016-01-01

    The renin-angiotensin-aldosterone (RAAS) and renal dopaminergic systems interact to maintain sodium balance. High NaCl intake increases renal synthesis of dopamine and dopaminergic receptor activity, decreasing epithelial sodium transport, whereas sodium deficit activates the RAAS, increasing epithelial sodium transport. We tested the hypothesis that attenuation of the natriuretic effect of dopamine D1-like receptors during salt restriction results in part from increased RAAS activity in seven salt-resistant normotensive adults using a double-blind placebo-controlled balanced crossover design. All subjects attained sodium balance on low (50 mmol Na+/day) and high (300 mmol Na+/day) NaCl diets, administered 4 weeks apart. Sodium, potassium, lithium, para-aminohippurate, and creatinine clearances were measured before, during, and after a 3-hour infusion of fenoldopam, a D1-like receptor agonist, with and without pretreatment with enalapril, an angiotensin converting enzyme inhibitor. On the high NaCl diet, fenoldopam-induced natriuresis was associated with the inhibition of renal proximal and distal tubule sodium transport. On the low NaCl diet, fenoldopam decreased renal distal tubule sodium transport but did not cause natriuresis. The addition of enalapril to fenoldopam restored the natriuretic effect of fenoldopam and its inhibitory effect on proximal tubule sodium transport. Thus, on a high NaCl diet fenoldopam causes natriuresis by inhibiting renal proximal and distal tubule transport, but on a low NaCl diet the increased RAAS activity prevents the D1-like receptor from inhibiting renal proximal tubule sodium transport, neutralizing the natriuretic effect of fenoldopam. These results demonstrate an interaction between the renin-angiotensin and renal dopaminergic systems in humans and highlight the influence of dietary NaCl on these interactions. PMID:25977313

  6. Testosterone Induces Molecular Changes in Dopamine Signaling Pathway Molecules in the Adolescent Male Rat Nigrostriatal Pathway

    PubMed Central

    Purves-Tyson, Tertia D.; Owens, Samantha J.; Double, Kay L.; Desai, Reena; Handelsman, David J.; Weickert, Cynthia Shannon

    2014-01-01

    Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor

  7. The effects of nigrostriatal dopamine depletion on the thalamic parafascicular nucleus.

    PubMed

    Kusnoor, Sheila V; Bubser, Michael; Deutch, Ariel Y

    2012-03-29

    Neuronal loss in Parkinson's disease (PD) is seen in a number of brain regions in addition to the substantia nigra (SN). Among these is the thalamic parafascicular nucleus (PF), which sends glutamatergic projections to the striatum and receives GABAergic inputs from the SN. Recent data suggest that lesions of nigrostriatal dopamine axons cause a loss of PF neurons, which has been interpreted to suggest that the PF cell loss seen in PD is secondary to dopamine denervation. However, the extent of a PF dopamine innervation in the rat is unclear, and it is possible that PF cell loss in parkinsonism is independent of nigrostriatal dopamine degeneration. We characterized the dopamine innervation of the PF in the rat and determined if 6-hydroxydopamine SN lesions cause PF neuron degeneration. Dual-label immunohistochemistry revealed that almost all tyrosine hydroxylase-immunoreactive (TH-ir) axons in the PF also expressed dopamine-beta-hydroxylase and were therefore noradrenergic or adrenergic. Moreover, an antibody directed against dopamine revealed only very rare PF dopaminergic axons. Retrograde-tract tracing-immunohistochemistry did not uncover an innervation of the PF from midbrain dopamine neurons. Nigrostriatal dopamine neuron lesions did not elicit degeneration of PF cells, as reflected by a lack of FluoroJade C staining. Similarly, neither unilateral 6-OHDA lesions of nigrostriatal axons nor the dorsal noradrenergic bundle decreased the number of PF neurons or the number of PF neurons retrogradely-labeled from the striatum. These data suggest that the loss of thalamostriatal PF neurons in Parkinson's Disease is a primary event rather than secondary to nigrostriatal dopamine degeneration.

  8. Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system.

    PubMed

    Kim, Heung Deok; Jeong, Kyoung Hoon; Jung, Un Ju; Kim, Sang Ryong

    2016-02-01

    We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD.

  9. Prokineticin-2 upregulation during neuronal injury mediates a compensatory protective response against dopaminergic neuronal degeneration

    PubMed Central

    Gordon, Richard; Neal, Matthew L.; Luo, Jie; Langley, Monica R.; Harischandra, Dilshan S.; Panicker, Nikhil; Charli, Adhithiya; Jin, Huajun; Anantharam, Vellareddy; Woodruff, Trent M.; Zhou, Qun-Yong; Kanthasamy, Anumantha G.; Kanthasamy, Arthi

    2016-01-01

    Prokineticin-2 (PK2), a recently discovered secreted protein, regulates important physiological functions including olfactory biogenesis and circadian rhythms in the CNS. Interestingly, although PK2 expression is low in the nigral system, its receptors are constitutively expressed on nigrostriatal neurons. Herein, we demonstrate that PK2 expression is highly induced in nigral dopaminergic neurons during early stages of degeneration in multiple models of Parkinson's disease (PD), including PK2 reporter mice and MitoPark mice. Functional studies demonstrate that PK2 promotes mitochondrial biogenesis and activates ERK and Akt survival signalling pathways, thereby driving neuroprotection. Importantly, PK2 overexpression is protective whereas PK2 receptor antagonism exacerbates dopaminergic degeneration in experimental PD. Furthermore, PK2 expression increased in surviving nigral dopaminergic neurons from PD brains, indicating that PK2 upregulation is clinically relevant to human PD. Collectively, our results identify a paradigm for compensatory neuroprotective PK2 signalling in nigral dopaminergic neurons that could have important therapeutic implications for PD. PMID:27703142

  10. Addiction pharmacogenetics: A systematic review of the genetic variation of the dopaminergic system

    PubMed Central

    Patriquin, Michelle A.; Bauer, Isabelle E.; Soares, Jair C.; Graham, David P.; Nielsen, David A.

    2015-01-01

    Substance use disorders have significant personal, familial, and societal consequences. Despite the serious consequences of substance use, only a few therapies are effective in treating substance use disorders, thus highlighting a need for improved treatment practices. Substance use treatment response depends on multiple factors such as genetic, biological, and social. It is essential that each component is represented in treatment plans. The dopaminergic system plays a critical role in pharmacotherapy for the addictions and an understanding of the role of variation of genes involved in this system is essential for its success. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines. A computerized literature search was conducted using PubMed and Scopus (all databases). Articles published up to April 2015 that examined the role of dopaminergic gene variation in the pharmacotherapy of alcohol, opioid, and cocaine substance use disorders were reviewed. Search terms were dopamine, gene, polymorphism, substance abuse, treatment, and response. Polymorphisms of the DRD2, ANKK1, DAT1, DBH, and DRD4 genes have been found to moderate the effects of the pharmacotherapy of alcohol, opioid, and cocaine substance use disorders. The integration of genetic information with clinical data will inform health professionals of the most efficacious pharmacotherapy intervention for substance use disorders. More studies are needed to confirm and extend these findings. PMID:26146874

  11. The neuroprotective effects of Semax in conditions of MPTP-induced lesions of the brain dopaminergic system.

    PubMed

    Levitskaya, N G; Sebentsova, E A; Andreeva, L A; Alfeeva, L Yu; Kamenskii, A A; Myasoedov, N F

    2004-05-01

    This report describes studies cf the effects of the ACTH(4-10) analog Semax (MEHFPGP) on the behavior of white rats with lesions to the brain dopaminergic system induced by the neurotoxin MPTP. Neurotoxin was given as single i.p. doses of 25 mg/kg. Neurotoxin injections were shown to decrease movement activity and increase anxiety in the animals. Daily intranasal administration of Semax at a dose of 0.2 mg/kg decreased the severity of MPTP-induced behavioral disturbances. The protective activity of Semax in MPTP-induced lesions of the brain dopaminergic system may be associated with both its modulating effect on the dopaminergic system and the neurotrophic action of the peptide.

  12. Dynamic Nigrostriatal Dopamine Biases Action Selection.

    PubMed

    Howard, Christopher D; Li, Hao; Geddes, Claire E; Jin, Xin

    2017-03-22

    Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn't reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons or optogenetic manipulation of dopamine concentration alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions, and they have important implications for neurological disorders, including Parkinson's disease and substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review

    PubMed Central

    Dahoun, T; Trossbach, S V; Brandon, N J; Korth, C; Howes, O D

    2017-01-01

    Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here we summarise the impact of DISC1 disruption on the dopamine system in animal models, considering its effects on presynaptic dopaminergic function (tyrosine hydroxylase levels, dopamine transporter levels, dopamine levels at baseline and after amphetamine administration) and postsynaptic dopaminergic function (dopamine D1 and D2 receptor levels, dopamine receptor-binding potential and locomotor activity after amphetamine administration). Our findings show that many but not all DISC1 models display (1) increased locomotion after amphetamine administration, (2) increased dopamine levels after amphetamine administration in the nucleus accumbens, and (3) inconsistent basal dopamine levels, dopamine receptor levels and binding potentials. There is also limited evidence for decreased tyrosine hydroxylase levels in the frontal cortex and increased dopamine transporter levels in the striatum but not nucleus accumbens, but these conclusions warrant further replication. The main dopaminergic findings are seen across different DISC1 models, providing convergent evidence that DISC1 has a role in regulating dopaminergic function. These results implicate dopaminergic dysregulation as a mechanism underlying the increased rate of schizophrenia seen in DISC1 variant carriers, and provide insights into how DISC1, and potentially DISC1-interacting proteins such as AKT and GSK-3, could be used as novel therapeutic targets for schizophrenia. PMID:28140405

  14. Molecular basis of the dopaminergic system in the cricket Gryllus bimaculatus.

    PubMed

    Watanabe, Takayuki; Sadamoto, Hisayo; Aonuma, Hitoshi

    2013-12-01

    In insects, dopamine modulates various aspects of behavior such as learning and memory, arousal and locomotion, and is also a precursor of melanin. To elucidate the molecular basis of the dopaminergic system in the field cricket Gryllus bimaculatus DeGeer, we identified genes involved in dopamine biosynthesis, signal transduction, and dopamine re-uptake in the cricket. Complementary DNA of two isoforms of tyrosine hydroxylase (TH), which convert tyrosine into L-3,4-dihydroxyphenylalanine, was isolated from the cricket brain cDNA library. In addition, four dopamine receptor genes (Dop1, Dop2, Dop3, and DopEcR) and a high-affinity dopamine transporter gene were identified. The two TH isoforms contained isoform-specific regions in the regulatory ACT domain and showed differential expression patterns in different tissues. In addition, the dopamine receptor genes had a receptor subtype-specific distribution: the Dop1, Dop2, and DopEcR genes were broadly expressed in various tissues at differential expression levels, and the Dop3 gene was restrictedly expressed in neuronal tissues and the testicles. Our findings provide a fundamental basis for understanding the dopaminergic regulation of diverse physiological processes in the cricket.

  15. The influence of the dopaminergic system on cognitive functioning: A molecular genetic approach.

    PubMed

    Reuter, Martin; Peters, Kristina; Schroeter, Katrin; Koebke, Wolfgang; Lenardon, Daniela; Bloch, Birte; Hennig, Juergen

    2005-10-14

    Many pharmacological and clinical studies have demonstrated the importance of the dopaminergic (DA) system for cognitive functioning but little is known about the genetic basis of general cognitive ability that has been demonstrated to be highly heritable. Attempts to detect associations between certain gene loci and endophenotypes of general cognitive ability have turned out to be more promising. Therefore, the aim of the present study was to investigate two dopaminergic candidate genes (COMT VAL158MET and DRD2 TAQ IA) for endophenotypes of cognitive functioning i.e. attention, vigilance, interference, time estimation and sensoric and motoric reaction times. Out of a gene data bank of more than 600 healthy Caucasian participants, 96 subjects (n = 48 males and n = 48 females) were recruited according to their genotype/allele pattern, resulting in six independent groups (COMT: VAL/VAL, VAL/MET, MET/MET)x(DRD2: A1-, A1+) of n = 16 subjects each. Results showed associations of the COMT gene with attention and with time estimation but most noteworthy was an interaction effect DRD2xVAL on interference performance as measured by the STROOP-test explaining 13% of the variance. Findings suggest that a balance between DA related catabolic enzyme activity and receptor density are good predictors for the endophenotype of cognitive interference and that the COMT gene is in accordance with previous studies related to cognitive functioning.

  16. The Dopaminergic Reward System and Leisure Time Exercise Behavior: A Candidate Allele Study

    PubMed Central

    Huppertz, Charlotte; Bartels, Meike; Groen-Blokhuis, Maria M.; Dolan, Conor V.; de Moor, Marleen H. M.; Abdellaoui, Abdel; van Beijsterveldt, Catharina E. M.; Ehli, Erik A.; Hottenga, Jouke-Jan; Willemsen, Gonneke; Xiao, Xiangjun; Scheet, Paul; Davies, Gareth E.; Boomsma, Dorret I.; Hudziak, James J.; de Geus, Eco J. C.

    2014-01-01

    Purpose. Twin studies provide evidence that genetic influences contribute strongly to individual differences in exercise behavior. We hypothesize that part of this heritability is explained by genetic variation in the dopaminergic reward system. Eight single nucleotide polymorphisms (SNPs in DRD1: rs265981, DRD2: rs6275, rs1800497, DRD3: rs6280, DRD4: rs1800955, DBH: rs1611115, rs2519152, and in COMT: rs4680) and three variable number of tandem repeats (VNTRs in DRD4, upstream of DRD5, and in DAT1) were investigated for an association with regular leisure time exercise behavior. Materials and Methods. Data on exercise activities and at least one SNP/VNTR were available for 8,768 individuals aged 7 to 50 years old that were part of the Netherlands Twin Register. Exercise behavior was quantified as weekly metabolic equivalents of task (MET) spent on exercise activities. Mixed models were fitted in SPSS with genetic relatedness as a random effect. Results. None of the genetic variants were associated with exercise behavior (P > .02), despite sufficient power to detect small effects. Discussion and Conclusions. We did not confirm that allelic variants involved in dopaminergic function play a role in creating individual differences in exercise behavior. A plea is made for large genome-wide association studies to unravel the genetic pathways that affect this health-enhancing behavior. PMID:24734235

  17. Obesity, attention deficit-hyperactivity disorder and the dopaminergic reward system.

    PubMed

    Campbell, Benjamin Charles; Eisenberg, Dan

    2007-03-01

    The obesity epidemic has focused attention on obesity's health consequences beyond cardio-vascular disease and diabetes. To evaluate the potential consequences of obesity for Attention Deficit-Hyperactivity Disorder (ADHD), we surveyed the literature. Current findings link both obesity and ADHD to the dopamine system and implicate dopamine genes in body weight, eating, and ADHD. Detailed consideration suggests that dopaminergic changes in the prefrontal cortex among individuals with the ADHD subtype Attention Deficit Disorder (ADD) may increase their risk for obesity. Thus, individuals and populations with a high prevalence of hyperdopaminergic genes may experience higher rates of obesity in the presence of abundant food. From an evolutionary perspective, alterations in the dopamine system appear to effect a wide range of behavioral phenotypes. We suggest that recent evolutionary changes in the dopamine receptor genes selected to increase cognitive and behavioral flexibility may now be associated with attention problems and increased food consumption in an obesogenic environment.

  18. [The role of genetic variants of the dopaminergic system in heroin dependence].

    PubMed

    Vereczkei, Andrea; Sasvári-Székely, Mária; Barta, Csaba

    2009-06-01

    Heroin dependence is a disorder with complex inheritance. It is influenced by multiple genetic and environmental factors. This paper gives an overview on the specific risk factors in the background of heroin addiction, especially within the dopaminergic system, which is one of the most important components of the brain's reward system. In connection with the development of heroin addiction the role of the dopamine D2 and D4 receptors, the dopamine transporter and the catechol-O-methyltransferase genes is discussed. Certain polymorphisms of the most extensively studied dopamine D2 receptor gene show strong association with heroin dependence. Dopamine D4 receptor and catechol-O-methyltransferase genes are also associated with the disease, but some results are still controversial. Only few studies have been done in association with the dopamine transporter gene and substance misuse and no convincing results have been found. To unravel the contradictions and better understand the pathogenesis of the disease more research needs to be conducted.

  19. Age-related changes in midbrain dopaminergic regulation of the human reward system

    PubMed Central

    Dreher, Jean-Claude; Meyer-Lindenberg, Andreas; Kohn, Philip; Berman, Karen Faith

    2008-01-01

    The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging. Significant losses over a normal lifespan have been reported for dopamine receptors and transporters, but very little is known about the neurofunctional consequences of this age-related dopaminergic decline. In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans, although indirect evidence from pharmacological and clinical studies also supports such an association, there has been no direct demonstration of a link between midbrain dopamine and reward-related neural response. Moreover, there are no in vivo data for alterations in this relationship in older humans. Here, by using 6-[18F]FluoroDOPA (FDOPA) positron emission tomography (PET) and event-related 3T functional magnetic resonance imaging (fMRI) in the same subjects, we directly demonstrate a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans, show that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship (from a positive to a negative correlation) between midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide system-level information about alteration of a key neural circuit in healthy aging. Taken together, our findings provide an important characterization of the interactions between midbrain dopamine function and the reward system in healthy young humans and older subjects, and identify the changes in this regulatory circuit that accompany aging. PMID:18794529

  20. Influence of paraquat on dopaminergic transporter in the rat brain.

    PubMed

    Ossowska, Krystyna; Wardas, Jadwiga; Kuter, Katarzyna; Nowak, Przemysław; Dabrowska, Joanna; Bortel, Aleksandra; Labus, Łukasz; Kwieciński, Adam; Krygowska-Wajs, Anna; Wolfarth, Stainsław

    2005-01-01

    Selective toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a parkinsonism inducing compound, is well known to be related to an uptake of its active metabolite MPP+ into dopaminergic neurons by dopamine transporter (DAT). The aim of the present study was to examine whether paraquat, a commonly used herbicide, which is an 1-methyl-4-phenyl-pyridinium ion (MPP+) analogue, affects DAT in vivo in rats. Paraquat administered at a dose of 10 mg/kg ip decreased the binding of [3H]GBR 12,935 to DAT measured by quantitative autoradiography in the dorsal and ventral caudate-putamen, but not in the substantia nigra pars compacta. Moreover, this compound increased the level of 3-methoxytyramine (3-MT) and 3-MT/dopamine ratio in the anterior and posterior caudate-putamen measured by HPLC with electrochemical detection. No other alterations in the levels of dopamine and its metabolites were found in the caudate-putamen and substantia nigra. The present study seems to suggest that systemic paraquat administration affects striatal DAT and dopamine metabolism in the nigrostriatal neurons in rats which may be crucial for its neurotoxic effects on dopaminergic neurons.

  1. Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 rats.

    PubMed

    Liu, Mei; Choi, Dong-Young; Hunter, Randy L; Pandya, Jignesh D; Cass, Wayne A; Sullivan, Patrick G; Kim, Hyoung-Chun; Gash, Don M; Bing, Guoying

    2010-02-01

    Trichloroethylene, a chlorinated solvent widely used as a degreasing agent, is a common environmental contaminant. Emerging evidence suggests that chronic exposure to trichloroethylene may contribute to the development of Parkinson's disease. The purpose of this study was to determine if selective loss of nigrostriatal dopaminergic neurons could be reproduced by systemic exposure of adult Fisher 344 rats to trichloroethylene. In our experiments, oral administration of trichloroethylene induced a significant loss of dopaminergic neurons in the substantia nigra pars compacta in a dose-dependent manner, whereas the number of both cholinergic and GABAergic neurons were not decreased in the striatum. There was a robust decline in striatal levels of 3, 4-dihydroxyphenylacetic acid without a significant depletion of striatal dopamine. Rats treated with trichloroethylene showed defects in rotarod behavior test. We also found a significantly reduced mitochondrial complex I activity with elevated oxidative stress markers and activated microglia in the nigral area. In addition, we observed intracellular alpha-synuclein accumulation in the dorsal motor nucleus of the vagus nerve, with some in nigral neurons, but little in neurons of cerebral cortex. Overall, our animal model exhibits some important features of Parkinsonism, and further supports that trichloroethylene may be an environmental risk factors for Parkinson's disease.

  2. Selenoprotein T Exerts an Essential Oxidoreductase Activity That Protects Dopaminergic Neurons in Mouse Models of Parkinson's Disease

    PubMed Central

    Boukhzar, Loubna; Hamieh, Abdallah; Cartier, Dorthe; Tanguy, Yannick; Alsharif, Ifat; Castex, Matthieu; Arabo, Arnaud; Hajji, Sana El; Bonnet, Jean-Jacques; Errami, Mohammed; Falluel-Morel, Anthony; Chagraoui, Abdeslam; Lihrmann, Isabelle

    2016-01-01

    Abstract Aims: Oxidative stress is central to the pathogenesis of Parkinson's disease (PD), but the mechanisms involved in the control of this stress in dopaminergic cells are not fully understood. There is increasing evidence that selenoproteins play a central role in the control of redox homeostasis and cell defense, but the precise contribution of members of this family of proteins during the course of neurodegenerative diseases is still elusive. Results: We demonstrated first that selenoprotein T (SelT) whose gene disruption is lethal during embryogenesis, exerts a potent oxidoreductase activity. In the SH-SY5Y cell model of dopaminergic neurons, both silencing and overexpression of SelT affected oxidative stress and cell survival. Treatment with PD-inducing neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone triggered SelT expression in the nigrostriatal pathway of wild-type mice, but provoked rapid and severe parkinsonian-like motor defects in conditional brain SelT-deficient mice. This motor impairment was associated with marked oxidative stress and neurodegeneration and decreased tyrosine hydroxylase activity and dopamine levels in the nigrostriatal system. Finally, in PD patients, we report that SelT is tremendously increased in the caudate putamen tissue. Innovation: These results reveal the activity of a novel selenoprotein enzyme that protects dopaminergic neurons against oxidative stress and prevents early and severe movement impairment in animal models of PD. Conclusions: Our findings indicate that selenoproteins such as SelT play a crucial role in the protection of dopaminergic neurons against oxidative stress and cell death, providing insight into the molecular underpinnings of this stress in PD. Antioxid. Redox Signal. 24, 557–574. PMID:26866473

  3. Dopaminergic therapy in aphasia

    PubMed Central

    Gill, Sumanjit K.

    2013-01-01

    Background The dopaminergic system is involved in a wide range of cognitive functions including motor control, reward, memory, attention, problem-solving and learning. This has stimulated interest in investigating the potential of dopaminergic drugs as cognitive enhancers in aphasic patients. Aim To discuss the evidence for the use of dopaminergic agents in patients with aphasia. Levodopa (L-dopa) and the dopamine agonist bromocriptine are the two drugs that have been trialled to date. We discuss, in some detail, the 15 studies that have been published on this topic from the first case report in 1988 to the present (2012), and assess the evidence from each. Main contribution In addition to summarising the effectiveness of the drugs that have been tried, we examine the possible cognitive mechanisms by which dopaminergic drugs may act on language function and aphasia recovery. Given the wide range of dopaminergic drugs, it is surprising that such a narrow range has been trialled in aphasic patients. Important lessons are to be learned from published studies and we discuss optimal trial designs to help guide future work. Conclusions The evidence for the efficacy of dopaminergic agents in aphasia therapy is mixed. Further trials with better tolerated agents are required. Optimal trial designs with appropriate control groups or blocks should be used. The mechanism of action is unclear, but at the cognitive level the evidence points towards either (re)learning of word-forms or their improved retrieval. PMID:25076804

  4. Role of brain dopaminergic system in the adrenomedullin-induced diuresis and natriuresis.

    PubMed

    Díaz, Emilia; Silva, María; Israel, Anita

    2003-11-01

    Intracerebroventricular (IVT) administration of adrenomedullin (AM) to conscious male hydrated rats increases urinary volume and sodium excretion. The possible involvement of brain dopamine (DA) system on the renal action of IVT-AM was investigated. AM-induced diuretic and natriuretic action was prevented following selective central dopaminergic denervation with 6-hydroxydopamine (6OHDA) in combination with desmethylimipramine (DMI). Selective D(2) DA receptor antagonism with haloperidol, sulpiride, and remoxipride; or with the D(1) DA receptor antagonist, SCH 23390, blunted the increase in urinary volume and sodium excretion induced by IVT-AM. The present results suggest that AM acts centrally, at least in part, via an interaction with endogenous DA through the activation of both DA D(1)/D(2) receptor subtype.

  5. Dopaminergic system and dream recall: An MRI study in Parkinson's disease patients.

    PubMed

    De Gennaro, Luigi; Lanteri, Olimpia; Piras, Fabrizio; Scarpelli, Serena; Assogna, Francesca; Ferrara, Michele; Caltagirone, Carlo; Spalletta, Gianfranco

    2016-03-01

    We investigated the role of the dopamine system [i.e., subcortical-medial prefrontal cortex (mPFC) network] in dreaming, by studying patients with Parkinson's Disease (PD) as a model of altered dopaminergic transmission. Subcortical volumes and cortical thickness were extracted by 3T-MR images of 27 PD patients and 27 age-matched controls, who were asked to fill out a dream diary upon morning awakening for one week. PD patients do not substantially differ from healthy controls with respect to the sleep, dream, and neuroanatomical measures. Multivariate correlational analyses in PD patients show that dopamine agonist dosage is associated to qualitatively impoverished dreams, as expressed by lower bizarreness and lower emotional load values. Visual vividness (VV) of their dream reports positively correlates with volumes of both the amygdalae and with thickness of the left mPFC. Emotional load also positively correlates with hippocampal volume. Beside the replication of our previous finding on the role of subcortical nuclei in dreaming experience of healthy subjects, this represents the first evidence of a specific role of the amygdala-mPFC dopaminergic network system in dream recall. The association in PD patients between higher dopamine agonist dosages and impoverished dream reports, however, and the significant correlations between VV and mesolimbic regions, however, provide an empirical support to the hypothesis that a dopamine network plays a key role in dream generation. The causal relation is however precluded by the intrinsic limitation of assuming the dopamine agonist dosage as a measure of the hypodopaminergic state in PD. Periodicals, Inc.

  6. Effect of acupuncture on 6-hydroxydopamine-induced nigrostratal dopaminergic neuronal cell death in rats.

    PubMed

    Kim, Yeung-Kee; Lim, Hyung-Ho; Song, Yun-Kyung; Lee, Hee-Hyuk; Lim, Sabina; Han, Seung-Moo; Kim, Chang-Ju

    In this study, we investigated the effect of acupuncture at the Zusanli acupoint (ST36) on the nigrostriatal dopaminergic neuronal cell death in the rats with Parkinson's disease. Two weeks after unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum, an apomorphine-induced rotational behavior test showed significant rotational asymmetry in the rats with Parkinson's disease. Immunostaining for tyrosine hydroxylase demonstrated a dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. Acupuncture at the ST36 for 14 days significantly inhibited rotational asymmetry in the rats with Parkinson's disease, and also protected against 6-OHDA-induced nigrostriatal dopaminergic neuronal loss. These effects of acupuncture were not observed for the non-acupoint (hip) acupuncture. The present study shows that acupuncture at the ST36 acupoint can be used as a useful strategy for the treatment of Parkinson's disease.

  7. Differentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture.

    PubMed

    Moreno, Edinson Lucumi; Hachi, Siham; Hemmer, Kathrin; Trietsch, Sebastiaan J; Baumuratov, Aidos S; Hankemeier, Thomas; Vulto, Paul; Schwamborn, Jens C; Fleming, Ronan M T

    2015-06-07

    A hallmark of Parkinson's disease is the progressive loss of nigrostriatal dopaminergic neurons. We derived human neuroepithelial cells from induced pluripotent stem cells and successfully differentiated them into dopaminergic neurons within phase-guided, three-dimensional microfluidic cell culture bioreactors. After 30 days of differentiation within the microfluidic bioreactors, in situ morphological, immunocytochemical and calcium imaging confirmed the presence of dopaminergic neurons that were spontaneously electrophysiologically active, a characteristic feature of nigrostriatal dopaminergic neurons in vivo. Differentiation was as efficient as in macroscopic culture, with up to 19% of differentiated neurons immunoreactive for tyrosine hydroxylase, the penultimate enzyme in the synthesis of dopamine. This new microfluidic cell culture model integrates the latest innovations in developmental biology and microfluidic cell culture to generate a biologically realistic and economically efficient route to personalised drug discovery for Parkinson's disease.

  8. Large-scale resting state network correlates of cognitive impairment in Parkinson's disease and related dopaminergic deficits

    PubMed Central

    Lebedev, Alexander V.; Westman, Eric; Simmons, Andrew; Lebedeva, Aleksandra; Siepel, Françoise J.; Pereira, Joana B.; Aarsland, Dag

    2014-01-01

    Cognitive impairment is a common non-motor feature of Parkinson's disease (PD). Understanding the neural mechanisms of this deficit is crucial for the development of efficient methods for treatment monitoring and augmentation of cognitive functions in PD patients. The current study aimed to investigate resting state fMRI correlates of cognitive impairment in PD from a large-scale network perspective, and to assess the impact of dopamine deficiency on these networks. Thirty PD patients with resting state fMRI were included from the Parkinson's Progression Marker Initiative (PPMI) database. Eighteen patients from this sample were also scanned with 123I-FP-CIT SPECT. A standardized neuropsychological battery was administered, evaluating verbal memory, visuospatial, and executive cognitive domains. Image preprocessing was performed using an SPM8-based workflow, obtaining time-series from 90 regions-of-interest (ROIs) defined from the AAL brain atlas. The Brain Connectivity Toolbox (BCT) was used to extract nodal strength from all ROIs, and modularity of the cognitive circuitry determined using the meta-analytical software Neurosynth. Brain-behavior covariance patterns between cognitive functions and nodal strength were estimated using Partial Least Squares. Extracted latent variable (LV) scores were matched with the performances in the three cognitive domains (memory, visuospatial, and executive) and striatal dopamine transporter binding ratios (SBR) using linear modeling. Finally, influence of nigrostriatal dopaminergic deficiency on the modularity of the “cognitive network” was analyzed. For the range of deficits studied, better executive performance was associated with increased dorsal fronto-parietal cortical processing and inhibited subcortical and primary sensory involvement. This profile was also characterized by a relative preservation of nigrostriatal dopaminergic function. The profile associated with better memory performance correlated with increased

  9. Chronic dopaminergic treatment in restless legs syndrome: does it affect the autonomic nervous system?

    PubMed

    Rocchi, Camilla; Albanese, Maria; Placidi, Fabio; Romigi, Andrea; Lauretti, Benedetta; Marfia, Girolama A; Liguori, Claudio; Marciani, Maria G; Mercuri, Nicola B; Izzi, Francesca

    2015-09-01

    The link between the autonomic nervous system and restless legs syndrome (RLS) has been recently postulated. Since dopaminergic agents are used as first-line treatment for RLS, the purpose of our study is to verify whether chronic pramipexole treatment could influence the autonomic control of cardiovascular reflexes and heart rate variability (HRV) in RLS during wakefulness. Consecutive drug naive RLS patients underwent polysomnography (PSG), subjective scales, and cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, handgrip and cold face before and after 3-month pramipexole therapy. HRV analysis was performed in the frequency domain using both autoregressive and fast Fourier transform algorithms in rest supine condition and during HUTT. Twenty RLS patients reported a significant reduction of RLS symptoms after pramipexole treatment, while PSG did not show significant improvements except for periodic limb movement index. Pramipexole induced a trend to a lower systolic blood pressure and a significant higher variation of systolic and diastolic blood pressure at HUTT. Cardiovascular responses to the other tests were unchanged. No significant differences in HRV spectral analysis between drug naive and treated patients were observed. Moreover, the within-group analysis of HRV between orthostatic and supine position did not show any significant change in sympathetic and parasympathetic components both in the drug naive and pramipexole groups. Chronic pramipexole treatment does not seem to affect autonomic balance during wakefulness. Considering that neither PSG data nor autonomic parameters are significantly modified by pramipexole, we hypothesize a non-dopaminergic autonomic dysfunction in RLS. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration.

    PubMed

    Qin, Liya; Liu, Yuxin; Hong, Jau-Shyong; Crews, Fulton T

    2013-06-01

    Parkinson's disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (TH+IR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation-mediated SN neurotoxicity. A comparison of control (NOX2(+/+) ) mice with NOX subunit gp91(phox) -deficient (NOX2(-/-) ) mice 10 months after LPS administration (5 mg/kg, i.p.) resulted in a 39% (P < 0.01) loss of TH+IR neurons in NOX2(+/+) mice, whereas NOX2(-/-) mice did not show a significant decrease. Microglia (Iba1+IR) showed morphological activation in NOX2(+/+) mice, but not in NOX2(-/-) mice at 1 hr. Treatment of NOX2(+/+) mice with LPS resulted in a 12-fold increase in NOX2 mRNA in midbrain and 5.5-6.5-fold increases in NOX2 protein (+IR) in SN compared with the saline controls. Brain reactive oxygen species (ROS), determined using diphenyliodonium histochemistry, was increased by LPS in SN between 1 hr and 20 months. Diphenyliodonium (DPI), an NOX inhibitor, blocked LPS-induced activation of microglia and production of ROS, TNFα, IL-1β, and MCP-1. Although LPS increased microglial activation and ROS at all ages studied, saline control NOX2(+/+) mice showed age-related increases in microglial activation, NOX, and ROS levels at 12 and 22 months of age. Together, these results suggest that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age.

  11. NADPH oxidase and aging drive microglial activation, oxidative stress and dopaminergic neurodegeneration following systemic LPS administration

    PubMed Central

    Qin, Liya; Liu, Yuxin; Hong, Jau-Shyong; Crews, Fulton T.

    2013-01-01

    Parkinson’s disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (TH+IR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation-mediated SN neurotoxicity. A comparison of control (NOX2+/+) mice with NOX subunit gp91phox-deficient (NOX2−/−) mice 10 months after LPS administration (5 mg/kg, i.p.) resulted in a 39% (p<0.01) loss of TH+IR neurons in NOX2+/+ mice, whereas, NOX2−/− mice did not show a significant decrease. Microglia (Iba1+IR) showed morphological activation in NOX2+/+ mice, but not in NOX2−/− mice at 1 hour. Treatment of NOX2+/+ mice with LPS resulted in a 12 fold increase in NOX2 mRNA in midbrain and 5.5–6.5 fold increases in NOX2 protein (+IR) in SN compared to the saline controls. Brain reactive oxygen species (ROS), determined by hydroethidine histochemistry, was increased by LPS in SN between 1 hour and 20 months. Diphenyliodonium (DPI), a NOX inhibitor, blocked LPS-induced activation of microglia and production of ROS, TNFα, IL-1β, and MCP-1. Although LPS increased microglial activation and ROS at all ages studied, saline control NOX2+/+ mice showed age-related increases in microglial activation, NOX and ROS levels at 12 and 22 months of age. Together, these results suggest that NOX contributes to persistent microglial activation, ROS production and dopaminergic neurodegeneration that persist and continue to increase with age. PMID:23536230

  12. Association of body mass index and the depletion of nigrostriatal dopamine in Parkinson's disease.

    PubMed

    Lee, Jae Jung; Oh, Jungsu S; Ham, Jee H; Lee, Dong H; Lee, Injoo; Sohn, Young H; Kim, Jae S; Lee, Phil Hyu

    2016-02-01

    Several antecedent studies had reported close relationship between low body weight and Parkinson's disease (PD). However, there have been few investigations about the role of body weight to nigrostriatal dopaminergic neurodegeneration. This study enrolled 398 de novo patients with PD whom underwent [18F] N-(3-Fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography scan and body mass index (BMI) measurement. The relationships between BMI and dopamine transporter (DAT) activity were analyzed using linear regression analysis. A multivariate analysis adjusted for age, gender, disease duration, smoking status, coffee and tea consumption, and residence area revealed that BMI remained independently and significantly associated with DAT activity in all striatal subregions. Moreover, multiple logistic regression analyses showed that BMI was a significant predictor for the lowest quartile of DAT activity in the anterior putamen, ventral striatum, caudate nucleus, and total striatum. The present findings suggest that a low BMI might be closely associated with low density of nigrostriatal dopaminergic neurons in PD, which could support the evidence for the role of low body weight to PD-related pathologies.

  13. Regulation of intraocular pressure in mice: structural analysis of dopaminergic and serotonergic systems in response to cabergoline.

    PubMed

    Platania, Chiara Bianca Maria; Leggio, Gian Marco; Drago, Filippo; Salomone, Salvatore; Bucolo, Claudio

    2013-11-01

    Elevated intraocular pressure (IOP) is the main recognized risk factor of glaucoma. To investigate the contribution of dopaminergic and serotonergic systems in IOP regulation, we used cabergoline, a mixed dopamine and serotonin agonist, in C57BL/6J WT and dopamine D₃ receptor knock-out (D₃R⁻/⁻) mice with normal eye pressure or steroid-induced ocular hypertension. Furthermore, we studied the structural basis of the cabergoline-mediated activation of the dopaminergic and serotonergic systems by molecular modeling. Topical application of cabergoline, significantly decreased, in a dose-dependent manner, the intraocular pressure in WT mice, both in an ocular normotensive group (-9, -5 and -2 mmHg with 5%, 1%, and 0.1%, respectively) and an ocular hypertensive group, with a prolonged effect in this latter group. No change of intraocular pressure was observed after topical application of cabergoline in D₃R⁻/⁻ mice. We modeled and optimized, with molecular dynamics, structures of hD₃, h5HT(1A) and h5HT(2A-C) receptors; thereafter we carried out molecular docking of cabergoline. Docking revealed that binding of cabergoline into D₃ and 5HT(1A) receptors is associated with a better desolvation energy in comparison to 5HT(2A-C) binding. In conclusion, the present study support the hypothesis that dopaminergic system is pivotal to regulate IOP and that D₃R represents an intriguing target in the treatment of glaucoma. Furthermore, the structure-based computational approach adopted in this study is able to build and refine structure models of homologous dopaminergic and serotonergic receptors that may be of interest for structure-based drug discovery of ligands, with dopaminergic selectivity or with multi-pharmacological profile, potentially useful to treat optic neuropathies.

  14. Cerebrospinal fluid 3,4-dihydroxyphenylacetic acid level after tolcapone administration as an indicator of nigrostriatal degeneration.

    PubMed

    Thiffault, Christine; Langston, J William; Di Monte, Donato A

    2003-09-01

    The development of reliable biological markers of nigrostriatal degeneration has important implications from both experimental and clinical viewpoints, since such biomarkers could be used for diagnostic and monitoring purposes in models of parkinsonism as well as in Parkinson's disease patients. In this study, levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the cerebrospinal fluid (CSF) of normal and parkinsonian squirrel monkeys in order to assess their reliability as indicators of nigrostriatal injury. In particular, we tested the hypothesis that these measurements may become more accurate by inhibiting catecholamine-O-methyltransferase (COMT) activity and therefore blocking the conversion of DOPAC to homovanillic acid. Oral administration of the COMT inhibitor tolcapone (2 doses of 15 mg/kg each with a 4-h interval) significantly reduced enzyme activity in the monkey brain. Tolcapone treatment enhanced CSF DOPAC concentrations in unlesioned animals (by approximately four times) as well as monkeys rendered parkinsonian after severe nigrostriatal dopaminergic injury caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Importantly, however, COMT inhibition greatly magnified the differences in CSF DOPAC levels between control and parkinsonian monkeys, since MPTP-induced DOPAC depletion was 35% in the absence vs >60% in the presence of tolcapone. Thus, tolcapone administration enhances the detection of DOPAC in the CSF and, by doing so, improves the reliability of CSF DOPAC as a marker of nigrostriatal degeneration.

  15. A novel thiol antioxidant that crosses the blood brain barrier protects dopaminergic neurons in experimental models of Parkinson's disease.

    PubMed

    Bahat-Stroomza, Merav; Gilgun-Sherki, Yossi; Offen, Daniel; Panet, Hana; Saada, Ann; Krool-Galron, Nili; Barzilai, Aari; Atlas, Daphne; Melamed, Eldad

    2005-02-01

    It is believed that oxidative stress (OS) plays an important role in the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD) and that treatment with antioxidants might be neuroprotective. However, most currently available antioxidants cannot readily penetrate the blood brain barrier after systemic administration. We now report that AD4, the novel low molecular weight thiol antioxidant and the N-acytel cysteine (NAC) related compound, is capable of penetrating the brain and protects neurons in general and especially dopaminergic cells against various OS-generating neurotoxins in tissue cultures. Moreover, we found that treatment with AD4 markedly decreased the damage of dopaminergic neurons in three experimental models of PD. AD4 suppressed amphetamine-induced rotational behaviour in rats with unilateral 6-OHDA-induced nigral lesion. It attenuated the reduction in striatal dopamine levels in mice treated with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP). It also reduced the dopaminergic neuronal loss following chronic intrajugular administration of rotenone in rats. Our findings suggest that AD4 is a novel potential new neuroprotective drug that might be effective at slowing down nigral neuronal degeneration and illness progression in patients with PD.

  16. An Efficient and Versatile System for Visualization and Genetic Modification of Dopaminergic Neurons in Transgenic Mice

    PubMed Central

    Kramer, Edgar R.

    2015-01-01

    Background & Aims The brain dopaminergic (DA) system is involved in fine tuning many behaviors and several human diseases are associated with pathological alterations of the DA system such as Parkinson’s disease (PD) and drug addiction. Because of its complex network integration, detailed analyses of physiological and pathophysiological conditions are only possible in a whole organism with a sophisticated tool box for visualization and functional modification. Methods & Results Here, we have generated transgenic mice expressing the tetracycline-regulated transactivator (tTA) or the reverse tetracycline-regulated transactivator (rtTA) under control of the tyrosine hydroxylase (TH) promoter, TH-tTA (tet-OFF) and TH-rtTA (tet-ON) mice, to visualize and genetically modify DA neurons. We show their tight regulation and efficient use to overexpress proteins under the control of tet-responsive elements or to delete genes of interest with tet-responsive Cre. In combination with mice encoding tet-responsive luciferase, we visualized the DA system in living mice progressively over time. Conclusion These experiments establish TH-tTA and TH-rtTA mice as a powerful tool to generate and monitor mouse models for DA system diseases. PMID:26291828

  17. New facts and the concept of physiological regulation of the dopaminergic system function and its disorders.

    PubMed

    Krzymowski, T; Stefanczyk-Krzymowska, S

    2015-06-01

    We present the main results of the study and justification of our opinion on the role of dopamine (DA) retrograde transfer in the cavernous sinus in the regulation of the dopaminergic (DArgic) system activity. We are convinced that under physiological conditions DA - which is continuously retrograde transferred in the cavernous sinus from venous brain effluent to arterial blood supplying the brain and carried by the arterial blood to endothelial cells and perivascular astrocytes of striatal DArgic cell groups - can inhibit dopamine transporter (DAT) expression by a down-regulation mechanism. A new concept of the genesis of DArgic system dysfunction with involvement of DA retrograde transfer in the cavernous sinus is presented. We suggest that future research that aims to explain the genesis of hypo- or hyperfunction of the DArgic system, and DArgic system dysfunction causing Parkinson's disease, attention deficit hyperactivity disorder (ADHD), schizophrenia, and many other psychiatric disorders, must involve two areas: 1) the cavernous sinus, where DA is taken up, and transferred from the venous blood of the cavernous sinus to the arterial blood supplying the brain. To regulate this process pharmacologically, understanding the mechanism and explanation of what determines its course is necessary; 2) brain DArgic structures, whose activity is regulated primarily by the action of DAT. It is essential to clarify whether the expression of the DAT is regulated directly by DA reaching the presynaptic membrane or by any factor secreted by specific perivascular glial cells (astrocytes) under the influence of DA and DA metabolites.

  18. Dose optimization for long-term rAAV-mediated RNA interference in the nigrostriatal projection neurons.

    PubMed

    Ulusoy, Ayse; Sahin, Gurdal; Björklund, Tomas; Aebischer, Patrick; Kirik, Deniz

    2009-09-01

    Short-hairpin RNA (shRNA)-mediated gene knockdown is a powerful tool for targeted gene silencing and an emerging novel therapeutic strategy. Recent publications, however, reported unexpected toxicity after utilizing viral-mediated shRNA knockdown in vivo. Thus, it is currently unclear whether shRNA-mediated knockdown strategy can be used as a safe and efficient tool for gene silencing. In this study, we have generated rAAV vectors expressing shRNAs targeting the rat tyrosine hydroxylase (TH) mRNA (shTH) for testing the efficacy of in vivo TH knockdown in the nigral dopaminergic neurons. At high titers, not only the shTH vectors but also the scrambled and green fluorescence protein (GFP)-only controls caused cell death. In a dose-response study, we identified a dose window leading to >60% decrease in TH(+) neurons without any change in vesicular monoamine transporter-2 (VMAT2) expression. Moreover, using the safe and efficient dose, we showed that dopamine (DA) synthesis rate was significantly reduced and this lead to emergence of motor deficits in the shTH-expressing rats. Interestingly, these animals showed very robust and long-lasting recovery after a single systemic L-3,4-dihydroxyphenylalanine (L-DOPA) administration beyond what can be achieved in 6-hydroxydopamine (6-OHDA)-lesioned rats. Our results have implications for both mechanistic and therapeutic studies utilizing long-term shRNA-mediated gene silencing in the nigrostriatal projection system.

  19. The Peptidyl-prolyl Isomerase Pin1 Up-regulation and Proapoptotic Function in Dopaminergic Neurons

    PubMed Central

    Ghosh, Anamitra; Saminathan, Hariharan; Kanthasamy, Arthi; Anantharam, Vellareddy; Jin, Huajun; Sondarva, Gautam; Harischandra, Dilshan S.; Qian, Ziqing; Rana, Ajay; Kanthasamy, Anumantha G.

    2013-01-01

    Parkinson disease (PD) is a chronic neurodegenerative disease characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra. The pathophysiological mechanisms underlying PD remain unclear. Pin1, a major peptidyl-prolyl isomerase, has recently been associated with certain diseases. Notably, Ryo et al. (Ryo, A., Togo, T., Nakai, T., Hirai, A., Nishi, M., Yamaguchi, A., Suzuki, K., Hirayasu, Y., Kobayashi, H., Perrem, K., Liou, Y. C., and Aoki, I. (2006) J. Biol. Chem. 281, 4117–4125) implicated Pin1 in PD pathology. Therefore, we sought to systematically characterize the role of Pin1 in PD using cell culture and animal models. To our surprise we observed a dramatic up-regulation of Pin1 mRNA and protein levels in dopaminergic MN9D neuronal cells treated with the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP+) as well as in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Notably, a marked expression of Pin1 was also observed in the substantia nigra of human PD brains along with a high co-localization of Pin1 within dopaminergic neurons. In functional studies, siRNA-mediated knockdown of Pin1 almost completely prevented MPP+-induced caspase-3 activation and DNA fragmentation, indicating that Pin1 plays a proapoptotic role. Interestingly, multiple pharmacological Pin1 inhibitors, including juglone, attenuated MPP+-induced Pin1 up-regulation, α-synuclein aggregation, caspase-3 activation, and cell death. Furthermore, juglone treatment in the MPTP mouse model of PD suppressed Pin1 levels and improved locomotor deficits, dopamine depletion, and nigral dopaminergic neuronal loss. Collectively, our findings demonstrate for the first time that Pin1 is up-regulated in PD and has a pathophysiological role in the nigrostriatal dopaminergic system and suggest that modulation of Pin1 levels may be a useful translational therapeutic strategy in PD. PMID:23754278

  20. Neural ablation of the PARK10 candidate Plpp3 leads to dopaminergic transmission deficits without neurodegeneration

    PubMed Central

    Gómez-López, Sandra; Martínez-Silva, Ana Valeria; Montiel, Teresa; Osorio-Gómez, Daniel; Bermúdez-Rattoni, Federico; Massieu, Lourdes; Escalante-Alcalde, Diana

    2016-01-01

    Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder, characterised by the progressive loss of midbrain dopaminergic neurons and a variety of motor symptoms. The gene coding for the phospholipid phosphatase 3, PLPP3 (formerly PPAP2B or LPP3), maps within the PARK10 locus, a region that has been linked with increased risk to late-onset PD. PLPP3 modulates the levels of a range of bioactive lipids controlling fundamental cellular processes within the central nervous system. Here we show that PLPP3 is enriched in astroglial cells of the adult murine ventral midbrain. Conditional inactivation of Plpp3 using a Nestin::Cre driver results in reduced mesencephalic levels of sphingosine-1-phosphate receptor 1 (S1P1), a well-known mediator of pro-survival responses. Yet, adult PLPP3-deficient mice exhibited no alterations in the number of dopaminergic neurons or in the basal levels of striatal extracellular dopamine (DA). Potassium-evoked DA overflow in the striatum, however, was significantly decreased in mutant mice. Locomotor evaluation revealed that, although PLPP3-deficient mice exhibit motor impairment, this is not progressive or responsive to acute L-DOPA therapy. These findings suggest that disruption of Plpp3 during early neural development leads to dopaminergic transmission deficits in the absence of nigrostriatal degeneration, and without causing an age-related locomotor decline consistent with PD. PMID:27063549

  1. Effects of Exposure to Heavy Particles on a Behavior Mediated by the Dopaminergic System

    NASA Astrophysics Data System (ADS)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.; McEwen, J.

    The effects of exposure to heavy particles on behaviors mediated by the central nervous system (CNS) are qualitatively different than the effects produced by exposure to other types of radiation. One behavior mediated by the CNS is the amphetamine-induced taste aversion, which is produced by pairing a novel tasting solution with injection of amphetamine. When the conditioning day is three days following irradiation, exposing rats to low doses of 56Fe particles (600 MeV/n or 1 GeV/n) eliminates the taste aversion produced by injection of amphetamine, which is dependent upon the integrity of the central dopaminergic system, but has no effect on the aversion produced by injection of lithium chloride which is mediated by the gastrointestinal system. In contrast to the effects obtained using heavy particles, exposing rats to 60Co gamma rays or to fission spectrum neutrons has no selective effect upon the acquisition of either amphetamine- or lithium chloride-induced taste aversions. When the conditioning day occurs four months following exposure to 1 GeV/n 56Fe particles, there is an enhancement of the amphetamine-induced taste aversion. The implications of these findings for approaches to risk assessment are considered

  2. Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit.

    PubMed

    Gonzalez-Reyes, Luis E; Verbitsky, Miguel; Blesa, Javier; Jackson-Lewis, Vernice; Paredes, Daniel; Tillack, Karsten; Phani, Sudarshan; Kramer, Edgar R; Przedborski, Serge; Kottmann, Andreas H

    2012-07-26

    Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non cell-autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson's disease. Variable Shh signaling results in graded inhibition of muscarinic autoreceptor- and glial cell line-derived neurotrophic factor (GDNF)-expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson's disease. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Sonic Hedgehog Maintains Cellular and Neurochemical Homeostasis in the Adult Nigrostriatal Circuit

    PubMed Central

    Gonzalez-Reyes, Luis E.; Verbitsky, Miguel; Blesa, Javier; Jackson-Lewis, Vernice; Paredes, Daniel; Tillack, Karsten; Phani, Sudarshan; Kramer, Edgar R.; Przedborski, Serge; Kottmann, Andreas H.

    2012-01-01

    SUMMARY Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non-cell autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson’s disease. Variable Shh signaling results in graded inhibition of muscarinic auto-receptor- and GDNF- expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a novel mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson’s disease. PMID:22841315

  4. Chronic low-dose melatonin treatment maintains nigrostriatal integrity in an intrastriatal rotenone model of Parkinson's disease.

    PubMed

    Carriere, Candace H; Kang, Na Hyea; Niles, Lennard P

    2016-02-15

    Parkinson's disease is a major neurodegenerative disorder which primarily involves the loss of dopaminergic neurons in the substantia nigra and related projections in the striatum. The pesticide/neurotoxin, rotenone, has been shown to cause systemic inhibition of mitochondrial complex I activity in nigral dopaminergic neurons, with consequent degeneration of the nigrostriatal pathway, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of chronic low-dose treatment with the antioxidant indoleamine, melatonin, which can upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle (0.04% ethanol in drinking water) or melatonin at a dose of 4 µg/mL in drinking water. The right striatum was lesioned by stereotactic injection of rotenone at three sites (4 μg/site) along its rostrocaudal axis. Apomorphine administration to lesioned animals resulted in a significant (p<0.001) increase in ipsilateral rotations, which was suppressed by melatonin. Nine weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. Melatonin treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counts indicated a significant (p<0.05) decrease in dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, chronic melatonin treatment blocked the loss of dopamine neurons in rotenone-lesioned animals. These findings strongly support the therapeutic potential of long-term and low-dose melatonin treatment in Parkinson's disease. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Signaling Pathways Involved in Renal Oxidative Injury: Role of the Vasoactive Peptides and the Renal Dopaminergic System

    PubMed Central

    Rukavina Mikusic, N. L.; Kravetz, M. C.; Kouyoumdzian, N. M.; Della Penna, S. L.; Rosón, M. I.; Fernández, B. E.; Choi, M. R.

    2014-01-01

    The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation. PMID:25436148

  6. Are striatal tyrosine hydroxylase interneurons dopaminergic?

    PubMed

    Xenias, Harry S; Ibáñez-Sandoval, Osvaldo; Koós, Tibor; Tepper, James M

    2015-04-22

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH-Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)-TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP-TH interneurons. Optogenetic activation of striatal EGFP-TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons.

  7. Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

    PubMed Central

    Xenias, Harry S.; Ibáñez-Sandoval, Osvaldo; Koós, Tibor

    2015-01-01

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH–Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)–TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP–TH interneurons. Optogenetic activation of striatal EGFP–TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons. PMID:25904808

  8. Lack of CCR5 modifies glial phenotypes and population of the nigral dopaminergic neurons, but not MPTP-induced dopaminergic neurodegeneration.

    PubMed

    Choi, Dong-Young; Lee, Myung Koo; Hong, Jin Tae

    2013-01-01

    Constitutive expression of C-C chemokine receptor (CCR) 5 has been detected in astrocytes, microglia and neurons, but its physiological roles in the central nervous system are obscure. The bidirectional interactions between neuron and glial cells through CCR5 and its ligands were thought to be crucial for maintaining normal neuronal activities. No study has described function of CCR5 in the dopaminergic neurodegeneration in Parkinson's disease. In order to examine effects of CCR5 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration, we employed CCR5 wild type (WT) and knockout (KO) mice. Immunostainings for tyrosine hydroxylase (TH) exhibited that CCR5 KO mice had lower number of TH-positive neurons even in the absence of MPTP. Difference in MPTP (15mg/kg×4 times, 2hr interval)-mediated loss of TH-positive neurons was subtle between CCR5 WT and KO mice, but there was larger dopamine depletion, behavioral impairments and microglial activation in CCR5 deficient mice. Intriguingly, CCR5 KO brains contained higher immunoreactivity for monoamine oxidase (MAO) B which was mainly localized within astrocytes. In agreement with upregulation of MAO B, concentration of MPP+ was higher in the substantia nigra and striatum of CCR5 KO mice after MPTP injection. We found remarkable activation of p38 MAPK in CCR5 deficient mice, which positively regulates MAO B expression. These results indicate that CCR5 deficiency modifies the nigrostriatal dopaminergic neuronal system and bidirectional interaction between neurons and glial cells via CCR5 might be important for dopaminergic neuronal survival.

  9. Prenatal methamphetamine exposure affects the mesolimbic dopaminergic system and behavior in adult offspring.

    PubMed

    Bubenikova-Valesova, Vera; Kacer, Petr; Syslova, Kamila; Rambousek, Lukas; Janovsky, Martin; Schutova, Barbora; Hruba, Lenka; Slamberova, Romana

    2009-10-01

    Methamphetamine is a commonly abused psychostimulant that causes addiction and is often abused by pregnant women. Acute or chronic administration of methamphetamine elevates the levels of the extracellular monoamine neurotransmitters, such as dopamine. The aim of the present study was to show whether prenatal exposure to methamphetamine (5mg/kg, entire gestation) or saline in Wistar rats induces changes in dopamine levels and its metabolites in the nucleus accumbens, and in behavior (locomotor activity, rearing, and immobility) after the administration of a challenge dose of methamphetamine (1mg/kg) or saline in male offspring. We found that adult offspring prenatally exposed to methamphetamine had higher basal levels of dopamine (about 288%), dihydroxyphenylacetic acid (about 67%) and homovanillic acid (about 74%) in nucleus accumbens. An increased basal level of dopamine corresponds to lower basal immobility in offspring prenatally exposed to methamphetamine. The acute injection of methamphetamine in adulthood increased the level of dopamine in the nucleus accumbens, which is related to an increase of locomotion and rearing (exploration). In addition, prenatally methamphetamine-exposed rats showed higher response to the challenge dose of methamphetamine, when compared to prenatally saline-exposed rats. In conclusion, rats exposed to methamphetamine in utero have shown changes in the mesolimbic dopaminergic system and were more sensitive to the administration of the acute dose of methamphetamine in adulthood.

  10. Positron emission tomography molecular imaging of dopaminergic system in drug addiction.

    PubMed

    Hou, Haifeng; Tian, Mei; Zhang, Hong

    2012-05-01

    Dopamine (DA) is involved in drug reinforcement, but its role in drug addiction remains unclear. Positron emission tomography (PET) is the first technology used for the direct measurement of components of the dopaminergic system in the living human brain. In this article, we reviewed the major findings of PET imaging studies on the involvement of DA in drug addiction, especially in heroin addiction. Furthermore, we summarized PET radiotracers that have been used to study the role of DA in drug addiction. To investigate presynaptic function in drug addiction, PET tracers have been developed to measure DA synthesis and transport. For the investigation of postsynaptic function, several radioligands targeting dopamine one (D1) receptor and dopamine two (D2) receptor are extensively used in PET imaging studies. Moreover, we also summarized the PET imaging findings of heroin addiction studies, including heroin-induced DA increases and the reinforcement, role of DA in the long-term effects of heroin abuse, DA and vulnerability to heroin abuse and the treatment implications. PET imaging studies have corroborated the role of DA in drug addiction and increase our understanding the mechanism of drug addiction. Copyright © 2012 Wiley Periodicals, Inc.

  11. Behavioral Functions of the Mesolimbic Dopaminergic System: an Affective Neuroethological Perspective

    PubMed Central

    Alcaro, Antonio; Huber, Robert; Panksepp, Jaak

    2008-01-01

    The mesolimbic dopaminergic (ML-DA) system has been recognized for its central role in motivated behaviors, various types of reward, and, more recently, in cognitive processes. Functional theories have emphasized DA's involvement in the orchestration of goal-directed behaviors, and in the promotion and reinforcement of learning. The affective neuroethological perspective presented here, views the ML-DA system in terms of its ability to activate an instinctual emotional appetitive state (SEEKING) evolved to induce organisms to search for all varieties of life-supporting stimuli and to avoid harms. A description of the anatomical framework in which the ML system is embedded is followed by the argument that the SEEKING disposition emerges through functional integration of ventral basal ganglia (BG) into thalamocortical activities. Filtering cortical and limbic input that spread into BG, DA transmission promotes the “release” of neural activity patterns that induce active SEEKING behaviors when expressed at the motor level. Reverberation of these patterns constitutes a neurodynamic process for the inclusion of cognitive and perceptual representations within the extended networks of the SEEKING urge. In this way, the SEEKING disposition influences attention, incentive salience, associative learning, and anticipatory predictions. In our view, the rewarding properties of drugs of abuse are, in part, caused by the activation of the SEEKING disposition, ranging from appetitive drive to persistent craving depending on the intensity of the affect. The implications of such a view for understanding addiction are considered, with particular emphasis on factors predisposing individuals to develop compulsive drug seeking behaviors. PMID:17905440

  12. Molecular Signatures of Natural Selection for Polymorphic Genes of the Human Dopaminergic and Serotonergic Systems: A Review.

    PubMed

    Taub, Daniel R; Page, Joshua

    2016-01-01

    A large body of research has examined the behavioral and mental health consequences of polymorphisms in genes of the dopaminergic and serotonergic systems. Along with this, there has been considerable interest in the possibility that these polymorphisms have developed and/or been maintained due to the action of natural selection. Episodes of natural selection on a gene are expected to leave molecular "footprints" in the DNA sequences of the gene and adjacent genomic regions. Here we review the research literature investigating molecular signals of selection for genes of the dopaminergic and serotonergic systems. The gene SLC6A4, which codes for a serotonin transport protein, was the one gene for which there was consistent support from multiple studies for a selective episode. Positive selection on SLC6A4 appears to have been initiated ∼ 20-25,000 years ago in east Asia and possibly in Europe. There are scattered reports of molecular signals of selection for other neurotransmitter genes, but these have generally failed at replication across studies. In spite of speculation in the literature about selection on these genes, current evidence from population genomic analyses supports selectively neutral processes, such as genetic drift and population dynamics, as the principal drivers of recent evolution in dopaminergic and serotonergic genes other than SLC6A4.

  13. The long-term effects of the herbicide atrazine on the dopaminergic system following exposure during pubertal development.

    PubMed

    Li, Yanshu; Sun, Yan; Yang, Junwei; Wu, Yanping; Yu, Jia; Li, Baixiang

    2014-03-15

    Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) is used worldwide as a herbicide, and its presence in the environment has resulted in documented human exposure. Atrazine has been shown to cause dopaminergic neurotoxicity. The juvenile period is particularly vulnerable to environmental agents, but only few studies have investigated the long-term effects of atrazine following exposure during the pubertal development. Therefore, we evaluated the effects of a 41-day exposure to atrazine on the dopaminergic system in rats. Sprague-Dawley rats were treated orally with atrazine at 25 or 50mg/kg bw, daily from postnatal day 22 to 62. The content of dopamine (DA) was examined in striatum samples by HPLC-FL, and the mRNA and protein expression of tyrosine hydroxylase (TH), orphan nuclear hormone (Nurr1), dopamine transporter (DAT) and vesicular monoaminetransporter 2 (VMAT2) were examined in samples of the ventral mid-brain by use of fluorescence PCR and Western-blot analysis when the rats reached the age of one year. Exposure of juvenile rats to the high dose of atrazine led to reduced levels of DA and mRNA of Nurr1 in one-year-old animals. This study shows that the long-term adverse effects of atrazine on the dopaminergic system have a special relevance after juvenile exposure.

  14. Molecular Signatures of Natural Selection for Polymorphic Genes of the Human Dopaminergic and Serotonergic Systems: A Review

    PubMed Central

    Taub, Daniel R.; Page, Joshua

    2016-01-01

    A large body of research has examined the behavioral and mental health consequences of polymorphisms in genes of the dopaminergic and serotonergic systems. Along with this, there has been considerable interest in the possibility that these polymorphisms have developed and/or been maintained due to the action of natural selection. Episodes of natural selection on a gene are expected to leave molecular “footprints” in the DNA sequences of the gene and adjacent genomic regions. Here we review the research literature investigating molecular signals of selection for genes of the dopaminergic and serotonergic systems. The gene SLC6A4, which codes for a serotonin transport protein, was the one gene for which there was consistent support from multiple studies for a selective episode. Positive selection on SLC6A4 appears to have been initiated ∼ 20–25,000 years ago in east Asia and possibly in Europe. There are scattered reports of molecular signals of selection for other neurotransmitter genes, but these have generally failed at replication across studies. In spite of speculation in the literature about selection on these genes, current evidence from population genomic analyses supports selectively neutral processes, such as genetic drift and population dynamics, as the principal drivers of recent evolution in dopaminergic and serotonergic genes other than SLC6A4. PMID:27375535

  15. Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: studies using heterologous expression systems of the dopamine transporter.

    PubMed

    Storch, Alexander; Ott, Stefanie; Hwang, Yu I; Ortmann, Rainer; Hein, Andreas; Frenzel, Stefan; Matsubara, Kazuo; Ohta, Shigeru; Wolf, Hans Uwe; Schwarz, Johannes

    2002-03-01

    Endogenous isoquinoline (IQ) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridine (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. We addressed the importance of the DAT molecule for selective dopaminergic toxicity by testing the differential cytotoxicity of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (3, IQs; 4,3,4-dihydroisoquinolines and 15, 1,2,3,4-tetrahydroisoquinolines) as well as MPP(+) in non-neuronal and neuronal heterologous expression systems of the DAT gene (human embryonic kidney HEK-293 and mouse neuroblastoma Neuro-2A cells, respectively). Cell death was estimated using the MTT assay and the Trypan blue exclusion method. Nine isoquinolines and MPP(+) showed general cytotoxicity in both parental cell lines after 72hr with half-maximal toxic concentrations (TC(50) values) in the micromolar range. The rank order of toxic potency was: papaverine>salsolinol=tetrahydropapaveroline=1-benzyl-TIQ=norsalsolinol>tetrahydropapaverine>2[N]-methyl-salsolinol>2[N]-methyl-norsalsolinol>2[N]-Me-IQ(+)=MPP(+). Besides MPP(+), only the 2[N]-methylated compounds 2[N]-methyl-IQ(+), 2[N]-methyl-norsalsolinol and 2[N]-methyl-salsolinol showed enhanced cytotoxicity in both DAT expressing cell lines with 2- to 14-fold reduction of TC(50) values compared to parental cell lines. The rank order of selectivity in both cell systems was: MPP(+)>2[N]-Me-IQ(+)>2[N]-methyl-norsalsolinol=2[N]-methyl-salsolinol. Our results suggest that 2[N]-methylated isoquinoline derivatives structurally related to MPTP/MPP(+) are selectively toxic to dopaminergic cells via uptake by the DAT, and therefore may play a role in the pathogenesis of Parkinson's disease.

  16. The role of the MYD88-dependent pathway in MPTP-induced brain dopaminergic degeneration

    PubMed Central

    2011-01-01

    Background Mounting evidence supports a significant role of inflammation in Parkinson's disease (PD) pathophysiology, with several inflammatory pathways being suggested as playing a role in the dopaminergic degeneration seen in humans and animal models of the disease. These include tumor necrosis factor, prostaglandins and oxidative-related stress components. However, the role of innate immunity has not been established in PD. Methods Based on the fact that the myeloid differentiation primary response gene (88) (MyD88) is the most common adaptor protein implicated in toll-like receptor (TLR) signaling, critical in the innate immune response, we undertook a study to investigate the potential contribution of this specific pathway to MPTP-induced brain dopaminergic degeneration using MyD88 knock out mice (MyD88-/-), following our observations that the MyD88-dependent pathway was critical for MPTP dopaminergic toxicity in the enteric nervous system. Post-mortem analyses assessing nigrostriatal dopaminergic degeneration and inflammation were performed using HPLC, western blots, autoradiography and immunofluorescence. Results Our results demonstrate that MyD88-/- mice are as vulnerable to MPTP-induced dopamine and DOPAC striatal depletion as wild type mice. Furthermore, MyD88-/- mice show similar striatal dopamine transporter and tyrosine hydroxylase loss, as well as dopaminergic cell loss in the substantia nigra pars compacta in response to MPTP. To evaluate the extent of the inflammatory response created by the MPTP regimen utilized, we further performed bioluminescence imaging using TLR2-luc/gfp transgenic mice and microglial density analysis, which revealed a modest brain microglial response following MPTP. This was accompanied by a significant astrocytic reaction in the striatum, which was of similar magnitude both in wild type and MyD88-/- mice. Conclusions Our results suggest that subacute MPTP-induced dopaminergic degeneration observed in the central nervous

  17. Dissociation of prefrontal cortex and nucleus accumbens dopaminergic systems in conditional learning in rats.

    PubMed

    George, David N; Jenkins, Trisha A; Killcross, Simon

    2011-11-20

    There is converging evidence that the prefrontal and mesolimbic dopaminergic (DAergic) systems are involved in the performance of a variety of tasks that require the use of contextual, or task-setting, information to select an appropriate response from a number of candidate responses. Performance on tasks of this nature are impaired in schizophrenia and in rats exposed to psychotomimetics; impairments that are often attenuated by administration of dopamine (DA) antagonists. Rats were trained on either a complex instrumental discrimination task, that required the use of task-setting cues, or a simple discrimination task that did not. Following training, microdialysis probes were implanted unilaterally in either the medial prefrontal cortex (mPFC) or nucleus accumbens (NAc) and samples were collected in freely moving animals during a behavioural test session. In Experiment 1, we found no difference in levels of DA in the mPFC of rats while they were performing the two discrimination tasks. Rats that performed the complex task did, however, show significantly higher mPFC DA levels relative to rats in the simple discrimination condition following the end of the behavioural test session. In Experiment 2, rats performing the conditional discrimination showed lower levels of DA in the NAc compared to the simple discrimination group both during the test session and after it. These results provide direct evidence that conditional discrimination tasks engage frontal and mesolimbic DAergic systems and are consistent with the proposal that regulation of fronto-striatal DA is involved in aspects of cognitive control that are known to be impaired in individuals with schizophrenia.

  18. Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons

    PubMed Central

    Hong, J; Sha, S; Zhou, L; Wang, C; Yin, J; Chen, L

    2015-01-01

    Sigma-1 receptor (σ1R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous σ1R knockout (σ1R+/− and σ1R−/−) mice, we investigated the influence of σ1R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in σ1R+/− or σ1R−/− mice (MPTP-σ1R+/− or MPTP-σ1R−/− mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of N-methyl-d-aspartate receptor (NMDAr) NR2B phosphorylation. The σ1R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP-σ1R+/− mice treated with the σ1R agonist PRE084 or MPTP-σ1R−/− mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of σ1R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of σ1R by PRE084 enhanced the DAT expression in WT mice or σ1R+/− mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in σ1R+/− mice or σ1R−/− mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-σ1R−/− mice did not. The inactivation of σ1R by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP-σ1R−/− mice. The number of activated astrocytes in MPTP-σ1R−/− mice was less than that in MPTP-WT mice. The findings indicate that the σ1R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of

  19. The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice.

    PubMed

    Farahmandfar, Maryam; Bakhtazad, Atefeh; Akbarabadi, Ardeshir; Zarrindast, Mohammad-Reza

    2016-06-15

    Dopaminergic modulations of glutamate receptors are essential for the prefrontal cortical (PFC) behavioral and cognitive functions. In order to understand the effect of dopamine/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of dopaminergic agents on ketamine-induced amnesia by using a one-trial passive avoidance task in mice. Pre-training administration of ketamine (5, 10 and 15mg/kg, i.p.) dose-dependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC administration of SKF 38393, D1 receptor agonist and quinpirol D2 receptor agonist, alone did not affect memory acquisition. However, amnesia induced by pre-training ketamine (15mg/kg) significantly decreased by pretreatment of SKF 38393 (2 and 4µg/mouse) and quinpirol (0.3, 1 and 3µg/mouse). Pre-training administration of SCH 23390, D1 receptor antagonist (0.75 and 1μg/mouse, intra-mPFC), and sulpiride D2 receptor antagonist (3μg/mouse, intra-mPFC) impaired memory acquisition. In addition, co-pretreatment of different doses of SCH 23390 and sulpiride with lower dose of ketamine (5mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. It may be concluded that dopaminergic system of medial prefrontal cortex is involved in the ketamine-induced impairment of memory acquisition.

  20. [Behavioral disorders in Parkinson's disease: from pathophysiology to the mastery of dopaminergic treatment].

    PubMed

    Thobois, S; Ardouin, C; Schmitt, E; Lhommée, E; Klinger, H; Xie, J; Lagrange, C; Kistner, A; Aya Kombo, M; Fleury, V; Poisson, A; Fraix, V; Broussolle, E; Pollak, P; Krack, P

    2010-10-01

    Behavioral changes in Parkinson's disease are complex and their pathophysiology is not yet fully understood. The dopaminergic system seems to play a major role and most of the behavioral disorders in Parkinson's disease can be classified into either hypodopaminergic if related to the disease itself or hyperdopaminergic if related to dopaminergic treatment. Subthalamic stimulation, which enables withdrawal of dopaminergic medication at an advanced stage in the disease, provides a model for the study of certain nonmotor, dopamine-sensitive symptoms. Such a study has shown that apathy, which is the most frequent behavioral problem in Parkinson's disease, is part of a much broader hypodopaminergic behavioral syndrome which also includes anxiety and depression. Nonmotor fluctuations--essential fluctuations in the patient's psychological state--are an expression of mesolimbic denervation, as shown in positron emission tomography. Drug-induced sensitization of the denervated mesolimbic system accounts for hyperdopaminergic behavioral problems that encompass impulse control disorders that can be alternatively classified as behavioral addictions. The association of impulse control disorders and addiction to the dopaminergic medication has been called dopamine dysregulation syndrome. While L-dopa is the most effective treatment for motor symptoms, dopamine agonists are more effective in improving the nonmotor levodopa-sensitive symptoms. On the other hand, L-dopa induces more motor complications and dopamine agonist more behavioral side effects. There is increasing data and awareness that patients' quality of life appears to be dictated by hypo- and hyperdopaminergic psychological symptoms stemming from mesolimbic denervation and dopaminergic treatment rather than by motor symptoms and motor complications related to nigrostriatal denervation and dopaminergic treatment. Better management requires knowledge of the clinical syndromes of hyper- and hypodopaminergic behaviors and

  1. Levodopa induces long-lasting modification in the functional activity of the nigrostriatal pathway.

    PubMed

    Riverol, Mario; Ordóñez, Cristina; Collantes, María; DiCaudo, Carla; Peñuelas, Iván; Arbizu, Javier; Marcilla, Irene; Luquin, María R

    2014-02-01

    posterior putamen were significantly lower than those in the placebo group. AADC levels in MPTP groups were similar to those of control animals in all striatal areas analyzed. This study shows that chronic levodopa administration to monkeys with partial nigrostriatal degeneration followed by a washout period induces modifications in the functional activity of the dopaminergic nigrostriatal pathway.

  2. Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.

    PubMed

    Morera-Herreras, Teresa; Ruiz-Ortega, José Angel; Linazasoro, Gurutz; Ugedo, Luisa

    2011-03-01

    It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density. The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats. We have previously shown that Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats. Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

  3. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease

    PubMed Central

    Benner, Eric J.; Mosley, R. Lee; Destache, Chris J.; Lewis, Travis B.; Jackson-Lewis, Vernice; Gorantla, Santhi; Nemachek, Craig; Green, Steven R.; Przedborski, Serge; Gendelman, Howard E.

    2004-01-01

    Degeneration of the nigrostriatal dopaminergic pathway, the hallmark of Parkinson's disease, can be recapitulated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. Herein, we demonstrate that adoptive transfer of copolymer-1 immune cells to MPTP recipient mice leads to T cell accumulation within the substantia nigra pars compacta, suppression of microglial activation, and increased local expression of astrocyte-associated glial cell line-derived neurotrophic factor. This immunization strategy resulted in significant protection of nigrostriatal neurons against MPTP-induced neurodegeneration that was abrogated by depletion of donor T cells. Such vaccine treatment strategies may provide benefit for Parkinson's disease. PMID:15197276

  4. Abnormal striatal dopaminergic neurotransmission during rest and task production in spasmodic dysphonia.

    PubMed

    Simonyan, Kristina; Berman, Brian D; Herscovitch, Peter; Hallett, Mark

    2013-09-11

    Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [(11)C]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D2/D3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC ΔBP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC ΔBP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC ΔBP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC ΔBP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D2/D3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder.

  5. Neuronal or inducible nitric oxide synthase (NOS) expression level is not involved in the different susceptibility to nigro-striatal dopaminergic neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) between C57BL/6 and BALB/c mice.

    PubMed

    Ito, Tsuyoshi; Uchida, Kazuyuki; Nakayama, Hiroyuki

    2013-01-01

    1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces severe degeneration of dopaminergic (DA-ergic) neurons when administrated to C57BL/6 mice, but such lesions are not observed in BALB/c mice. To clarify the factors which influence such marked strain differences in the susceptibility to MPTP, the involvement of neuronal NOS (nNOS) and inducible NOS (iNOS) was investigated. MPTP was intraperitoneally (ip) administrated to adult C57BL/6 (highly sensitive) and BALB/c (resistant) mice. Immunohistochemical analysis using an antibody to tyrosine hydroxylase (TH) showed a significant decrease in TH-immunopositive areas in the striatum and TH-positive cells in the substantia nigra pars compacta (SNpc) of MPTP-treated C57BL/6 mice at 1 and 7 days (d) after administration, compared to control C57BL/6 mice. On the other hand, MPTP-treated BALB/c mice showed no significant changes. By Western blot analysis, TH, MAO-B, DAT, nNOS and iNOS protein expression levels were examined in intact and MPTP-treated mice. Intact BALB/c mice showed higher DAT protein expression in the striatum and TH protein expression in the midbrain than intact C57BL/6 mice. In addition, MPTP-treated BALB/c mice showed a more significant increase of MAO-B expression than MPTP-treated C57BL/6 mice at 12 h. The increase of nNOS and iNOS protein expressions in MPTP-treated BALB/c mice was more pronounced in the striatum and midbrain than in MPTP-treated C57BL/6 mice at 12 h and 2 d. These results indicate that MAO-B, DAT, nNOS or iNOS expression levels do not influence the different strain susceptibility to MPTP. Copyright © 2011 Elsevier GmbH. All rights reserved.

  6. β-synuclein aggregates and induces neurodegeneration in dopaminergic neurons.

    PubMed

    Taschenberger, Grit; Toloe, Johan; Tereshchenko, Julia; Akerboom, Jasper; Wales, Pauline; Benz, Roland; Becker, Stefan; Outeiro, Tiago F; Looger, Loren L; Bähr, Mathias; Zweckstetter, Markus; Kügler, Sebastian

    2013-07-01

    Whereas the contribution of α-synuclein to neurodegeneration in Parkinson disease is well accepted, the putative impact of its close homologue, β-synuclein, is enigmatic. β-Synuclein is widely expressed throughout the central nervous system, as is α-synuclein, but the physiological functions of both proteins remain unknown. Recent findings have supported the view that β-synuclein can act as an ameliorating regulator of α-synuclein-induced neurotoxicity, having neuroprotective rather than neurodegenerative capabilities, and being nonaggregating due to the absence of most of the aggregation-promoting NAC domain. However, a mutation of β-synuclein linked to dementia with Lewy bodies rendered the protein neurotoxic in transgenic mice, and fibrillation of β-synuclein has been demonstrated in vitro. Neurotoxicity and aggregation properties of α-, β-, and γ-synuclein were comparatively elucidated in the rat nigro-striatal projection and in cultured neurons. Supporting the hypothesis that β-synuclein can act as a neurodegeneration-inducing factor, we demonstrated that wild-type β-synuclein is neurotoxic for cultured primary neurons. Furthermore, β-synuclein formed proteinase K-resistant aggregates in dopaminergic neurons in vivo, leading to pronounced and progressive neurodegeneration in rats. Expression of β-synuclein caused mitochondrial fragmentation, but this fragmentation did not render mitochondria nonfunctional in terms of ion handling and respiration even at late stages of neurodegeneration. A comparison of the neurodegenerative effects induced by α-, β-, and γ-synuclein revealed that β-synuclein was eventually as neurotoxic as α-synuclein for nigral dopaminergic neurons, whereas γ-synuclein proved to be nontoxic and had very low aggregation propensity. Our results suggest that the role of β-synuclein as a putative modulator of neuropathology in aggregopathies like Parkinson disease and dementia with Lewy bodies needs to be revisited. © 2013

  7. Interaction between the dopaminergic and opioidergic systems in dorsal hippocampus in modulation of formalin-induced orofacial pain in rats.

    PubMed

    Reisi, Zahra; Haghparast, Amir; Pahlevani, Pouyan; Shamsizadeh, Ali; Haghparast, Abbas

    2014-09-01

    The hippocampus is a region of the brain that serves several functions. The dopaminergic system acts through D1- and D2-like receptors to interfere in pain modulation and the opioid receptors play major roles in analgesic processes and there are obvious overlaps between these two systems. The present study investigated the interaction between the opioidergic and dopaminergic systems in the dorsal hippocampus (CA1) region for formalin-induced orofacial pain. Two guide cannulae were stereotaxically implanted in the CA1 region and morphine (0.5, 1, 2 and 4 μg/0.5 μl saline) and naloxone (0.3, 1 and 3 μg/0.5 μl saline) were used as the opioid receptor agonist and antagonist, respectively. SKF-38393 (1 μg/0.5 μl saline) was used as a D1-like receptor agonist, quinpirole (2 μg/0.5 μl saline) as a D2-like receptor agonist, SCH-23390 (0.5 μg/0.5 μl saline) as a D1-like receptor antagonist and sulpiride (3 μg/0.5 μl DMSO) as a D2-like receptor antagonist. To induce orofacial pain, 50 μl of 1% formalin was subcutaneously injected into the left side of the upper lip. Our results showed that different doses of morphine significantly reduced orofacial pain in both phases induced by formalin. Naloxone (1 and 3 μg) reversed morphine induced analgesia in CA1. SKF-38393 and quinpirole with naloxone (1 μg) significantly decreased formalin-induced orofacial pain in both phases. SCH-23390 had no effect on the antinociceptive response of morphine in both phases of orofacial pain. Sulpiride reversed the antinociceptive effects of morphine only in the first phase, but this result was not significant. Our findings suggest that there is cross-talk between the opioidergic and dopaminergic systems. Opioidergic neurons also exerted antinociceptive effects by modulation of the dopaminergic system in the CA1 region of the brain.

  8. The role of purinergic and dopaminergic systems on MK-801-induced antidepressant effects in zebrafish.

    PubMed

    da Silva, Raquel Bohrer; Siebel, Anna Maria; Bonan, Carla Denise

    2015-12-01

    Depression is a serious disease characterized by low mood, anhedonia, loss of interest in daily activities, appetite and sleep disturbances, reduced concentration, and psychomotor agitation. There is a growing interest in NMDA antagonists as a promising target for the development of new antidepressants. Considering that purinergic and dopaminergic systems are involved in depression and anxiety states, we characterized the role of these signaling pathways on MK-801-induced antidepressant effects in zebrafish. Animals treated with MK-801 at the doses of 5, 10, 15, or 20μM during 15, 30, or 60min spent longer time in the top area of aquariums in comparison to control group, indicating an anxiolytic/antidepressant effect induced by this drug. Animals treated with MK-801 spent longer time period at top area until 2 (5μM MK-801) and 4 (20μM MK-801) hours after treatment, returning to basal levels from 24h to 7days after exposure. Repeated MK-801 treatment did not induce cumulative effects, since animals treated daily during 7days had the same behavioral response pattern observed since the first until the 7th day. In order to investigate the effects of adenosine A1 and A2A receptor antagonist and agonist and the influence of modulation of adenosine levels on MK-801 effects, we treated zebrafish with caffeine, DPCPX, CPA, ZM 241385, CGS 21680, AMPCP, EHNA, dipyridamole, and NBTI during 30min before MK-801 exposure. The non-specific adenosine receptor antagonist caffeine (50mg/kg) and the selective A1 receptor antagonist DPCPX (15mg/kg) prevented the behavioral changes induced by MK-801. The non-specific nucleoside transporter (NT) inhibitor dipyridamole (10mg/kg) exacerbated the behavioral changes induced by MK-801. Dopamine receptor antagonists (sulpiride and SCH 23390) did not change the behavioral alterations induced by MK-801. Our findings demonstrated that antidepressant-like effects of MK-801 in zebrafish are mediated through adenosine A1 receptor activation

  9. Neonatal exposure to estradiol valerate increases dopamine content in nigrostriatal pathway during adulthood in the rat.

    PubMed

    Cruz, G; Riquelme, R; Espinosa, P; Jara, P; Dagnino-Subiabre, A; Renard, G M; Sotomayor-Zárate, R

    2014-05-01

    Research in programming has focused in the study of stimuli that affect sensitive periods of development such as prenatal and neonatal stage. We previously showed that exposure to estradiol valerate to female rats during the first 12 h of life increased catecholamine content in ventromedial-arcuatus hypothalamus of the adult rat. However, changes in others dopaminergic circuits have not been studied. The purpose of this work was to determine the neurotransmitters changes induced by neonatal estradiol valerate (0.1 mg/50 μl s. c. per rat) administration on nigrostriatal pathway of adult female rats. Sesame oil (50 μl s. c. per rat) was administered in a control parallel group. EV-1 adult rats presented effective markers of long-term estrogenization as decreased serum levels of progesterone and a reduction in the size of estrogen-sensitive organs. In the brain, neonatal estradiol valerate administration led to a significant increase in dopamine content in striatum, substantia nigra and ventral tegmental area. With respect to the contents of dopamine metabolites, only 3-methoxytyramine content increased in substantia nigra and ventral tegmental area. In addition, the content of noradrenaline increased only in striatum. Interestingly, estrogenized rats lacked locomotor activity induced by acute dose of amphetamine (1 mg/kg i. p.). Altogether, these results show that neonatal exposure to estradiol valerate permanently modified the content of monoamine neurotransmitters in nigrostriatal pathway and amphetamine-induced locomotor activity of adult female rats. This might imply that estrogenized rats could have changes in the expression of key proteins in dopaminergic regulation, as tyrosine hydroxylase and dopamine transporter. © Georg Thieme Verlag KG Stuttgart · New York.

  10. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    SciTech Connect

    Lara-Camacho, V. M. Ávila-García, M. C. Ávila-Rodríguez, M. A.

    2014-11-07

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [{sup 11}C]-DTBZ, [{sup 11}C]-RAC, and [{sup 18}F]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  11. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Lara-Camacho, V. M.; Ávila-García, M. C.; Ávila-Rodríguez, M. A.

    2014-11-01

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [11C ]-DTBZ, [11C ]-RAC, and [18F ]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  12. Effect of Early Overfeeding on Palatable Food Preference and Brain Dopaminergic Reward System at Adulthood: Role of Calcium Supplementation.

    PubMed

    Conceição, E P S; Carvalho, J C; Manhães, A C; Guarda, D S; Figueiredo, M S; Quitete, F T; Oliveira, E; Moura, E G; Lisboa, P C

    2016-05-01

    Rats raised in small litters (SL) are obese and hyperphagic. In the present study, we evaluated whether obesity is associated with changes in the mesocorticolimbic dopaminergic reward system in these animals at adulthood. We also assessed the anti-obesity effects of dietary calcium supplementation. To induce early overfeeding, litters were adjusted to three pups on postnatal day (PN)3 (SL group). Control litters were kept with 10 pups each until weaning (NL group). On PN120, SL animals were subdivided into two groups: SL (standard diet) and SL-Ca [SL with calcium supplementation (10 g calcium carbonate/kg rat chow) for 60 days]. On PN175, animals were subjected to a food challenge: animals could choose between a high-fat (HFD) or a high-sugar diet (HSD). Food intake was recorded after 30 min and 12 h. Euthanasia occurred on PN180. SL rats had higher food intake, body mass and central adiposity. Sixty days of dietary calcium supplementation (SL-Ca) prevented these changes. Only SL animals preferred the HFD at 12 h. Both SL groups had lower tyrosine hydroxylase content in the ventral tegmental area, lower dopaminergic transporter content in the nucleus accumbens, and higher type 2 dopamine receptor (D2R) content in the hypothalamic arcuate nucleus (ARC). They also had higher neuropeptide Y (NPY) and lower pro-opiomelanocortin contents in the ARC. Calcium treatment normalised only D2R and NPY contents. Precocious obesity induces long-term effects in the brain dopaminergic system, which can be associated with an increased preference for fat at adulthood. Calcium treatment prevents this last alteration, partially through its actions on ARC D2R and NPY proteins.

  13. Are dopaminergic pathways involved in theory of mind? A study in Parkinson's disease.

    PubMed

    Péron, Julie; Vicente, Siobhan; Leray, Emmanuelle; Drapier, Sophie; Drapier, Dominique; Cohen, Renaud; Biseul, Isabelle; Rouaud, Tiphaine; Le Jeune, Florence; Sauleau, Paul; Vérin, Marc

    2009-01-01

    M deficit would appear to be present in PD patients where the degenerative process has spread beyond the dopaminergic pathways, but not in early PD patients where neuronal loss is thought to be restricted to the nigrostriatal and mesolimbic dopaminergic systems. In conclusion, our results suggest that the dopaminergic pathways are not involved in ToM.

  14. Withania somnifera alleviates parkinsonian phenotypes by inhibiting apoptotic pathways in dopaminergic neurons.

    PubMed

    Prakash, Jay; Chouhan, Shikha; Yadav, Satyndra Kumar; Westfall, Susan; Rai, Sachchida Nand; Singh, Surya Pratap

    2014-12-01

    Maneb (MB) and paraquat (PQ) are environmental toxins that have been experimentally used to induce selective damage of dopaminergic neurons leading to the development of Parkinson's disease (PD). Although the mechanism of this selective neuronal toxicity in not fully understood, oxidative stress has been linked to the pathogenesis of PD. The present study investigates the mechanisms of neuroprotection elicited by Withania somnifera (Ws), a herb traditionally recognized by the Indian system of medicine, Ayurveda. An ethanolic root extract of Ws was co-treated with the MB-PQ induced mouse model of PD and was shown to significantly rescue canonical indicators of PD including compromised locomotor activity, reduced dopamine in the substantia nigra and various aspects of oxidative damage. In particular, Ws reduced the expression of iNOS, a measure of oxidative stress. Ws also significantly improved the MB + PQ mediated induction of a pro-apoptotic state by reducing Bax and inducing Bcl-2 protein expression, respectively. Finally, Ws reduced expression of the pro-inflammatory marker of astrocyte activation, GFAP. Altogether, the present study suggests that Ws treatment provides nigrostriatal dopaminergic neuroprotection against MB-PQ induced Parkinsonism by the modulation of oxidative stress and apoptotic machinery possibly accounting for the behavioural effects.

  15. Dose Optimization for Long-term rAAV-mediated RNA Interference in the Nigrostriatal Projection Neurons

    PubMed Central

    Ulusoy, Ayse; Sahin, Gurdal; Björklund, Tomas; Aebischer, Patrick; Kirik, Deniz

    2009-01-01

    Short-hairpin RNA (shRNA)–mediated gene knockdown is a powerful tool for targeted gene silencing and an emerging novel therapeutic strategy. Recent publications, however, reported unexpected toxicity after utilizing viral-mediated shRNA knockdown in vivo. Thus, it is currently unclear whether shRNA-mediated knockdown strategy can be used as a safe and efficient tool for gene silencing. In this study, we have generated rAAV vectors expressing shRNAs targeting the rat tyrosine hydroxylase (TH) mRNA (shTH) for testing the efficacy of in vivo TH knockdown in the nigral dopaminergic neurons. At high titers, not only the shTH vectors but also the scrambled and green fluorescence protein (GFP)–only controls caused cell death. In a dose–response study, we identified a dose window leading to >60% decrease in TH+ neurons without any change in vesicular monoamine transporter-2 (VMAT2) expression. Moreover, using the safe and efficient dose, we showed that dopamine (DA) synthesis rate was significantly reduced and this lead to emergence of motor deficits in the shTH-expressing rats. Interestingly, these animals showed very robust and long-lasting recovery after a single systemic L-3,4-dihydroxyphenylalanine (L-DOPA) administration beyond what can be achieved in 6-hydroxydopamine (6-OHDA)–lesioned rats. Our results have implications for both mechanistic and therapeutic studies utilizing long-term shRNA-mediated gene silencing in the nigrostriatal projection system. PMID:19584816

  16. Minocycline enhances MPTP toxicity to dopaminergic neurons.

    PubMed

    Yang, Lichuan; Sugama, Shuei; Chirichigno, Jason W; Gregorio, Jason; Lorenzl, Stefan; Shin, Dong H; Browne, Susan E; Shimizu, Yoshinori; Joh, Tong H; Beal, M Flint; Albers, David S

    2003-10-15

    Minocycline has been shown previously to have beneficial effects against ischemia in rats as well as neuroprotective properties against excitotoxic damage in vitro, nigral cell loss via 6-hydroxydopamine, and to prolong the life-span of transgenic mouse models of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). We investigated whether minocycline would protect against toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that selectively destroys nigrostriatal dopaminergic (DA) neurons and produces a clinical state similar to Parkinson's disease (PD) in rodents and primates. We found that although minocycline inhibited microglial activation, it significantly exacerbated MPTP-induced damage to DA neurons. We present evidence suggesting that this effect may be due to inhibition of DA and 1-methyl-4-phenylpridium (MPP+) uptake into striatal vesicles. Copyright 2003 Wiley-Liss, Inc.

  17. Attenuation of malonate-induced degeneration of the nigrostriatal pathway by inhibitors of nitric oxide synthase.

    PubMed

    Connop, B P; Boegman, R J; Beninger, R J; Jhamandas, K

    1996-04-01

    Focal infusions of the succinate dehydrogenase inhibitor, malonate, into the substantia nigra pars compacta (SNc) of adult Sprague-Dawley rats resulted in a substantial depletion of ipsilateral striatal tyrosine hydroxylase (TH) activity. The percentage decrease in striatal TH activity following intranigral malonate (0.5 mumol/0.5 microliter) infusion was similar at 4 (58%) and 7 days (62%) post-infusion. To assess the role of N-methyl-D-aspartate (NMDA) receptor activation in malonate neurotoxicity, animals were pretreated with the NMDA receptor antagonist MK-801 (2 x 5 mg/kg, i.p.). Four days post-infusion of malonate (0.5 mumol/0.5 microliter) into the SNc, striatal TH activity was depleted by 58% in vehicle pretreated animals and 14% in the presence of MK-801 indicating a significant neuroprotective effect of MK-801 on malonate action. To determine the role of nitric oxide (NO) in malonate-induced nigral toxicity, the actions of malonate were evaluated in the presence of the nitric oxide synthase (NOS) inhibitors, 7-nitro indazole (7-NI) and N omega-nitro-L-arginine methyl ester (L- NAME). Systemic injections of 7-NI (20, 30, 40, 50 and 75 mg/kg, i.p.) produced a dose-related inhibition of nigral NOS activity which was maximal at a dose of 40 mg/kg. Intranigral infusion of malonate with 20 and 50 mg/kg 7-NI pretreatment produced a 46 and 31% decrease in striatal TH activity, respectively. Thus, a significant protective effect at the higher but not lower dose of 7-NI was observed. Pretreatment with a L- NAME regimen (2 x 250 mg/kg; i.p.), previously shown to inhibit brain NOS activity by greater than 86%, also produced a significant neuroprotective effect against malonate-induced neurotoxicity (30% decrease). The results of this study suggest that malonate-induced toxicity to the dopaminergic neurons of the nigrostriatal pathway is mediated, at least in part, by NMDA receptor activation and the formation of NO.

  18. Dorsal-to-Ventral Shift in Midbrain Dopaminergic Projections and Increased Thalamic/Raphe Serotonergic Function in Early Parkinson Disease.

    PubMed

    Joutsa, Juho; Johansson, Jarkko; Seppänen, Marko; Noponen, Tommi; Kaasinen, Valtteri

    2015-07-01

    Loss of nigrostriatal neurons leading to dopamine depletion in the dorsal striatum is the pathologic hallmark of Parkinson disease contributing to the primary motor symptoms of the disease. However, Parkinson pathology is more widespread in the brain, affecting also other dopaminergic pathways and neurotransmitter systems, but these changes are less well characterized. This study aimed to investigate the mesencephalic striatal and extrastriatal dopaminergic projections together with extrastriatal serotonin transporter binding in Parkinson disease. Two hundred sixteen patients with Parkinson disease and 204 control patients (patients without neurodegenerative parkinsonism syndromes and normal SPECT imaging) were investigated with SPECT using the dopamine/serotonin transporter ligand (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ((123)I-FP-CIT) in the clinical setting. The group differences and midbrain correlations were analyzed voxel by voxel over the entire brain. We found that Parkinson patients had lower (123)I-FP-CIT uptake in the striatum and ventral midbrain but higher uptake in the thalamus and raphe nuclei than control patients. In patients with Parkinson disease, the correlation of the midbrain tracer uptake was shifted from the putamen to widespread corticolimbic areas. All findings were highly significant at the voxel level familywise error-corrected P value of less than 0.05. Our findings show that Parkinson disease is associated not only with the degeneration of the nigrostriatal dopamine neurotransmission, but also with a parallel shift toward mesolimbic and mesocortical function. Furthermore, Parkinson disease patients seem to have upregulation of brain serotonin transporter function at the early phase of the disease. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  19. The effect of CA1 dopaminergic system in harmaline-induced amnesia.

    PubMed

    Nasehi, M; Ketabchi, M; Khakpai, F; Zarrindast, M-R

    2015-01-29

    In the present study, the effects of bilateral injections of dopaminergic drugs into the hippocampal CA1 regions (intra-CA1) on harmaline-induced amnesia were examined in male mice. A one-trial step-down passive avoidance task was used for the assessment of memory retention in adult male mice. Pre-training intra-peritoneal (i.p.) administration of harmaline (1 mg/kg) induced impairment of memory retention. Moreover, intra-CA1 administration of dopamine D1 receptor antagonist, SCH23390 (0.02 μg/mouse), dopamine D1 receptor agonist, SKF38393 (0.5 μg/mouse), dopamine D2 receptor antagonist, sulpiride (1 μg/mouse) and dopamine D2 receptor agonist, quinpirole (0.25 and 0.5 μg/mouse) suppressed the learning of a single-trial passive avoidance task. Also, pre-training intra-CA1 injection of subthreshold doses of SCH23390 (0.001 μg/mouse) or sulpiride (0.25 μg/mouse) with the administration of harmaline (1 mg/kg, i.p.) reversed impairment of memory formation. However, pre-training intra-CA1 injection of SKF38393 (0.1 μg/mouse) or quinpirole (0.1 μg/mouse) increased pre-training harmaline (0.25 and 0.5 mg/kg, i.p.)-induced retrieval impairment. Moreover, SKF Ca blocker (SKF) (0.01 μg/mouse) decrease the amnesia induced by harmaline (1 mg/kg), while co-administration of SKF (0.01 μg/mouse)/sulpiride (0.25 μg/mouse) or SCH23390 (0.001 μg/mouse)/sulpiride (0.25 μg/mouse) potentiate amnesia caused by harmaline. These findings implicate the involvement of CA1 dopaminergic mechanism in harmaline-induced impairment of memory acquisition.

  20. Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System

    PubMed Central

    Matzkin, María E.; Muñiz, Javier A.; Cadet, Jean Lud; Garcia-Rill, Edgar; Urbano, Francisco J.; Vitullo, Alfredo D.; Bisagno, Veronica

    2015-01-01

    Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3×10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology. PMID:26560700

  1. Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System.

    PubMed

    González, Candela R; González, Betina; Matzkin, María E; Muñiz, Javier A; Cadet, Jean Lud; Garcia-Rill, Edgar; Urbano, Francisco J; Vitullo, Alfredo D; Bisagno, Veronica

    2015-01-01

    Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3×10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology.

  2. Evidence for a dopaminergic deficit in sporadic amyotrophic lateral sclerosis on positron emission scanning

    SciTech Connect

    Takahashi, Hirohide; Snow, B.J.; Bhatt, M.H.; Peppard, R.; Eisen, A.; Calne, D.B. )

    1993-10-23

    Although rare, the chronic neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and idiopathic parkinsonism coexist to a greater degree than expected by chance. This suggests that patients with ALS may have subclinical lesions of the nigrostriatal dopaminergic pathway. To study this hypothesis, the authors did positron emission tomography with 6-fluorodopa on 16 patients with sporadic ALS and without extrapyramidal disease, and compared the results with age-matched controls. They found a significant progressive fall in 6-fluorodopa uptake with time since diagnosis, and reduced dopaminergic function in 3 patients with ALS of long duration. This supports the hypothesis that ALS and IP may share pathogenesis, and, perhaps, etiology.

  3. Genes in the dopaminergic system and delinquent behaviors across the life course: the role of social controls and risks.

    PubMed

    Boardman, Jason D; Menard, Scott; Roettger, Michael E; Knight, Kelly E; Boutwell, Brian B; Smolen, Andrew

    2014-06-01

    This paper examines the interaction between social control and social risk mechanisms and genes within the dopaminergic system (DAT1 and DRD2) as related to serious and violent forms of delinquent behavior among adolescents and young adults. We use nine waves of data from the National Youth Survey Family Study to examine the relevance of protective or risky social factors at four social levels including school, neighborhood, friends, and family within the gene-environment interaction framework. We extend previous work in this area by providing a testable typology of gene-environment interactions derived from current theories in this area. We find consistent evidence that the associations between putatively risky genotypes and delinquent behavior are suppressed within protective social environments. We also provide some evidence that supports the differential susceptibility hypothesis for these outcomes. Our findings largely confirm the conclusions of previous work and continue to highlight the critical role of the social environment within candidate gene studies of complex behaviors.

  4. Effects of titanium dioxide nanoparticles on α-synuclein aggregation and the ubiquitin-proteasome system in dopaminergic neurons.

    PubMed

    Wu, Jie; Xie, Hongjun

    2016-01-01

    Dopaminergic neurons (PC12 cells) were treated with different doses of titanium dioxide nanoparticles (TiO2-NPs), to investigate their effects on α-Synuclein (α-Syn) aggregation and their mechanism of action. Western blotting and immunofluorescent staining were performed. Exposure to TiO2-NPs increased α-Syn expression (p < 0.05) and induced dose-dependent α-Syn aggregation. Pretreatment with N-acetylcysteine partially inhibited α-Syn expression induced by a 200 μg/ml dose of TiO2-NPs. TiO2-NPs reduced the expressions of parkin and ubiquitin C-terminal hydrolase protein, and were associated with oxidative stress in PC12 cells. Dysfunction of the ubiquitin-proteasome system also contributed to α-Syn aggregation. The potentially neurotoxic TiO2-NPs may cause Parkinson's disease.

  5. The peptidyl-prolyl isomerase Pin1 up-regulation and proapoptotic function in dopaminergic neurons: relevance to the pathogenesis of Parkinson disease.

    PubMed

    Ghosh, Anamitra; Saminathan, Hariharan; Kanthasamy, Arthi; Anantharam, Vellareddy; Jin, Huajun; Sondarva, Gautam; Harischandra, Dilshan S; Qian, Ziqing; Rana, Ajay; Kanthasamy, Anumantha G

    2013-07-26

    Parkinson disease (PD) is a chronic neurodegenerative disease characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra. The pathophysiological mechanisms underlying PD remain unclear. Pin1, a major peptidyl-prolyl isomerase, has recently been associated with certain diseases. Notably, Ryo et al. (Ryo, A., Togo, T., Nakai, T., Hirai, A., Nishi, M., Yamaguchi, A., Suzuki, K., Hirayasu, Y., Kobayashi, H., Perrem, K., Liou, Y. C., and Aoki, I. (2006) J. Biol. Chem. 281, 4117-4125) implicated Pin1 in PD pathology. Therefore, we sought to systematically characterize the role of Pin1 in PD using cell culture and animal models. To our surprise we observed a dramatic up-regulation of Pin1 mRNA and protein levels in dopaminergic MN9D neuronal cells treated with the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP(+)) as well as in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Notably, a marked expression of Pin1 was also observed in the substantia nigra of human PD brains along with a high co-localization of Pin1 within dopaminergic neurons. In functional studies, siRNA-mediated knockdown of Pin1 almost completely prevented MPP(+)-induced caspase-3 activation and DNA fragmentation, indicating that Pin1 plays a proapoptotic role. Interestingly, multiple pharmacological Pin1 inhibitors, including juglone, attenuated MPP(+)-induced Pin1 up-regulation, α-synuclein aggregation, caspase-3 activation, and cell death. Furthermore, juglone treatment in the MPTP mouse model of PD suppressed Pin1 levels and improved locomotor deficits, dopamine depletion, and nigral dopaminergic neuronal loss. Collectively, our findings demonstrate for the first time that Pin1 is up-regulated in PD and has a pathophysiological role in the nigrostriatal dopaminergic system and suggest that modulation of Pin1 levels may be a useful translational therapeutic strategy in PD.

  6. Effects of early and late neonatal bromocriptine treatment on hypothalamic neuropeptides, dopaminergic reward system and behavior of adult rats.

    PubMed

    Carvalho, Janaine C; Lisboa, Patricia C; de Oliveira, Elaine; Peixoto-Silva, Nayara; Pinheiro, Cintia R; Fraga, Mabel C; Claudio-Neto, Sylvio; Franci, Celso R; Manhães, Alex C; Moura, Egberto G

    2016-06-14

    In humans, bromocriptine (BRO) is used as a treatment for many disorders, such as prolactinomas, even during pregnancy and lactation. Previously we demonstrated that maternal BRO treatment at the end of lactation programs offspring for obesity and several endocrine dysfunctions. Here, we studied the long-term effects of direct BRO injection in neonatal Wistar rats on their dopaminergic pathway, anxiety-like behavior and locomotor activity at adulthood. Male pups were either s.c. injected with BRO (0.1μg/once daily) from postnatal day (PN) 1 to 10 or from PN11 to 20. Controls were injected with methanol-saline. Body mass, food intake, neuropeptides, dopamine pathway parameters, anxiety-like behavior and locomotor activity were analyzed. The dopamine pathway was analyzed in the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (DS) at PN180. PN1-10 BRO-treated animals had normal body mass and adiposity but lower food intake and plasma prolactin (PRL). This group had higher POMC in the arcuate nucleus (ARC), higher tyrosine hydroxylase (TH) in the VTA, higher dopa decarboxylase (DDc), higher D2R and μu-opioid receptor in the NAc. Concerning behavior in elevated plus maze (EPM), BRO-treated animals displayed more anxiety-like behaviors. PN11-20 BRO-treated showed normal body mass and adiposity but higher food intake and plasma PRL. This group had lower POMC in the ARC, lower TH in the VTA and lower DAT in the NAc. BRO-treated animals showed less anxiety-like behaviors in the EPM. Thus, neonatal BRO injection, depending on the time of treatment, leads to different long-term dysfunctions in the dopaminergic reward system, food intake behavior and anxiety levels, findings that could be partially due to PRL and POMC changes. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Effect of inhibition of fatty acid amide hydrolase on MPTP-induced dopaminergic neuronal damage.

    PubMed

    Viveros-Paredes, J M; Gonzalez-Castañeda, R E; Escalante-Castañeda, A; Tejeda-Martínez, A R; Castañeda-Achutiguí, F; Flores-Soto, M E

    2017-01-16

    Parkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our study included 4 experimental groups (n = 6 mice per group): a control group receiving no treatment, a group receiving URB597 (0.2mg/kg) every 3 days for 30 days, a group treated with MPTP (30mg/kg) for 5 days, and a group receiving URB597 and subsequently MPTP injections. Three days after the last dose, we conducted a series of behavioural tests (beam test, pole test, and stride length test) to compare motor coordination between groups. We subsequently analysed immunoreactivity of dopaminergic cells and microglia in the SNpc and striatum. Mice treated with URB597 plus MPTP were found to perform better on behavioural tests than mice receiving MPTP only. According to the immunohistochemistry study, mice receiving MPTP showed fewer dopaminergic cells and fibres in the SNpc and striatum. Animals treated with URB597 plus MPTP displayed increased tyrosine hydroxylase immunoreactivity compared to those treated with MPTP only. Regarding microglial immunoreactivity, the group receiving MPTP showed higher Iba1 immunoreactivity in the striatum and SNpc than did the group treated with URB597 plus MPTP. Our results show that URB597 exerts a protective effect since it inhibits dopaminergic neuronal death, decreases microglial immunoreactivity, and improves MPTP-induced motor alterations. Copyright © 2016 Sociedad Española de Neurología. Publicado

  8. Neuroprotective Effects of β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson's Disease Induced by MPTP.

    PubMed

    Viveros-Paredes, Juan M; González-Castañeda, Rocio E; Gertsch, Juerg; Chaparro-Huerta, Veronica; López-Roa, Rocio I; Vázquez-Valls, Eduardo; Beas-Zarate, Carlos; Camins-Espuny, Antoni; Flores-Soto, Mario E

    2017-07-06

    Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the cannabinoid signalling system in PD. β-caryophyllene (BCP) is a natural bicyclic sesquiterpene that is an agonist of the cannabinoid type 2 receptor (CB2R). Previous studies have suggested that BCP exerts prophylactic and/or curative effects against inflammatory bowel disease through its antioxidative and/or anti-inflammatory action. The present study describes the neuroprotective effects of BCP in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine model of PD, and we report the results of our investigation of its neuroprotective mechanism in neurons and glial cells. In the murine model, BCP pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in the SN and striatum, and alleviated MPTP-induced glia activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. The observed neuroprotection and inhibited glia activation were reversed upon treatment with the CB2R selective antagonist AM630, confirming the involvement of the CB2R. These results indicate that BCP acts via multiple neuroprotective mechanisms in our murine model and suggest that BCP may be viewed as a potential treatment and/or preventative agent for PD.

  9. Ascending midbrain dopaminergic axons require descending GAD65 axon fascicles for normal pathfinding

    PubMed Central

    García-Peña, Claudia M.; Kim, Minkyung; Frade-Pérez, Daniela; Ávila-González, Daniela; Téllez, Elisa; Mastick, Grant S.; Tamariz, Elisa; Varela-Echavarría, Alfredo

    2014-01-01

    The Nigrostriatal pathway (NSP) is formed by dopaminergic axons that project from the ventral midbrain to the dorsolateral striatum as part of the medial forebrain bundle. Previous studies have implicated chemotropic proteins in the formation of the NSP during development but little is known of the role of substrate-anchored signals in this process. We observed in mouse and rat embryos that midbrain dopaminergic axons ascend in close apposition to descending GAD65-positive axon bundles throughout their trajectory to the striatum. To test whether such interaction is important for dopaminergic axon pathfinding, we analyzed transgenic mouse embryos in which the GAD65 axon bundle was reduced by the conditional expression of the diphtheria toxin. In these embryos we observed dopaminergic misprojection into the hypothalamic region and abnormal projection in the striatum. In addition, analysis of Robo1/2 and Slit1/2 knockout embryos revealed that the previously described dopaminergic misprojection in these embryos is accompanied by severe alterations in the GAD65 axon scaffold. Additional studies with cultured dopaminergic neurons and whole embryos suggest that NCAM and Robo proteins are involved in the interaction of GAD65 and dopaminergic axons. These results indicate that the fasciculation between descending GAD65 axon bundles and ascending dopaminergic axons is required for the stereotypical NSP formation during brain development and that known guidance cues may determine this projection indirectly by instructing the pathfinding of the axons that are part of the GAD65 axon scaffold. PMID:24926237

  10. Epothilone D prevents binge methamphetamine-mediated loss of striatal dopaminergic markers.

    PubMed

    Killinger, Bryan A; Moszczynska, Anna

    2016-02-01

    Exposure to binge methamphetamine (METH) can result in a permanent or transient loss of dopaminergic (DAergic) markers such as dopamine (DA), dopamine transporter, and tyrosine hydroxylase (TH) in the striatum. We hypothesized that the METH-induced loss of striatal DAergic markers was, in part, due to a destabilization of microtubules (MTs) in the nigrostriatal DA pathway that ultimately impedes anterograde axonal transport of these markers. To test this hypothesis, adult male Sprague-Dawley rats were treated with binge METH or saline in the presence or absence of epothilone D (EpoD), a MT-stabilizing compound, and assessed 3 days after the treatments for the levels of several DAergic markers as well as for the levels of tubulins and their post-translational modifications (PMTs). Binge METH induced a loss of stable long-lived MTs within the striatum but not within the substantia nigra pars compacta (SNpc). Treatment with a low dose of EpoD increased the levels of markers of stable MTs and prevented METH-mediated deficits in several DAergic markers in the striatum. In contrast, administration of a high dose of EpoD appeared to destabilize MTs and potentiated the METH-induced deficits in several DAergic markers. The low-dose EpoD also prevented the METH-induced increase in striatal DA turnover and increased behavioral stereotypy during METH treatment. Together, these results demonstrate that MT dynamics plays a role in the development of METH-induced losses of several DAergic markers in the striatum and may mediate METH-induced degeneration of terminals in the nigrostriatal DA pathway. Our study also demonstrates that MT-stabilizing drugs such as EpoD have a potential to serve as useful therapeutic agents to restore function of DAergic nerve terminals following METH exposure when administered at low doses. Administration of binge methamphetamine (METH) negatively impacts neurotransmission in the nigrostriatal dopamine (DA) system. The effects of METH include

  11. Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration.

    PubMed

    Jimenez-Ferrer, Itzia; Jewett, Michael; Tontanahal, Ashmita; Romero-Ramos, Marina; Swanberg, Maria

    2017-10-01

    Parkinson's Disease (PD) is a complex and heterogeneous neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and pathological intracellular accumulation of alpha-synuclein (α-syn). In the vast majority of PD patients, the disease has a complex etiology, defined by multiple genetic and environmental risk factors. Common genetic variants in the human leukocyte-antigen (HLA) region have been associated to PD risk and the carriage of these can double the risk to develop PD. Among these common genetic variants are the ones that modulate the expression of MHCII genes. MHCII molecules encoded in the HLA-region are responsible for antigen presentation to the adaptive immune system and have a key role in inflammatory processes. In addition to cis‑variants affecting MHCII expression, a transactivator encoded by the Mhc2ta gene is the major regulator of MHCII expression. We have previously identified variations in the promoter region of Mhc2ta, encoded in the VRA4 region, to regulate MHCII expression in rats. The expression of MHCII is known to be required in the response to α-syn. However, how the expression of MHCII affects the activation of microglial or the impact of physiological, differential Mhc2ta expression on degeneration of dopaminergic neurons has not previously been addressed. Here we addressed the implications of common genetic allelic variants of the major regulator of MHCII expression on α-syn-induced microglia activation and the severity of the dopaminergic neurodegeneration. We used a viral vector technology to overexpress α-syn in two rat strains; Dark agouti (DA) wild type and DA.VRA4-congenic rats. The congenic strain carries PVG alleles in the VRA4 locus and therefore displays lower Mhc2ta expression levels compared to DA rats. We analyzed the impact of this physiological differential Mhc2ta expression on gliosis, inflammation, degeneration of the nigro-striatal dopamine system

  12. Concurrent maternal and pup postnatal tobacco smoke exposure in Wistar rats changes food preference and dopaminergic reward system parameters in the adult male offspring.

    PubMed

    Pinheiro, C R; Moura, E G; Manhães, A C; Fraga, M C; Claudio-Neto, S; Abreu-Villaça, Y; Oliveira, E; Lisboa, P C

    2015-08-20

    Children from pregnant smokers are more susceptible to become obese adults and to become drug or food addicts. Drugs and food activate the mesolimbic reward pathway, causing a sense of pleasure that induces further consumption. Here, we studied the relationship between tobacco smoke exposure during lactation with feeding, behavior and brain dopaminergic reward system parameters at adulthood. Nursing Wistar rats and their pups were divided into two groups: tobacco smoke-exposed (S: 4times/day, from the 3rd to the 21th day of lactation), and ambient air-exposed (C). On PN175, both offspring groups were subdivided for a food challenge: S and C that received standard chow (SC) or that chose between high-fat (HFD) and high-sucrose diets (HSDs). Food intake was recorded after 30min and 12h. Offspring were tested in the elevated plus maze and open field on PN178-179; they were euthanized for dopaminergic analysis on PN180. SSD (self-selected diet) animals presented a higher food intake compared to SC ones. S-SSD animals ate more than C-SSD ones at 30min and 12h. Both groups preferred the HFD. However, S-SSD animals consumed relatively more HFD than C-SSD at 30min. No behavioral differences were observed between groups. S animals presented lower tyrosine hydroxylase (TH) content in the ventral tegmental area, lower TH, dopaminergic receptor 2, higher dopaminergic receptor 1 contents in the nucleus accumbens and lower OBRb in hypothalamic arcuate nucleus. Tobacco-smoke exposure during lactation increases preference for fat in the adult progeny possibly due to alterations in the dopaminergic system. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Targeting Wnt signaling at the neuroimmune interface for dopaminergic neuroprotection/repair in Parkinson’s disease

    PubMed Central

    L’Episcopo, Francesca; Tirolo, Cataldo; Caniglia, Salvo; Testa, Nuccio; Morale, Maria Concetta; Serapide, Maria Francesca; Pluchino, Stefano; Marchetti, Bianca

    2014-01-01

    During the past three decades, the Wingless-type MMTV integration site (Wnt) signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence points to a dysregulation of Wnt signaling in major neurodegenerative pathologies including Parkinson’s disease (PD), a common neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic (mDA) neurons and deregulated activation of astrocytes and microglia. This review highlights the emerging link between Wnt signaling and key inflammatory pathways during mDA neuron damage/repair in PD progression. In particular, we summarize recent evidence documenting that aging and neurotoxicant exposure strongly antagonize Wnt/β-catenin signaling in mDA neurons and subventricular zone (SVZ) neuroprogenitors via astrocyte–microglial interactions. Dysregulation of the crosstalk between Wnt/β-catenin signaling and anti-oxidant/anti-inflammatory pathways delineate novel mechanisms driving the decline of SVZ plasticity with age and the limited nigrostriatal dopaminergic self-repair in PD. These findings hold a promise in developing therapies that target Wnt/β-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD. PMID:24431301

  14. The effects of antidepressant treatment on serotonergic and dopaminergic systems in Fawn-Hooded rats: a quantitative autoradiography study.

    PubMed

    Chen, Feng; Lawrence, Andrew J

    2003-06-20

    Fawn-Hooded (FH) rats exhibit a phenotype including depressive behaviour and high alcohol preference, and as such tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) reduce alcohol consumption in this rat strain [Psychiatr. Genet. 12 (2002) 1-16]. However, the neurochemical effects of these antidepressants on monoamine systems in the brain, especially in mesolimbic areas have not been studied in FH rats. Therefore, the present study investigated neurochemical effects of subchronic treatment (10 days) with desipramine (DMI) and sertraline on several neurochemical markers of serotonin and dopamine systems. Binding to these markers including dopamine transporters (DATs), 5-HT transporters (SERTs), 5-HT(1A)- and 5-HT(2A)-receptors in rat brain sections was performed by quantitative autoradiography. The findings from the present study revealed that DMI and sertraline exhibited differential effects on SERTs and DATs in FH rat brain. For example, DMI caused a dramatic up-regulation of DATs whereas sertraline had no effect on DAT binding. In addition, both antidepressants showed some common and some differential effects on the binding to 5-HT(1A)- and 5-HT(2A)-receptors dependent upon region. These data demonstrate that DMI and sertraline differentially effect serotonergic and dopaminergic systems in mesolimbic regions in FH rats, suggesting that there may be different neurochemical mechanisms underlying their efficacy to reduce ethanol consumption in this animal model.

  15. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents.

    PubMed

    Eremin, Kirill O; Kudrin, Vladimir S; Saransaari, Pirjo; Oja, Simo S; Grivennikov, Igor A; Myasoedov, Nikolay F; Rayevsky, Kirill S

    2005-12-01

    Corticotrophin (ACTH) and its analogues, particularly Semax (Met-Glu-His-Phe-Pro-Gly-Pro), demonstrate nootropic activity. Close functional and anatomical links have been established between melanocortinergic and monoaminergic brain systems. The aim of present work was to investigate the effects of Semax on neurochemical parameters of dopaminergic- and serotonergic systems in rodents. The tissue content of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum was significantly increased (+25%) 2 h after Semax administration. The extracellular striatal level of 5-HIAA gradually increased up to 180% within 1-4 h after Semax (0.15 mg/kg, ip) administration. This peptide alone failed to alter the tissue and extracellular concentrations of dopamine and its metabolites. Semax injected 20 min prior D: -amphetamine dramatically enhanced the effects of the latter on the extracellular level of dopamine and on the locomotor activity of animals. Our results reveal the positive modulatory effect of Semax on the striatal serotonergic system and the ability of Semax to enhance both the striatal release of dopamine and locomotor behavior elicited by D-amphetamine.

  16. Nurr1 regulates Top IIβ and functions in axon genesis of mesencephalic dopaminergic neurons

    PubMed Central

    2012-01-01

    Background NURR1 (also named as NR4A2) is a member of the steroid/thyroid hormone receptor family, which can bind to DNA and modulate expression of target genes. Previous studies have shown that NURR1 is essential for the nigral dopaminergic neuron phenotype and function maintenance, and the defects of the gene are possibly associated with Parkinson's disease (PD). Results In this study, we used new born Nurr1 knock-out mice combined with Affymetrix genechip technology and real time polymerase chain reaction (PCR) to identify Nurr1 regulated genes, which led to the discovery of several transcripts differentially expressed in the nigro-striatal pathway of Nurr1 knock-out mice. We found that an axon genesis gene called Topoisomerase IIβ (Top IIβ) was down-regulated in Nurr1 knock-out mice and we identified two functional NURR1 binding sites in the proximal Top IIβ promoter. While in Top IIβ null mice, we saw a significant loss of dopaminergic neurons in the substantial nigra and lack of neurites along the nigro-striatal pathway. Using specific TOP II antagonist ICRF-193 or Top IIβ siRNA in the primary cultures of ventral mesencephalic (VM) neurons, we documented that suppression of TOP IIβ expression resulted in VM neurites shortening and growth cones collapsing. Furthermore, microinjection of ICRF-193 into the mouse medial forebrain bundle (MFB) led to the loss of nigro-striatal projection. Conclusion Taken together, our findings suggest that Top IIβ might be a down-stream target of Nurr1, which might influence the processes of axon genesis in dopaminergic neurons via the regulation of TOP IIβ expression. The Nurr1-Top IIβ interaction may shed light on the pathologic role of Nurr1 defect in the nigro-striatal pathway deficiency associated with PD. PMID:22296971

  17. Negative cerebral blood volume fMRI response coupled with Ca²⁺-dependent brain activity in a dopaminergic road map of nociception.

    PubMed

    Hsu, Yi-Hua; Chang, Chen; Chen, Chiao-Chi V

    2014-04-15

    Decreased cerebral blood volume/flow (CBV/CBF) contributes to negative blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signals. But it is still strongly debated whether these negative BOLD or CBV/CBF signals are indicative of decreased or increased neuronal activity. The fidelity of Ca(2+) signals in reflecting neuronal excitation is well documented. However, the roles of Ca(2+) signals and Ca(2+)-dependent activity in negative fMRI signals have never been explored; an understanding of this is essential to unraveling the underlying mechanisms and correctly interpreting the hemodynamic response of interest. The present study utilized a nociception-induced negative CBV fMRI response as a model. Ca(2+) signals were investigated in vivo using Mn(2+)-enhanced MRI (MEMRI), and the downstream Ca(2+)-dependent signaling was investigated using phosphorylated cAMP response-element-binding (pCREB) immunohistology. The results showed that nociceptive stimulation led to (1) striatal CBV decreases, (2) Ca(2+) increases via the nigrostriatal pathway, and (3) substantial expression of pCREB in substantia nigra dopaminergic neurons and striatal neurons. Interestingly, the striatal negative fMRI response was abolished by blocking substantia nigra activity but was not affected by blocking the striatal activity. This suggests the importance of input activity other than output in triggering the negative CBV signals. These findings indicate that the striatal negative CBV fMRI signals are associated with Ca(2+) increases and Ca(2+)-dependent signaling along the nigrostriatal pathway. The obtained data reveal a new brain road map in response to nociceptive stimulation of hemodynamic changes in association with Ca(2+) signals within the dopaminergic system.

  18. Gastrodin ameliorates memory deficits in 3,3'-iminodipropionitrile-induced rats: possible involvement of dopaminergic system.

    PubMed

    Wang, Xiaona; Yan, Shaofeng; Wang, Aiqin; Li, Yanli; Zhang, Feng

    2014-08-01

    3,3'-Iminodipropionitrile (IDPN), one of the nitrile derivatives, can induce neurotoxicity, and therefore cause motor dysfunction and cognitive deficits. Gastrodin is a main bioactive constituent of a Chinese herbal medicine (Gastrodia elata Blume) widely used for treating various neurological disorders and showed greatly improved mental function. This study was designed to determine whether administration of gastrodin attenuates IDPN-induced working memory deficits in Y-maze task, and to explore the underlying mechanisms. Results showed that exposure to IDPN (150 mg/kg/day, v.o.) significantly impaired working memory and that long-term gastrodin (200 mg/kg/day, v.o.) could effectively rescue these IDPN-induced memory impairments as indicated by increased spontaneous alternation in the Y-maze test. Additionally, gastrodin treatment prevented IDPN-induced reductions of dopamine (DA) and its metabolites, as well as elevation of dopamine turnover ratio (DOPAC + HVA)/DA. Gastrodin treatment also prevented alterations in dopamine D2 receptor and dopamine transporter protein levels in the rat hippocampus. Our results suggest that long-term gastrodin treatment may have potential therapeutic values for IDPN-induced cognitive impairments, which was mediated, in part, by normalizing the dopaminergic system.

  19. Chewing Prevents Stress-Induced Hippocampal LTD Formation and Anxiety-Related Behaviors: A Possible Role of the Dopaminergic System

    PubMed Central

    Koizumi, So; Onozuka, Minoru

    2015-01-01

    The present study examined the effects of chewing on stress-induced long-term depression (LTD) and anxiogenic behavior. Experiments were performed in adult male rats under three conditions: restraint stress condition, voluntary chewing condition during stress, and control condition without any treatments except handling. Chewing ameliorated LTD development in the hippocampal CA1 region. It also counteracted the stress-suppressed number of entries to the center region of the open field when they were tested immediately, 30 min, or 60 min after restraint. At the latter two poststress time periods, chewing during restraint significantly increased the number of times of open arm entries in the elevated plus maze, when compared with those without chewing. The in vivo microdialysis further revealed that extracellular dopamine concentration in the ventral hippocampus, which is involved in anxiety-related behavior, was significantly greater in chewing rats than in those without chewing from 30 to 105 min after stress exposure. Development of LTD and anxiolytic effects ameliorated by chewing were counteracted by administering the D1 dopamine receptor antagonist SCH23390, which suggested that chewing may activate the dopaminergic system in the ventral hippocampus to suppress stress-induced anxiogenic behavior. PMID:26075223

  20. Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson's disease model induced by MPTP.

    PubMed

    Filichia, Emily; Hoffer, Barry; Qi, Xin; Luo, Yu

    2016-09-13

    Accumulating evidence suggest mitochondria-mediated pathways play an important role in dopaminergic neuronal cell death in Parkinson's disease (PD). Drp1, a key regulator of mitochondrial fission, has been shown to be activated and translocated to mitochondria under stress, leading to excessive mitochondria fission and dopaminergic neuronal death in vitro. However, whether Drp1 inhibition can lead to long term stable preservation of dopaminergic neurons in PD-related mouse models remains unknown. In this study, using a classical MPTP animal PD model, we showed for the first time Drp1 activation and mitochondrial translocation in vivo after MPTP administration. Inhibition of Drp1 activation by a selective peptide inhibitor P110, blocked MPTP-induced Drp1 mitochondrial translocation and attenuated dopaminergic neuronal loss, dopaminergic nerve terminal damage and behavioral deficits caused by MPTP. MPTP-induced microglial activation and astrogliosis were not affected by P110 treatment. Instead, inhibition of Drp1 mitochondrial translocation diminished MPTP-induced p53, BAX and PUMA mitochondrial translocation. This study demonstrates that inhibition of Drp1 hyperactivation by a Drp1 peptide inhibitor P110 is neuroprotective in a MPTP animal model. Our data also suggest that the protective effects of P110 treatment might be mediated by inhibiting the p53 mediated apoptotic pathways in neurons through inhibition of Drp1-dependent p53 mitochondrial translocation.

  1. Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat.

    PubMed

    Pascual, Maria; Boix, Jordi; Felipo, Vicente; Guerri, Consuelo

    2009-02-01

    Adolescence is a developmental period which the risk of drug and alcohol abuse increases. Since mesolimbic dopaminergic system undergoes developmental changes during adolescence, and this system is involved in rewarding effects of drugs of abuse, we addressed the hypothesis that ethanol exposure during juvenile/adolescent period over-activates mesolimbic dopaminergic system inducing adaptations which can trigger long-term enduring behavioural effects of alcohol abuse. We treated juvenile/adolescent or adult rats with ethanol (3 g/kg) for two-consecutive days at 48-h intervals over 14-day period. Here we show that intermittent ethanol treatment during the juvenile/adolescence period alters subsequent ethanol intake. In vivo microdialysis demonstrates that ethanol elicits a similar prolonged dopamine response in the nucleus accumbens of both adolescent and adult animals pre-treated with multiple doses of ethanol, although the basal dopamine levels were higher in ethanol-treated adolescents than in adult-treated animals. Repeated ethanol administration also down-regulates the expression of DRD2 and NMDAR2B phosphorylation in prefrontal cortex of adolescent animals, but not of adult rats. Finally, ethanol treatment during adolescence changes the acetylation of histones H3 and H4 in frontal cortex, nucleus accumbens and striatum, suggesting chromatin remodelling changes. In summary, our findings demonstrate the sensitivity of adolescent brain to ethanol effects on dopaminergic and glutamatergic neurotransmission, and suggest that abnormal plasticity in reward-related processes and epigenetic mechanisms could contribute to the vulnerability of adolescents to alcohol addiction.

  2. Progranulin gene delivery protects dopaminergic neurons in a mouse model of Parkinson's disease.

    PubMed

    Van Kampen, Jackalina M; Baranowski, David; Kay, Denis G

    2014-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity and akinesia/bradykinesia resulting from the progressive loss of nigrostriatal dopaminergic neurons. To date, only symptomatic treatment is available for PD patients, with no effective means of slowing or stopping the progression of the disease. Progranulin (PGRN) is a 593 amino acid multifunction protein that is widely distributed throughout the CNS, localized primarily in neurons and microglia. PGRN has been demonstrated to be a potent regulator of neuroinflammation and also acts as an autocrine neurotrophic factor, important for long-term neuronal survival. Thus, enhancing PGRN expression may strengthen the cells resistance to disease. In the present study, we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of PGRN gene delivery as a therapy for the prevention or treatment of PD. Viral vector delivery of the PGRN gene was an effective means of elevating PGRN expression in nigrostriatal neurons. When PGRN expression was elevated in the SNC, nigrostriatal neurons were protected from MPTP toxicity in mice, along with a preservation of striatal dopamine content and turnover. Further, protection of nigrostriatal neurons by PGRN gene therapy was accompanied by reductions in markers of MPTP-induced inflammation and apoptosis as well as a complete preservation of locomotor function. We conclude that PGRN gene therapy may have beneficial effects in the treatment of PD.

  3. The ethyl acetate fraction of a methanolic extract of unripe noni (Morinda citrifolia Linn.) fruit exhibits a biphasic effect on the dopaminergic system in mice.

    PubMed

    Pandy, Vijayapandi; Narasingam, Megala; Vijeepallam, Kamini; Mohan, Syam; Mani, Vasudevan; Mohamed, Zahurin

    2017-08-05

    In earlier ex vivo studies, we reported the biphasic effect of a methanolic extract of unripe Morinda citrifolia fruit (MMC) on dopamine-induced contractility in isolated rat vas deferens preparations. The present in vivo study was designed and undertaken to further explore our earlier ex vivo findings. This study examined the effect of the ethyl acetate fraction of a methanolic extract of unripe Morinda citrifolia Linn. fruit (EA-MMC; 5-100 mg/kg, p.o.) on the dopaminergic system using mouse models of apomorphine-induced climbing time and climbing behavior, methamphetamine-induced stereotypy (sniffing, biting, gnawing, and licking) and haloperidol-induced catalepsy using the bar test. Acute treatment with EA-MMC at a low dose (25 mg/kg, p.o.) significantly attenuated the apomorphine-induced climbing time and climbing behavior in mice. Similarly, EA-MMC (5 and 10 mg/kg, p.o.) significantly inhibited methamphetamine-induced stereotyped behavior in mice. These results demonstrated that the antidopaminergic effect of EA-MMC was observed at relatively lower doses (<25 mg/kg, p.o.). On the other hand, EA-MMC showed dopaminergic agonistic activity at a high dose (3,000 mg/kg, p.o.), which was evident from alleviation of haloperidol (a dopamine D2 blocker)-induced catalepsy in mice. Therefore, it is concluded that EA-MMC might possess a biphasic effect on the dopaminergic system, i.e., an antagonistic effect at lower doses (<25 mg/kg, p.o.) and an agonistic effect at higher doses (>1,000 mg/kg, p.o.). However, further receptor-ligand binding assays are necessary to confirm the biphasic effects of M. citrifolia fruit on the dopaminergic system.

  4. The ethyl acetate fraction of a methanolic extract of unripe noni (Morinda citrifolia Linn.) fruit exhibits a biphasic effect on the dopaminergic system in mice

    PubMed Central

    Pandy, Vijayapandi; Narasingam, Megala; Vijeepallam, Kamini; Mohan, Syam; Mani, Vasudevan; Mohamed, Zahurin

    2017-01-01

    In earlier ex vivo studies, we reported the biphasic effect of a methanolic extract of unripe Morinda citrifolia fruit (MMC) on dopamine-induced contractility in isolated rat vas deferens preparations. The present in vivo study was designed and undertaken to further explore our earlier ex vivo findings. This study examined the effect of the ethyl acetate fraction of a methanolic extract of unripe Morinda citrifolia Linn. fruit (EA-MMC; 5–100 mg/kg, p.o.) on the dopaminergic system using mouse models of apomorphine-induced climbing time and climbing behavior, methamphetamine-induced stereotypy (sniffing, biting, gnawing, and licking) and haloperidol-induced catalepsy using the bar test. Acute treatment with EA-MMC at a low dose (25 mg/kg, p.o.) significantly attenuated the apomorphine-induced climbing time and climbing behavior in mice. Similarly, EA-MMC (5 and 10 mg/kg, p.o.) significantly inhibited methamphetamine-induced stereotyped behavior in mice. These results demonstrated that the antidopaminergic effect of EA-MMC was observed at relatively lower doses (<25 mg/kg, p.o.). On the other hand, EA-MMC showed dopaminergic agonistic activity at a high dose (3,000 mg/kg, p.o.), which was evident from alleviation of haloperidol (a dopamine D2 blocker)-induced catalepsy in mice. Therefore, it is concluded that EA-MMC might possess a biphasic effect on the dopaminergic system, i.e., an antagonistic effect at lower doses (<25 mg/kg, p.o.) and an agonistic effect at higher doses (>1,000 mg/kg, p.o.). However, further receptor-ligand binding assays are necessary to confirm the biphasic effects of M. citrifolia fruit on the dopaminergic system. PMID:28450692

  5. Cystamine/cysteamine rescues the dopaminergic system and shows neurorestorative properties in an animal model of Parkinson's disease.

    PubMed

    Cisbani, G; Drouin-Ouellet, J; Gibrat, C; Saint-Pierre, M; Lagacé, M; Badrinarayanan, S; Lavallée-Bourget, M H; Charest, J; Chabrat, A; Boivin, L; Lebel, M; Bousquet, M; Lévesque, M; Cicchetti, F

    2015-10-01

    The neuroprotective properties of cystamine identified in pre-clinical studies have fast-tracked this compound to clinical trials in Huntington's disease, showing tolerability and benefits on motor symptoms. We tested whether cystamine could have such properties in a Parkinson's disease murine model and now provide evidence that it can not only prevent the neurodegenerative process but also can reverse motor impairments created by a 6-hydroxydopamine lesion 3 weeks post-surgery. Importantly, we report that cystamine has neurorestorative properties 5 weeks post-lesion as seen on the number of nigral dopaminergic neurons which is comparable with treatments of cysteamine, the reduced form of cystamine used in the clinic, as well as rasagiline, increasingly prescribed in early parkinsonism. All three compounds induced neurite arborization of the remaining dopaminergic cells which was further confirmed in ex vivo dopaminergic explants derived from Pitx3-GFP mice. The disease-modifying effects displayed by cystamine/cysteamine would encourage clinical testing.

  6. Acute nigro-striatal blockade alters cortico-striatal encoding: an in vivo electrophysiological study.

    PubMed

    Prosperetti, Chiara; Di Giovanni, Giuseppe; Stefani, Alessandro; Möller, Jens C; Galati, Salvatore

    2013-09-01

    Spreading of slow cortical rhythms into the basal ganglia (BG) is a relatively well-demonstrated phenomenon in the Parkinsonian state, both in humans and animals. Accordingly, striatal dopamine (DA) depletion, either acute or chronic, drives cortical-globus pallidus (GP) and cortical-substantia nigra pars reticulata (SNr) slow wave coherences in urethane-anesthetized rats. This paper investigates the striatal dynamics following acute DA depletion by tetrodotoxin (TTX) injection in the medial forebrain bundle (MFB) with respect to the transmission of slow cortical rhythms throughout the BG in more detail. The acute DA depletion offers the advantage of detecting electrophysiological changes irrespectively of chronically developing compensatory mechanisms. We observed that the acute blockade of the dopaminergic nigro-striatal pathway reshapes the firing rate and pattern of the different striatal neuron subtypes according to cortical activity, possibly reflecting a remodeled intrastriatal network. The observed alterations differ amongst striatal neuronal subtypes with the striatal medium spiny neurons and fast-spiking neurons being the most affected, while the tonically active neurons seem to be less affected. These acute changes might contribute to the diffusion of cortical activity to BG and the pathophysiology of Parkinson's disease (PD). Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons

    PubMed Central

    Bayliss, Jacqueline A.; Lemus, Moyra B.; Santos, Vanessa V.; Deo, Minh; Davies, Jeffrey S.; Kemp, Bruce E.; Elsworth, John D.

    2016-01-01

    Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate that Metformin treatment is neuroprotective in Parkinson’s Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP-induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin’s neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD. PMID:27467571

  8. Regulation of isoproterenol-induced salivary gland hyperplasia in young and old mice by substances affecting serotoninergic and dopaminergic systems

    SciTech Connect

    Dontsov, V.I.

    1986-09-01

    This paper studies the effect of substances modulating serotoninergic and dopaminergic structures on induction of hyperplasia of the salivary glands by isoproterenol in young and old mice. /sup 3/H-thymidine was injected into the gland tissue in the experiments. The effect of serotonin and dopamine on isoproterenol-induced proliferation of salivary gland cells and number of activated splenic lymphocytes in old mice is shown. It is found that excitation of serotoninergic structures inhibits, whereas excitation of dopaminergic structures stimulates the response of mice to isoproterenol.

  9. Pleiotrophin over-expression provides trophic support to dopaminergic neurons in parkinsonian rats.

    PubMed

    Taravini, Irene Re; Chertoff, Mariela; Cafferata, Eduardo G; Courty, José; Murer, Mario G; Pitossi, Fernando J; Gershanik, Oscar S

    2011-06-07

    Pleiotrophin is known to promote the survival and differentiation of dopaminergic neurons in vitro and is up-regulated in the substantia nigra of Parkinson's disease patients. To establish whether pleiotrophin has a trophic effect on nigrostriatal dopaminergic neurons in vivo, we injected a recombinant adenovirus expressing pleiotrophin in the substantia nigra of 6-hydroxydopamine lesioned rats. The viral vector induced pleiotrophin over-expression by astrocytes in the substantia nigra pars compacta, without modifying endogenous neuronal expression. The percentage of tyrosine hydroxylase-immunoreactive cells as well as the area of their projections in the lesioned striatum was higher in pleiotrophin-treated animals than in controls. These results indicate that pleiotrophin over-expression partially rescues tyrosine hydroxylase-immunoreactive cell bodies and terminals of dopaminergic neurons undergoing 6-hydroxydopamine-induced degeneration.

  10. Pleiotrophin over-expression provides trophic support to dopaminergic neurons in parkinsonian rats

    PubMed Central

    2011-01-01

    Background Pleiotrophin is known to promote the survival and differentiation of dopaminergic neurons in vitro and is up-regulated in the substantia nigra of Parkinson's disease patients. To establish whether pleiotrophin has a trophic effect on nigrostriatal dopaminergic neurons in vivo, we injected a recombinant adenovirus expressing pleiotrophin in the substantia nigra of 6-hydroxydopamine lesioned rats. Results The viral vector induced pleiotrophin over-expression by astrocytes in the substantia nigra pars compacta, without modifying endogenous neuronal expression. The percentage of tyrosine hydroxylase-immunoreactive cells as well as the area of their projections in the lesioned striatum was higher in pleiotrophin-treated animals than in controls. Conclusions These results indicate that pleiotrophin over-expression partially rescues tyrosine hydroxylase-immunoreactive cell bodies and terminals of dopaminergic neurons undergoing 6-hydroxydopamine-induced degeneration. PMID:21649894

  11. Changes in GABA(B) receptor mRNA expression in the rodent basal ganglia and thalamus following lesion of the nigrostriatal pathway.

    PubMed

    Johnston, T; Duty, S

    2003-01-01

    Loss of striatal dopaminergic innervation in Parkinson's disease (PD) is accompanied by widespread alterations in GABAergic activity within the basal ganglia and thalamus. Accompanying changes in GABA(B) receptor binding have been noted in some basal ganglia regions in parkinsonian primates, suggesting that plasticity of this receptor may also occur in PD. However, the molecular mechanisms underlying the changes in receptor binding and the manner and extent to which different GABA(B) receptor mRNA subunits and splice-variants are affected remain unknown. This study used in situ hybridisation to examine the full profile of changes in expression of the known rat GABA(B) receptor genes and gene variants in the basal ganglia and thalamus of rats, brought about by degeneration of the nigrostriatal tract. All of the GABA(B) mRNA species examined showed unique expression patterns throughout the basal ganglia and thalamus. In addition, all exhibited a marked loss of expression (between 46 and 80%) in the substantia nigra pars compacta of animals bearing a complete 6-hydroxydopamine-induced lesion of the nigrostriatal tract, confirming the presence of these variants in dopaminergic neurones in this region. Further analysis of autoradioagrams revealed additional changes only in GABA(B(1a)) mRNA in discrete anatomical regions. Expression of the GABA(B(1a)) variant was significantly increased in the substantia nigra pars reticulata (33+/-2%), entopeduncular nucleus (26+/-1%) and the subthalamic nucleus (16+/-1%). Since these regions all receive reduced GABAergic innervation following nigrostriatal tract lesioning, it is possible that the increased expression occurs as a compensatory measure. In conclusion, these data demonstrate that GABA(B) receptor genes exhibit regional- and subunit/variant-specific plasticity at the molecular level under parkinsonian conditions.

  12. Gene regulatory logic of dopaminergic neuron differentiation

    PubMed Central

    Flames, Nuria; Hobert, Oliver

    2009-01-01

    Dopamine signaling regulates a variety of complex behaviors and defects in dopaminergic neuron function or survival result in severe human pathologies, such as Parkinson's disease 1. The common denominator of all dopaminergic neurons is the expression of dopamine pathway genes, which code for a set of phylogenetically conserved proteins involved in dopamine synthesis and transport. Gene regulatory mechanisms that result in the activation of dopamine pathway genes and thereby ultimately determine the identity of dopaminergic neurons are poorly understood in any system studied to date 2. We show here that a simple cis-regulatory element, the DA motif, controls the expression of all dopamine pathway genes in all dopaminergic cell types in C. elegans. The DA motif is activated by the ETS transcription factor, AST-1. Loss of ast-1 results in the failure of all distinct dopaminergic neuronal subtypes to terminally differentiate. Ectopic expression of ast-1 is sufficient to activate the dopamine production pathway in some cellular contexts. Vertebrate dopaminergic pathway genes also contain phylogenetically conserved DA motifs that can be activated by the mouse ETS transcription factor Etv1/ER81 and a specific class of dopaminergic neurons fails to differentiate in mice lacking Etv1/ER81. Moreover, ectopic Etv1/ER81 expression induces dopaminergic fate marker expression in neuronal primary cultures. Mouse Etv1/ER81 can also functionally substitute for ast-1 in C.elegans. Our studies reveal an astoundingly simple and apparently conserved regulatory logic of dopaminergic neuron terminal differentiation and may provide new entry points into the diagnosis or therapy of conditions in which dopamine neurons are defective. PMID:19287374

  13. Nicotine neuroprotection against nigrostriatal damage: importance of the animal model.

    PubMed

    Quik, Maryka; O'Neill, Michael; Perez, Xiomara A

    2007-05-01

    Parkinson's disease is a neurodegenerative movement disorder that is characterized by a loss of nigrostriatal dopamine-containing neurons. Unexpectedly, there is a reduced incidence of Parkinson's disease in tobacco users. This finding is important because the identification of the component(s) responsible for this effect could lead to therapeutic strategies to slow down or halt the progression of Parkinson's disease. Results from cell culture models consistently show that nicotine protects against neurotoxicity. However, data from animal models of nigrostriatal damage are conflicting, thus raising questions about a neuroprotective role of nicotine. Accumulating evidence indicates that discrepancies are observed primarily in mouse models of the disease. By contrast, reproducible protection occurs in rat models and in a nonhuman primate parkinsonian model that closely resembles the human disease. These findings highlight the need to use the appropriate animal model and treatment conditions when testing putative neuroprotective agents.

  14. Polymorphisms in dopaminergic system genes; association with criminal behavior and self-reported aggression in violent prison inmates from Pakistan

    PubMed Central

    Qadeer, Muhammad Imran; Amar, Ali; Mann, J. John; Hasnain, Shahida

    2017-01-01

    Genetic factors contribute to antisocial and criminal behavior. Dopamine transporter DAT-1 (SLC6A3) and DRD2 gene for the dopamine-2 receptor are dopaminergic system genes that regulate dopamine reuptake and signaling, and may be part of the pathogenesis of psychiatric disorders including antisocial behaviors and traits. No previous studies have analyzed DAT-1 and DRD2 polymorphisms in convicted murderers, particularly from Indian subcontinent. In this study we investigated the association of 40 bp VNTR polymorphism of DAT-1 and Taq1 variant of DRD2 gene (rs1800479) with criminal behavior and self-reported aggression in 729 subjects, including 370 men in Pakistani prisons convicted of first degree murder(s) and 359 control men without any history of violence or criminal tendency. The 9R allele of DAT-1 VNTR polymorphism was more prevalent in convicted murderers compared with control samples, for either one or two risk alleles (OR = 1.49 and 3.99 respectively, P = 0.003). This potential association of DAT-1 9R allele polymorphism with murderer phenotype was confirmed assuming different genetic models of inheritance. However, no genetic association was found for DRD2 Taq1 polymorphism. In addition, a combined haplotype (9R-A2) of DAT-1 and DRD2 genes was associated with this murderer phenotype. Further, 9R allele of DAT-1 was also associated with response to verbal abuse and parental marital complications, but not with other measures pertinent to self-reported aggression. These results suggest that 9R allele, which may influence levels of intra-synaptic dopamine in the brain, may contribute to criminal tendency in this sample of violent murderers of Pakistani origin. Future studies are needed to replicate this finding in other populations of murderers and see if this finding extends to other forms of violence and lesser degrees of aggression. PMID:28582390

  15. Polymorphisms in dopaminergic system genes; association with criminal behavior and self-reported aggression in violent prison inmates from Pakistan.

    PubMed

    Qadeer, Muhammad Imran; Amar, Ali; Mann, J John; Hasnain, Shahida

    2017-01-01

    Genetic factors contribute to antisocial and criminal behavior. Dopamine transporter DAT-1 (SLC6A3) and DRD2 gene for the dopamine-2 receptor are dopaminergic system genes that regulate dopamine reuptake and signaling, and may be part of the pathogenesis of psychiatric disorders including antisocial behaviors and traits. No previous studies have analyzed DAT-1 and DRD2 polymorphisms in convicted murderers, particularly from Indian subcontinent. In this study we investigated the association of 40 bp VNTR polymorphism of DAT-1 and Taq1 variant of DRD2 gene (rs1800479) with criminal behavior and self-reported aggression in 729 subjects, including 370 men in Pakistani prisons convicted of first degree murder(s) and 359 control men without any history of violence or criminal tendency. The 9R allele of DAT-1 VNTR polymorphism was more prevalent in convicted murderers compared with control samples, for either one or two risk alleles (OR = 1.49 and 3.99 respectively, P = 0.003). This potential association of DAT-1 9R allele polymorphism with murderer phenotype was confirmed assuming different genetic models of inheritance. However, no genetic association was found for DRD2 Taq1 polymorphism. In addition, a combined haplotype (9R-A2) of DAT-1 and DRD2 genes was associated with this murderer phenotype. Further, 9R allele of DAT-1 was also associated with response to verbal abuse and parental marital complications, but not with other measures pertinent to self-reported aggression. These results suggest that 9R allele, which may influence levels of intra-synaptic dopamine in the brain, may contribute to criminal tendency in this sample of violent murderers of Pakistani origin. Future studies are needed to replicate this finding in other populations of murderers and see if this finding extends to other forms of violence and lesser degrees of aggression.

  16. Maternal Omega-3 Supplement Improves Dopaminergic System in Pre- and Postnatal Inflammation-Induced Neurotoxicity in Parkinson's Disease Model.

    PubMed

    Delattre, Ana Marcia; Carabelli, Bruno; Mori, Marco Aurélio; Kempe, Paula G; Rizzo de Souza, Luiz E; Zanata, Silvio M; Machado, Ricardo B; Suchecki, Deborah; Andrade da Costa, Belmira L S; Lima, Marcelo M S; Ferraz, Anete C

    2017-04-01

    Evidence suggests that idiopathic Parkinson's disease (PD) is the consequence of a neurodevelopmental disruption, rather than strictly a consequence of aging. Thus, we hypothesized that maternal supplement of omega-3 polyunsaturated fatty acids (ω-3 PUFA) may be associated with neuroprotection mechanisms in a self-sustaining cycle of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)-model of PD. To test this hypothesis, behavioral and neurochemical assay were performed in prenatally LPS-exposed offspring at postnatal day 21. To further determine whether prenatal LPS exposure and maternal ω-3 PUFAs supplementation had persisting effects, brain injury was induced on PN 90 rats, following bilateral intranigral LPS injection. Pre- and postnatal inflammation damage not only affected dopaminergic neurons directly, but it also modified critical features, such as activated microglia and astrocyte cells, disrupting the support provided by the microenvironment. Unexpectedly, our results failed to show any involvement of caspase-dependent and independent apoptosis pathway in neuronal death mechanisms. On the other hand, learning and memory deficits detected with a second toxic exposure were significantly attenuated in maternal ω-3 PUFAs supplementation group. In addition, ω-3 PUFAs promote beneficial effect on synaptic function, maintaining the neurochemical integrity in remaining neurons, without necessarily protect them from neuronal death. Thus, our results suggest that ω-3 PUFAs affect the functional ability of the central nervous system in a complex way in a multiple inflammation-induced neurotoxicity animal model of PD and they disclose new ways of understanding how these fatty acids control responses of the brain to different challenges.

  17. Targeting the-Dopaminergic Nervous System: Altering Behavior in Larval Zebrafish

    EPA Science Inventory

    Zebrafish (Dania rerio) are becoming an important model system in studying the effects of environmental chemicals on behavior. In order to develop a rapid in vivo screen to prioritize toxic chemicals, we have begun assessing the acute locomotor effects of drugs that act on the do...

  18. Targeting the-Dopaminergic Nervous System: Altering Behavior in Larval Zebrafish

    EPA Science Inventory

    Zebrafish (Dania rerio) are becoming an important model system in studying the effects of environmental chemicals on behavior. In order to develop a rapid in vivo screen to prioritize toxic chemicals, we have begun assessing the acute locomotor effects of drugs that act on the do...

  19. Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems

    PubMed Central

    Hall, F. S.; Itokawa, K.; Schmitt, A.; Moessner, R.; Sora, I.; Lesch, K. P.; Uhl, G. R.

    2013-01-01

    Dopamine (DA) is accumulated and compartmentalized by the dopamine transporter (DAT; SLC3A6) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2). These transporters work at the plasma and vesicular membranes of dopaminergic neurons, respectively, and thus regulate levels of DA in neuronal compartments that include the extravesicular cytoplasmic compartment. DA in this compartment has been hypothesized to contribute to oxidative damage that can reduce the function of dopaminergic neurons in aging brains and may contribute to reductions in dopaminergic neurochemical markers, locomotor behavior and responses to dopaminergic drugs that are found in aged animals. The studies reported here examined aged mice with heterozygous deletions of VMAT2 or of DAT, which each reduce transporter expression to about 50% of levels found in wild-type (WT) mice. Aged mice displayed reduced locomotor responses under a variety of circumstances, including in response to locomotor stimulants, as well as changes in monoamine levels and metabolites in a regionally dependent manner. Several effects of aging were more pronounced in heterozygous VMAT2 knockout (KO) mice, including aging induced reductions in locomotion and reduced locomotor responses to cocaine. By contrast, some effects of aging were reduced or not observed in heterozygous DAT KO mice. These findings support the idea that altered DAT and VMAT2 expression affect age-related changes in dopaminergic function. These effects are most likely mediated by alterations in DA compartmentalization, and might be hypothesized to be more exacerbated by other factors that affect the metabolism of cytosolic DA. PMID:23978383

  20. The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine.

    PubMed

    Corrigall, W A; Franklin, K B; Coen, K M; Clarke, P B

    1992-01-01

    Rats were trained to self-administer nicotine on a fixed-ratio schedule of reinforcement. Infusion of the nicotinic antagonist chlorisondamine into the cerebral ventricles produced a sustained reduction in nicotine self-administration compared to vehicle-treated controls. Lesions of the mesolimbic dopamine system were produced by microinfusion of 6-hydroxydopamine into the nucleus accumbens. Following production of the lesions, nicotine self-administration was markedly reduced for the 3-week test period; motor impairment did not appear to be responsible. Post mortem analysis of brain tissue showed that the lesion produced a pronounced decrease in dopamine content of the nucleus accumbens and the olfactory tubercle, and a small depletion in the striatum. These data demonstrate that the reinforcing effects of nicotine occur within the central nervous system, and that the mesolimbic dopamine projection plays an important role in these effects.

  1. Behavioral and electrophysiological effects of endocannabinoid and dopaminergic systems on salient stimuli

    PubMed Central

    Laricchiuta, Daniela; Musella, Alessandra; Rossi, Silvia; Centonze, Diego

    2014-01-01

    Rewarding effects have been related to enhanced dopamine (DA) release in corticolimbic and basal ganglia structures. The DAergic and endocannabinoid interaction in the responses to reward is described. This study investigated the link between endocannabinoid and DAergic transmission in the processes that are related to response to two types of reward, palatable food and novelty. Mice treated with drugs acting on endocannabinoid system (ECS) (URB597, AM251) or DAergic system (haloperidol) were submitted to approach-avoidance conflict tasks with palatable food or novelty. In the same mice, the cannabinoid type-1 (CB1)-mediated GABAergic transmission in medium spiny neurons of the dorsomedial striatum was analyzed. The endocannabinoid potentiation by URB597 magnified approach behavior for reward (food and novelty) and in parallel inhibited dorsostriatal GABAergic neurotransmission. The decreased activity of CB1 receptor by AM251 (alone or with URB597) or of DAergic D2 receptor by haloperidol had inhibitory effects toward the reward and did not permit the inhibition of dorsostriatal GABAergic transmission. When haloperidol was coadministered with URB597, a restoration effect on reward and reward-dependent motor activity was observed, only if the reward was the palatable food. In parallel, the coadministration led to restoring inhibition of CB1-mediated GABAergic transmission. Thus, in the presence of simultaneous ECS activation and inhibition of DAergic system the response to reward appears to be a stimulus-dependent manner. PMID:24904335

  2. Impact of Early Consumption of High-Fat Diet on the Mesolimbic Dopaminergic System

    PubMed Central

    Tantot, F.; Glangetas, C.; Janthakhin, Y.; Boitard, C.; De Smedt-Peyrusse, V.; Pape, J. R.; Vancassel, S.; Trifilieff, P.; Georges, F.; Coutureau, E.

    2017-01-01

    Increasing evidence suggest that consumption of high-fat diet (HFD) can impact the maturation of brain circuits, such as during adolescence, which could account for behavioral alterations associated with obesity. In the present study, we used behavioral sensitization to amphetamine to investigate the effect of periadolescent HFD exposure (pHFD) in rats on the functionality of the dopamine (DA) system, a central actor in food reward processing. pHFD does not affect responding to an acute injection, however, a single exposure to amphetamine is sufficient to induce locomotor sensitization in pHFD rats. This is paralleled by rapid neurobiological adaptations within the DA system. In pHFD-exposed animals, a single amphetamine exposure induces an increase in bursting activity of DA cells in the ventral tegmental area (VTA) as well as higher DA release and greater expression of (tyrosine hydroxylase, TH) in the nucleus accumbens (NAc). Post-synaptically, pHFD animals display an increase in NAc D2 receptors and c-Fos expression after amphetamine injection. These findings highlight the vulnerability of DA system to the consumption of HFD during adolescence that may support deficits in reward-related processes observed in obesity. PMID:28580417

  3. Perfluorooctane sulfonate (PFOS) exposure could modify the dopaminergic system in several limbic brain regions.

    PubMed

    Salgado, R; López-Doval, S; Pereiro, N; Lafuente, A

    2016-01-05

    Perfluorooctane sulfonate (PFOS) is the most representative of a rising class of persistent organic pollutants perfluorochemicals. In the present study, its neurotoxicity was examined using adult male rats orally treated with 0.5; 1.0; 3.0 and 6.0 mg of PFOS/kg/day for 28 days. At the end of the treatment, the dopamine concentration and its metabolism expressed like the ratio 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine and homovanillic acid (HVA)/dopamine were measured in the amygdala, prefrontal cortex and hippocampus. Gene and protein expression of the dopamine receptors D1 and D2 were also determined in these limbic areas. The obtained results suggest that: (1) PFOS can alter the dopamine system by modifying its neuronal activity and/or its D1 and D2 receptors in the studied brain regions; (2) the dopamine concentration and metabolism seem to be more sensitive against PFOS toxicity in the hippocampus than in the other analyzed brain areas; (3) the inhibited gene and protein expression of the D1 receptors induced by PFOS in the amygdala could be related to several changes in the HPA axis activity, and lastly; (4) the observed alterations on the dopamine system induced by PFOS could be a possible neurotoxicity mechanism of PFOS, leading to many neurological diseases.

  4. The tegmental-accumbal dopaminergic system mediates the anxiolytic effect of acupuncture during ethanol withdrawal.

    PubMed

    Zhao, ZhengLin; Kim, Sang Chan; Zhao, RongJie; Wu, YiYan; Zhang, Jie; Liu, HongFeng; Kim, Young Woo; Zhu, XiaoDong; Gu, ChangHong; Lee, Chul Won; Lee, Bong Hyo; Jang, Eun Young; Ko, Hae Li; Yang, Chae Ha

    2015-06-15

    This study investigated the involvement of the mesolimbic dopamine (DA) system in the anxiolytic effects of acupuncture during ethanol withdrawal (EW). Rats were intraperitoneally treated with 3g/kg/day of ethanol for 28 days and experienced 3 days of withdrawal. During EW, the rats were bilaterally treated with acupuncture at acupoints HT7 (Shenmen) or PC6 (Neiguan) or at a non-acupoint (tail) once daily for 1min over 3 days. High-performance liquid chromatographic (HPLC) analysis showed that EW significantly decreased both DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens shell (NaccSh); however, these processes were inhibited by acupuncture at HT7 but not at PC6. Real-time polymerase chain reaction and western blot assays also revealed that acupuncture at HT7 prevented the EW-induced reductions in tyrosine hydroxylase mRNA expression in the ventral tegmental area (VTA) and tyrosine hydroxylase protein expression in the NaccSh. A prior intra-NaccSh infusion of a cocktail of the selective DA1 receptor antagonist SCH23390 and the selective DA2 receptor antagonist eticlopride blocked the anxiolytic effect of acupuncture at HT7 in elevated plus maze tests. In addition, acupuncture at HT7 suppressed EW-induced increased BDNF levels in the VTA. These findings suggest that acupuncture at HT7 improves the VTA-Nacc DAergic function via inhibition of BDNF expression in the VTA, thereby exerting anxiolytic effects during EW.

  5. Functional Analysis of Dopaminergic Systems in a DYT1 Knock-in Mouse Model of Dystonia

    PubMed Central

    Song, Chang-Hyun; Fan, Xueliang; Exeter, Cicely J.; Hess, Ellen J.; Jinnah, H. A.

    2012-01-01

    The dystonias are a group of disorders characterized by involuntary twisting movements and abnormal posturing. The most common of the inherited dystonias is DYT1 dystonia, which is due to deletion of a single GAG codon (ΔE) in the TOR1A gene that encodes torsinA. Since some forms of dystonia have been linked with dysfunction of brain dopamine pathways, the integrity of these pathways was explored in a knock-in mouse model of DYT1 dystonia. In DYT1(ΔE) knock-in mice, neurochemical measures revealed only small changes in the content of dopamine or its metabolites in tissue homogenates from caudoputamen or midbrain, but microdialysis studies revealed robust decreases in baseline and amphetamine-stimulated extracellular dopamine in the caudoputamen. Quantitative stereological methods revealed no evidence for striatal or midbrain atrophy, but substantia nigra neurons immunopositive for tyrosine hydroxylase were slightly reduced in numbers and enlarged in size. Behavioral studies revealed subtle abnormalities in gross motor activity and motor coordination without overt dystonia. Neuropharmacological challenges of dopamine systems revealed normal behavioral responses to amphetamine and a minor increase in sensitivity to haloperidol. These results demonstrate that this DYT1(ΔE) knock-in mouse model of dystonia harbors neurochemical and structural changes of the dopamine pathways, as well as motor abnormalities. PMID:22659308

  6. Differences in Dopaminergic Modulation to Motor Cortical Plasticity between Parkinson's Disease and Multiple System Atrophy

    PubMed Central

    Kawashima, Shoji; Ueki, Yoshino; Mima, Tatsuya; Fukuyama, Hidenao; Ojika, Kosei; Matsukawa, Noriyuki

    2013-01-01

    Dopamine modulates the synaptic plasticity in the primary motor cortex (M1). To evaluate whether the functioning of the cortico-striatal circuit is necessary for this modulation, we applied a paired associative stimulation (PAS) protocol that comprised an electric stimulus to the right median nerve at the wrist and subsequent transcranial magnetic stimulation of the left M1, to 10 patients with Parkinson's disease (PD) and 10 with multiple system atrophy of the parkinsonian type (MSA-P) with and without dopamine replacement therapy (-on/off). To investigate the M1 function, motor-evoked potentials (MEPs) were measured before and after the PAS. In both patient groups without medication, the PAS protocol failed to increase the averaged amplitude of MEPs. The dopamine replacement therapy in PD, but not in MSA-P effectively restored the PAS-induced MEP increase. This suggests that not the existence of dopamine itself but the activation of cortico-striatal circuit might play an important role for cortical plasticity in the human M1. PMID:23658735

  7. Differences in dopaminergic modulation to motor cortical plasticity between Parkinson's disease and multiple system atrophy.

    PubMed

    Kawashima, Shoji; Ueki, Yoshino; Mima, Tatsuya; Fukuyama, Hidenao; Ojika, Kosei; Matsukawa, Noriyuki

    2013-01-01

    Dopamine modulates the synaptic plasticity in the primary motor cortex (M1). To evaluate whether the functioning of the cortico-striatal circuit is necessary for this modulation, we applied a paired associative stimulation (PAS) protocol that comprised an electric stimulus to the right median nerve at the wrist and subsequent transcranial magnetic stimulation of the left M1, to 10 patients with Parkinson's disease (PD) and 10 with multiple system atrophy of the parkinsonian type (MSA-P) with and without dopamine replacement therapy (-on/off). To investigate the M1 function, motor-evoked potentials (MEPs) were measured before and after the PAS. In both patient groups without medication, the PAS protocol failed to increase the averaged amplitude of MEPs. The dopamine replacement therapy in PD, but not in MSA-P effectively restored the PAS-induced MEP increase. This suggests that not the existence of dopamine itself but the activation of cortico-striatal circuit might play an important role for cortical plasticity in the human M1.

  8. Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate

    PubMed Central

    Schrantee, Anouk; Tremoleda, Jordi L.; Wylezinska-Arridge, Marzena; Bouet, Valentine; Hesseling, Peter; Meerhoff, Gideon F.; de Bruin, Kora M.; Koeleman, Jan; Freret, Thomas; Boulouard, Michel; Desfosses, Emilie; Galineau, Laurent; Gozzi, Alessandro; Dauphin, François; Gsell, Willy; Booij, Jan; Lucassen, Paul J.; Reneman, Liesbeth

    2017-01-01

    Dexamphetamine (AMPH) is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA) neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart), followed by a 1-week washout period. We then used pharmacological MRI (phMRI) with a methylphenidate (MPH) challenge, as a sensitive and non-invasive in-vivo measure of DAergic function. We subsequently validated the DA-ergic changes post-mortem, using a.o. high-performance liquid chromatography (HPLC) and autoradiography. In the AMPH pre-treated group, we observed a significantly larger BOLD response to the MPH challenge, particularly in DA-ergic brain areas and their downstream projections. Subsequent autoradiography studies showed that AMPH pre-treatment significantly reduced DA transporter (DAT) density in the caudate-putamen (CPu) and nucleus accumbens, whereas HPLC analysis revealed increases in the DA metabolite homovanillic acid in the CPu. Our results suggest that AMPH pre-treatment alters DAergic responsivity, a change that can be detected with phMRI in rats. These phMRI changes likely reflect increased DA release together with reduced DAT binding. The ability to assess subtle synaptic changes using phMRI is promising for both preclinical studies of drug discovery, and for clinical studies where phMRI can be a useful tool to non-invasively investigate DA abnormalities, e.g. in neuropsychiatric disorders. PMID:28241065

  9. Enduring, Sexually Dimorphic Impact of In Utero Exposure to Elevated Levels of Glucocorticoids on Midbrain Dopaminergic Populations

    PubMed Central

    Gillies, Glenda E.; Virdee, Kanwar; Pienaar, Ilse; Al-Zaid, Felwah; Dalley, Jeffrey W.

    2016-01-01

    Glucocorticoid hormones (GCs) released from the fetal/maternal glands during late gestation are required for normal development of mammalian organs and tissues. Accordingly, synthetic glucocorticoids have proven to be invaluable in perinatal medicine where they are widely used to accelerate fetal lung maturation when there is risk of pre-term birth and to promote infant survival. However, clinical and pre-clinical studies have demonstrated that inappropriate exposure of the developing brain to elevated levels of GCs, either as a result of clinical over-use or after stress-induced activation of the fetal/maternal adrenal cortex, is linked with significant effects on brain structure, neurological function and behaviour in later life. In order to understand the underlying neural processes, particular interest has focused on the midbrain dopaminergic systems, which are critical regulators of normal adaptive behaviours, cognitive and sensorimotor functions. Specifically, using a rodent model of GC exposure in late gestation (approximating human brain development at late second/early third trimester), we demonstrated enduring effects on the shape and volume of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) (origins of the mesocorticolimbic and nigrostriatal dopaminergic pathways) on the topographical organisation and size of the dopaminergic neuronal populations and astrocytes within these nuclei and on target innervation density and neurochemical markers of dopaminergic transmission (receptors, transporters, basal and amphetamine-stimulated dopamine release at striatal and prefrontal cortical sites) that impact on the adult brain. The effects of antenatal GC treatment (AGT) were both profound and sexually-dimorphic, not only in terms of quantitative change but also qualitatively, with several parameters affected in the opposite direction in males and females. Although such substantial neurobiological changes might presage marked behavioural

  10. Lateral habenula as a link between dopaminergic and serotonergic systems contributes to depressive symptoms in Parkinson's disease.

    PubMed

    Luo, Xiao Feng; Zhang, Bei Lin; Li, Ji Cheng; Yang, Ying Ying; Sun, Yan Fei; Zhao, Hua

    2015-01-01

    Degeneration of substantia nigra dopaminergic neurons is a key pathological change of Parkinson's disease (PD), and its motor consequences have been widely recognized. Recently, mood disorders associated with PD have begun to attract a great deal of interest, however, their pathogenesis remains unclear. PD is associated with not only degenerative changes in dopaminergic neurons in the substantia nigra but also changes in serotonergic neurons in the raphe nuclei. The abnormalities in central 5-hydroxytryptamine (5-HT) neurotransmission are thought to play a key role in the pathogenesis of depression. The lateral habenula (LHb) is closely related to the substantia nigra and raphe nuclei, and its hyperactivity is closely related to the pathogenesis of depression. In this study, we screened rats with depressive-like behaviors from PD model animals and found that cytochrome c oxidase activity in the LHb of these rats was twice that seen in the control rats. In the forced swim test, LHb lesions caused a decrease in depressive-like behavior of PD rats as indexed by decreased immobility times and increased climbing times. Additionally, LHb lesions caused an enhance in 5-HT levels in the raphe nuclei. These results suggest that LHb lesions may improve depressive-like behavior in PD rats by increasing 5-HT levels in the raphe nuclei. Thus, LHb contributes to the depressive-like behavior in PD rats via mediating the effects of dopaminergic neurons in the substantia nigra on serotonergic neurons in the raphe nuclei.

  11. The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism

    PubMed Central

    Sonsalla, Patricia K.; Coleman, Christal; Wong, Lai-Yoong; Harris, Suzan L.; Richardson, Jason R.; Gadad, Bharathi S.; Li, Wenhao; German, Dwight C.

    2013-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by a prominent loss of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. The peptide angiotensin II (AngII) plays a role in oxidative-stress induced disorders and is thought to mediate its detrimental actions via activation of AngII AT1 receptors. The brain renin-angiotensin system is implicated in neurodegenerative disorders including PD. Blockade of the angiotensin converting enzyme or AT1 receptors provides protection in acute animal models of parkinsonism. We demonstrate here that treatment of mice with the angiotensin converting enzyme inhibitor captopril protects the striatum from acutely administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP), and that chronic captopril protects the nigral DA cell bodies from degeneration in a progressive rat model of parkinsonism created by the chronic intracerebral infusion of 1-methyl-4-phenylpyridinium (MPP+). The accompanying activation of microglia in the substantia nigra of MPP+-treated rats was reduced by the chronic captopril treatment. These findings indicate that captopril is neuroprotective for nigrostriatal DA neurons in both acute and chronic rodent PD models. Targeting the brain AngII pathway may be a feasible approach to slowing neurodegeneration in PD. PMID:24184050

  12. The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism.

    PubMed

    Sonsalla, Patricia K; Coleman, Christal; Wong, Lai-Yoong; Harris, Suzan L; Richardson, Jason R; Gadad, Bharathi S; Li, Wenhao; German, Dwight C

    2013-12-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a prominent loss of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. The peptide angiotensin II (AngII) plays a role in oxidative-stress induced disorders and is thought to mediate its detrimental actions via activation of AngII AT1 receptors. The brain renin-angiotensin system is implicated in neurodegenerative disorders including PD. Blockade of the angiotensin converting enzyme or AT1 receptors provides protection in acute animal models of parkinsonism. We demonstrate here that treatment of mice with the angiotensin converting enzyme inhibitor captopril protects the striatum from acutely administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP), and that chronic captopril protects the nigral DA cell bodies from degeneration in a progressive rat model of parkinsonism created by the chronic intracerebral infusion of 1-methyl-4-phenylpyridinium (MPP+). The accompanying activation of microglia in the substantia nigra of MPP+-treated rats was reduced by the chronic captopril treatment. These findings indicate that captopril is neuroprotective for nigrostriatal DA neurons in both acute and chronic rodent PD models. Targeting the brain AngII pathway may be a feasible approach to slowing neurodegeneration in PD. © 2013.

  13. Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation.

    PubMed

    Earley, Christopher J; Uhl, George R; Clemens, Stefan; Ferré, Sergi

    2017-03-01

    Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact induce a hyperdopaminergic state are summarized. On the basis of these data, the concept of a dynamic nature of the dopamine effects in a circadian context is presented. The possible interactions of cell adhesion molecules expressed by the dopaminergic systems and their possible effects on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally distinct dopamine receptor subtypes can reshape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase the receptor expression of a different receptor subtype with opposite modulatory actions. Such dopamine receptor interactions at both spinal and supraspinal levels appear to play important roles in RLS. In addition, these

  14. Design and Synthesis of Dopaminergic Agonists.

    PubMed

    Matute, Maria Soledad; Matute, Rosa; Merino, Pedro

    2016-01-01

    The use of dopaminergic agonists is key in the treatment of Parkinson's disease and related central nervous system (CNS) neurodegenerative disorders. Despite there are a number of commercialized dopaminergic agonists that are currently being used successfully in the first stages of the disease, they often fail to provide sustained clinical benefit for a long period due to the appearance of side-effects such as augmentation, sleepiness, nausea, hypothension, and compulsive behaviors among others. New dopaminergic agonists with less side effects are being developed. These novel compounds offer an alternative when the disease progresses and patients fail to respond to standard dopaminergic treatments or side-effects increased. Chemistry, and in particular chemical synthesis, has played a major role in bringing synthetic dopaminergic agonists to the clinic and continues to be crucial for the development of new and necessary drugs for long-term treatments with less undesired side effects. A number of structural modifications of parent compounds have led to enhanced agonism but also partial agonism or even antagonism of one or more dopamine receptors. In some cases, these activities are accompanied by agonist effect at serotonin receptors which suggests a potential clinical application in the treatment of schizophrenia In this review, chemical synthesis of dopaminergic agents, their affinity, and the corresponding agonist/antagonist effects will be highlighted.

  15. Short post-weaning social isolation induces long-term changes in the dopaminergic system and increases susceptibility to psychostimulants in female rats.

    PubMed

    Lampert, Carine; Arcego, Danusa Mar; de Sá Couto-Pereira, Natividade; Dos Santos Vieira, Aline; Toniazzo, Ana Paula; Krolow, Rachel; Garcia, Emily; Vendite, Deusa Aparecida; Calcagnotto, Maria Elisa; Dalmaz, Carla

    2017-10-01

    Childhood and adolescence are sensitive periods of development, marked by high brain maturation and plasticity. Exposure to early life stress, such as social isolation, is able to prompt changes in sensitive brain circuitries, essentially in the mesolimbic dopaminergic system and increase the risk for addictive behaviors later in life. Post-weaning social isolation can stimulate the consumption of rewarding substances, like drugs of abuse and palatable foods. However, most studies analyze long periods of social isolation and very little is known about the effects of a brief social isolation in a sensitive period of development and its association with palatable food on the reward system sensitization. Furthermore, females are more susceptible to the reinforcing effect of drugs than males. Therefore, the aim of this study was to analyze the effects of a short post-weaning social isolation combined with a free access to a chronic high sugar diet (HSD) on the dopaminergic system, oxidative status and behavioral response to an amphetamine-like drug in adulthood. We used female Wistar rats that were socially isolated from post-natal days (PD) 21 to 35 and received free access to a HSD until PD 60. On PD 65, animals were submitted to a challenge with diethylpropion (DEP), an amphetamine-like drug and different responses were analyzed: locomotor activity, immmunocontent of dopamine related proteins, and the oxidative status in the striatum, before and after the DEP challenge. We showed that a short post-weaning social isolation (SI) increased the locomotor response to DEP, when compared with previous saline administration. Social isolation also increased dopamine transporter, tyrosine hydroxylase, and decreased dopamine D2 receptor immunocontent. Additionally, SI increased the overall oxidative status parameters after the challenge with DEP. Interestingly, the exposure to a HSD prevented the SI effects on locomotor response, but did not interfere in the dopaminergic

  16. Different mechanisms for dopaminergic excitation induced by opiates and cannabinoids in the rat midbrain.

    PubMed

    Melis, M; Gessa, G L; Diana, M

    2000-08-01

    1. The mechanism underlying morphine and cannabinoid-induced excitation of meso-accumbens and nigro-striatal dopaminergic neurons was investigated by extracellular single unit recording techniques coupled with antidromic activation from the nucleus accumbens and striatum respectively, in unanesthetized rats. 2. The intravenous administration of cumulative doses (1-4 mg/kg) of morphine, dose-dependently increased the firing rate of dopaminergic neurons projecting to the nucleus accumbens and neostriatum, while the same doses inhibited the activity of pars reticulata neurons of the substantia nigra. Both effects were antagonized by naloxone (0.1 mg/kg i.v.) but not by the selective CB1 receptor antagonist SR 141716A (1 mg/kg i.v.). 3. The intravenous administration of cumulative doses (0.125-0.5 mg/kg) of delta9-tetrahydrocannabinol (delta9-THC) also increased the firing rate of meso-accumbens and nigro-striatal dopaminergic neurons; this effect was antagonized by SR 141716A (1 mg/kg i.v.), but not by naloxone. 4. Furthermore, nor delta9-THC up to a dose of 1 mg/kg, maximally effective in stimulating dopamine neurons, neither SR 141716A (1 mg/kg i.v.) at a dose able to reverse the stimulatory effect of delta9, THC on dopamine cells, did alter the activity of SNr neurons. 5. The results indicate that morphine and delta9-THC activate dopaminergic neurons through distinct receptor-mediated mechanisms; morphine may act by removing the inhibitory input from substantia nigra pars reticulata neurons (an effect mediated by mu-opioid receptors). Alternatively, the delta9-THC-induced excitation of dopaminergic neurons seems to be mediated by CB1 cannabinoid receptors, while neither mu-opioid receptors nor substantia nigra pars reticulata neurons are involved.

  17. Localization of nigrostriatal dopamine receptor subtypes and adenylate cyclase

    SciTech Connect

    Filloux, F.; Dawson, T.M.; Wamsley, J.K.

    1988-04-01

    Quantitative autoradiography using (/sup 3/H)-SCH 23390, (/sup 3/H)-sulpiride and (/sup 3/H)-forskolin was used to assess the effects of single and combined neurotoxin lesions of the nigrostriatal pathway in the rat brain on dopamine (DA) receptor subtypes and adenylate cyclase (AC), respectively. Ibotenic acid (IA) lesions of the caudate-putamen (CPu) resulted in near total loss of both (/sup 3/H)-SCH 23390 and of (/sup 3/H)-forskolin binding in the ipsilateral CPu and substantia nigra reticulata (SNR). (/sup 3/H)-sulpiride binding in the CPu was only partially removed by this same lesion, and nigral (/sup 3/H)-sulpiride binding was virtually unchanged. 6-Hydroxydopamine (6-OHDA) and IA lesions of the substantia nigra compacta (SNC) did not affect (/sup 3/H)-SCH 23390 or (/sup 3/H)-forskolin binding, but largely removed (/sup 3/H)-sulpiride binding in the SNC. A 6-OHDA lesion of the nigrostriatal pathway followed by an ipsilateral IA injection of the CPu failed to further reduce (/sup 3/H)-sulpiride binding in the CPu. These results demonstrate that postsynaptic DA receptors in the CPu are of both the D1 and D2 variety; however, a portion of D2 receptors in the CPu may be presynaptic on afferent nerve terminals to this structure. D1 receptors in the SNR are presynaptic on striatonigral terminals, whereas the D2 receptors of the SNC are autoreceptors on nigral DA neurons. The existence of presynaptic D2 receptors on nigrostriatal DA-ergic terminals could not be confirmed by this study. Co-localization of D1 receptors and AC occurs in both the CPu and SNR.

  18. (G2019S) LRRK2 causes early-phase dysfunction of SNpc dopaminergic neurons and impairment of corticostriatal long-term depression in the PD transgenic mouse.

    PubMed

    Chou, Jun-Shiao; Chen, Chu-Yu; Chen, Ying-Ling; Weng, Yi-Hsin; Yeh, Tu-Hsueh; Lu, Chin-Song; Chang, Ya-Ming; Wang, Hung-Li

    2014-08-01

    Twelve- to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive neuronal death of substantia nigra pars compacta (SNpc) dopaminergic cells. In the present study, we hypothesized that prior to a late-phase death of SNpc dopaminergic neurons, (G2019S) LRRK2 also causes an early-phase neuronal dysfunction of SNpc dopaminergic cells in the (G2019S) LRRK2 mouse. Eight to nine-month-old (G2019S) LRRK2 transgenic mice exhibited the symptom of hypoactivity in the absence of the degeneration of SNpc dopaminergic neurons or nigrostriatal dopaminergic terminals. Whole-cell current-clamp recordings of SNpc dopaminergic cells in brain slices demonstrated a significant decrease in spontaneous firing frequency of SNpc dopaminergic neurons of 8-month-old (G2019S) LRRK2 mice. Carbon fiber electrode amperometry recording using striatal slices showed that (G2019S) LRRK2 transgenic mice at the age of 8 to 9months display an impaired evoked dopamine release in the dorsolateral striatum. Normal nigrostriatal dopaminergic transmission is required for the induction of long-term synaptic plasticity expressed at corticostriatal glutamatergic synapses of striatal medium spiny neurons. Whole-cell voltage-clamp recordings showed that in contrast to medium spiny neurons of 8 to 9-month-old wild-type mice, high-frequency stimulation of corticostriatal afferents failed to induce long-term depression (LTD) of corticostriatal EPSCs in medium spiny neurons of (G2019S) LRRK2 mice at the same age. Our study provides the evidence that mutant (G2019S) LRRK2 causes early-phase dysfunctions of SNpc dopaminergic neurons, including a decrease in spontaneous firing rate and a reduction in evoked dopamine release, and impairment of corticostriatal LTD in the (G2019S) LRRK2 transgenic mouse.

  19. Acupuncture attenuates cocaine-induced expression of behavioral sensitization in rats: possible involvement of the dopaminergic system in the ventral tegmental area.

    PubMed

    Lee, Bombi; Han, Seung-Moo; Shim, Insop

    2009-01-09

    Acupuncture is widely used for the treatment of many functional disorders, such as substance abuse, and has the suppressive effect on the central nervous system. Many studies have suggested that behavioral sensitization by repeated injections of cocaine produce an increase in locomotor activity and an increase in the expression of tyrosine hydroxylase (TH), in the central dopaminergic system. In order to investigate the effects of acupuncture on the repeated cocaine-induced neuronal and behavioral sensitization alternations, we examined the influence of acupuncture on the repeated cocaine-induced locomotor activity and the expression of TH in the brain using immunohistochemistry. Male SD rats were given repeated injections of cocaine hydrochloride (15 mg/kg, i.p. for 10 consecutive days) followed by one challenge injection on the 4th day after the last daily injection. Cocaine challenge produced a large increase in the locomotor activity and the expression of TH in the ventral tegmental area (VTA). Treatment with acupuncture bilaterally at the Shenman (HT7) points for 1 min significantly inhibited the increase of locomotor activity as well as the TH expression in the VTA. Our data demonstrated that the inhibitory effects of acupuncture on cocaine-induced expression of behavioral sensitization were closely associated with the reduction of dopamine (DA) biosynthesis and the postsynaptic neuronal activity. These results provide evidence that acupuncture may be effective for inhibiting the behavioral effects of cocaine by possible modulation of the central dopaminergic system.

  20. Intervention with exercise restores motor deficits but not nigrostriatal loss in a progressive MPTP mouse model of Parkinson's disease.

    PubMed

    Sconce, M D; Churchill, M J; Greene, R E; Meshul, C K

    2015-07-23

    Many studies have investigated exercise therapy in Parkinson's disease (PD) and have shown benefits in improving motor deficits. However, exercise does not slow down the progression of the disease or induce the revival of lost nigrostriatal neurons. To examine the dichotomy of behavioral improvement without the slowing or recovery of dopaminergic cell or terminal loss, we tested exercise therapy in an intervention paradigm where voluntary running wheels were installed half-way through our progressive PD mouse model. In our model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is administered over 4 weeks with increased doses each week (8, 16, 24, 32-kg/mg). We found that after 4 weeks of MPTP treatment, mice that volunteered to exercise had behavioral recovery in several measures despite the loss of 73% and 53% tyrosine hydroxylase (TH) within the dorsolateral (DL) striatum and the substantia nigra (SN), respectively which was equivalent to the loss seen in the mice that did not exercise but were also administered MPTP for 4 weeks. Mice treated with 4 weeks of MPTP showed a 41% loss of vesicular monoamine transporter II (VMAT2), a 71% increase in the ratio of glycosylated/non-glycosylated dopamine transporter (DAT), and significant increases in glutamate transporters including VGLUT1, GLT-1, and excitatory amino acid carrier 1. MPTP mice that exercised showed recovery of all these biomarkers back to the levels seen in the vehicle group and showed less inflammation compared to the mice treated with MPTP for 4 weeks. Even though we did not measure tissue dopamine (DA) concentration, our data suggest that exercise does not alleviate motor deficits by sparing nigrostriatal neurons, but perhaps by stabilizing the extraneuronal neurotransmitters, as evident by a recovery of DA and glutamate transporters. However, suppressing inflammation could be another mechanism of this locomotor recovery. Although exercise will not be a successful treatment alone, it could

  1. Maternal nicotine exposure during lactation alters food preference, anxiety-like behavior and the brain dopaminergic reward system in the adult rat offspring.

    PubMed

    Pinheiro, C R; Moura, E G; Manhães, A C; Fraga, M C; Claudio-Neto, S; Younes-Rapozo, V; Santos-Silva, A P; Lotufo, B M; Oliveira, E; Lisboa, P C

    2015-10-01

    The mesolimbic reward pathway is activated by drugs of abuse and palatable food, causing a sense of pleasure, which promotes further consumption of these substances. Children whose parents smoke are more vulnerable to present addictive-like behavior to drugs and food.We evaluated the association between maternal nicotine exposure during lactation with changes in feeding, behavior and in the dopaminergic reward system. On postnatal day (PN) 2,Wistar rat dams were implanted with minipumps releasing nicotine (N; 6 mg/kg/day, s.c.) or saline (C) for 14 days. On PN150 and PN160, offspring were divided into 4 groups for a food challenge: N and C that received standard chow(SC); and N and C that could freely self-select (SSD) between high-fat and high-sugar diets (HFD and HSD, respectively). Offspring were tested in the elevated plus maze (EPM) and open field (OF) arena on PN152–153. On PN170, offspring were euthanized for central dopaminergic analysis. SSD animals showed an increased food intake compared to SC ones and a preference for HFD. However, N-SSD animals consumed relatively more HSD than C-SSD ones. Regarding behavior, N animals showed an increase in the time spent in the EPM center and a reduction in relative activity in the OF center. N offspring presented lower dopamine receptor (D2R) and transporter (DAT) contents in the nucleus accumbens, and lower D2R in the arcuate nucleus. Postnatal exposure to nicotine increases preference for sugar and anxiety levels in the adult progeny possibly due to a decrease in dopaminergic action in the nucleus accumbens and arcuate nucleus.

  2. Cooperative synthesis of dopamine by non-dopaminergic neurons as a compensatory mechanism in the striatum of mice with MPTP-induced Parkinsonism.

    PubMed

    Kozina, Elena A; Kim, Aleksandr R; Kurina, Anna Y; Ugrumov, Michael V

    2017-02-01

    Since the late 80s it has been repeatedly shown that besides dopaminergic neurons, the brain contains so-called monoenzymatic neurons possessing one of the enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH) or aromatic l-amino acid decarboxylase (AADC). However, the data on the existence of monoenzymatic neurons in the striatum remain controversial, and little is known about their functional significance. The aim of this study was to test our hypothesis that monoenzymatic TH-containing neurons produce DA in cooperation with the neurons containing AADC, which might help to compensate DA deficiency under the failure of the nigrostriatal dopaminergic system. Using a combination of techniques: retrograde tracing, qPCR and immunolabeling for TH, AADC and MAP2, we showed that the striatum of mice with normal and degraded dopaminergic system comprises of monoenzymatic TH- and AADC-containing neurons. To provide evidence for cooperative synthesis of DA, we used an ex vivo model of inhibiting of DA synthesis by blocking transport of l-DOPA, produced in monoenzymatic TH-containing neurons, to neurons containing AADC by means of l-leucine, a competitive inhibitor of the membrane transporter of large neutral amino acids, and l-DOPA. With this original approach, cooperative synthesis of DA in the striatum was proven in MPTP-treated mice but not in the control. Furthermore, we demonstrated that the proportion of DA produced through cooperative synthesis in the striatum of MPTP-treated mice increases as the degradation of dopaminergic system proceeds. An increase in the proportion of cooperative synthesis of DA alongside degradation of the dopaminergic system is also proved by an increase of both TH gene expression and the number of TH-immunoreactive structures in the striatum. Thus, these data suggest that the cooperative synthesis of DA in the degraded striatum is an up-regulated compensatory reaction, which plays an increasing role as DA deficiency rises, and might

  3. Synaptophysin and the dopaminergic system in hippocampus are involved in the protective effect of rutin against trimethyltin-induced learning and memory impairment.

    PubMed

    Zhang, Lei; Zhao, Qi; Chen, Chun-Hai; Qin, Qi-Zhong; Zhou, Zhou; Yu, Zheng-Ping

    2014-09-01

    This study aimed to investigate the protective effect of rutin against trimethyltin-induced spatial learning and memory impairment in mice. This study focused on the role of synaptophysin, growth-associated protein 43 and the action of the dopaminergic system in mechanisms associated with rutin protection and trimethyltin-induced spatial learning and memory impairment. Cognitive learning and memory was measured by Morris Water Maze. The expression of synaptophysin and growth-associated protein 43 in hippocampus was analyzed by western blot. The concentrations of dopamine, homovanillic acid, and dihyroxyphenylacetic acid in hippocampus were detected using reversed phase high-performance liquid chromatography with electrochemical detection. Trimethyltin-induced spatial learning impairment showed a dose-dependent mode. Synaptophysin but not growth-associated protein 43 was decreased in the hippocampus after trimethyltin administration. The concentration of dopamine decreased, while homovanillic acid increased in the hippocampus after trimethyltin administration. Mice pretreated with 20 mg/kg of rutin for 7 consecutive days exhibited improved water maze performance. Moreover, rutin pretreatment reversed the decrease of synaptophysin expression and dopamine alteration. These results suggest that rutin may protect against spatial memory impairment induced by trimethyltin. Synaptophysin and the dopaminergic system may be involved in trimethyltin-induced neuronal damage in hippocampus.

  4. Fetal allogeneic dopaminergic cell suspension grafts in the ventricular system of the rat: characterization of transplant morphology and graft-host interactions.

    PubMed

    Oertel, J; Samii, M; Walter, G F

    2004-05-01

    Experimental transplantation trials of fetal cells in Parkinson's and Huntington's disease or multiple sclerosis still require allogeneic graft material and raise questions of graft rejection and immunosuppression. Alternatively to the striatum, the lateral ventricles have been discussed as grafting site in Parkinson's and Huntington's disease although little is known of the specific immunology of the ventricular system. To address this question, 28 adult female LEW1.W rats received intraventricular allogeneic dopaminergic cell suspension grafts from E14 DA rat fetuses. Twelve animals with syngeneic grafts served as control. Immunohistochemical examination was performed with staining for MHC expression, microglia-macrophages, various lymphocyte subsets, dopaminergic neurons and astrocytes at 4 days, and 1, 3, 6, and 12 weeks after transplantation. In all animals, intraventricular transplants were found, which showed maturation and integration in the host parenchyma at the later time points. Animals with allogeneic grafts developed a vivid immune response with strong MHC class I expression and dense lymphocyte infiltrates. Surprisingly, this immune response subsided at 12 weeks and healthy grafts remained. These results indicate (1) that, in contrast to intraparenchymal grafts, a strong immune response to allogeneic fetal cell suspension grafts can be elicited by intraventricular grafting, (2) that a peculiar immunological role of the ventricular system has to be considered in further studies, and (3) that a vivid immune response to allografts in the brain may subside without graft destruction.

  5. Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity.

    PubMed

    Gaugler, Meret Nora; Genc, Ozgur; Bobela, Wojciech; Mohanna, Safa; Ardah, Mustafa Taleb; El-Agnaf, Omar Mukhtar; Cantoni, Marco; Bensadoun, Jean-Charles; Schneggenburger, Ralf; Knott, Graham W; Aebischer, Patrick; Schneider, Bernard Laurent

    2012-05-01

    α-Synuclein (α-syn) is a presynaptic protein present at most nerve terminals, but its function remains largely unknown. The familial forms of Parkinson's disease associated with multiplications of the α-syn gene locus indicate that overabundance of this protein might have a detrimental effect on dopaminergic transmission. To investigate this hypothesis, we use adeno-associated viral (AAV) vectors to overexpress human α-syn in the rat substantia nigra. Moderate overexpression of either wild-type (WT) or A30P α-syn differs in the motor phenotypes induced, with only the WT form generating hemiparkinsonian impairments. Wild-type α-syn causes a reduction of dopamine release in the striatum that exceeds the loss of dopaminergic neurons, axonal fibers, and the reduction in total dopamine. At the ultrastructural level, the reduced dopamine release corresponds to a decreased density of dopaminergic vesicles and synaptic contacts in striatal terminals. Interestingly, the membrane-binding-deficient A30P mutant does neither notably reduce dopamine release nor it cause ultrastructural changes in dopaminergic axons, showing that α-syn's membrane-binding properties are critically involved in the presynaptic defects. To further determine if the affinity of the protein for membranes determines the extent of motor defects, we compare three forms of α-syn in conditions leading to pronounced degeneration. While membrane-binding α-syns (wild-type and A53T) induce severe motor impairments, an N-terminal deleted form with attenuated affinity for membranes is inefficient in inducing motor defects. Overall, these results demonstrate that α-syn overabundance is detrimental to dopamine neurotransmission at early stages of the degeneration of nigrostriatal dopaminergic axons.

  6. Methamphetamine-induced neurotoxicity linked to UPS dysfunction and autophagy related changes that can be modulated by PKCδ in dopaminergic neuronal cells

    PubMed Central

    Lin, Mengshien; Shivalingappa, Prashanth Chandramani; Jin, Huajun; Ghosh, Anamitra; Anantharam, Vellareddy; Ali, Syed; Kanthasamy, Anumantha G.; Kanthasamy, Arthi

    2012-01-01

    A compromised protein degradation machinery has been implicated in methamphetamine (MA)-induced neurodegeneration. However, the signaling mechanisms that induce autophagy and UPS dysfunction are not well understood. The present study investigates the contributions of PKC delta (PKCδ) mediated signaling events in MA-induced autophagy, UPS dysfunction and cell death. Using an in vitro mesencephalic dopaminergic cell culture model, we demonstrate that MA-induced early induction of autophagy is associated with reduction in proteasomal function and concomitant dissipation of mitochondrial membrane potential (MMP), followed by significantly increased of PKCδ activation, caspase-3 activation, accumulation of ubiquitin positive aggregates and microtubule associated light chain-3 (LC3-II) levels. Interestingly, siRNA mediated knockdown of PKCδ or overexpression of cleavage resistant mutant of PKCδ dramatically reduced MA-induced autophagy, proteasomal function, and associated accumulation of ubiquitinated protein aggregates, which closely paralleled cell survival. Importantly, when autophagy was inhibited either pharmacologically (3-MA) or genetically (siRNA mediated silencing of LC3), the dopaminergic cells became sensitized to MA-induced apoptosis through caspase-3 activation. Conversely, overexpression of LC3 partially protected against MA-induced apoptotic cell death, suggesting a neuroprotective role for autophagy in MA-induced neurotoxicity. Notably, rat striatal tissue isolated from MA treated rats also exhibited elevated LC3-II, ubiquitinated protein levels, and PKCδ cleavage. Taken together, our data demonstrate that MA-induced autophagy serves as an adaptive strategy for inhibiting mitochondria mediated apoptotic cell death and degradation of aggregated proteins. Our results also suggest that the sustained activation of PKCδ leads to UPS dysfunction, resulting in the activation of caspase-3 mediated apoptotic cell death in the nigrostriatal dopaminergic

  7. Simultaneous effects on parvalbumin-positive interneuron and dopaminergic system development in a transgenic rat model for sporadic schizophrenia

    PubMed Central

    Hamburg, Hannah; Trossbach, Svenja V.; Bader, Verian; Chwiesko, Caroline; Kipar, Anja; Sauvage, Magdalena; Crum, William R.; Vernon, Anthony C.; Bidmon, Hans J.; Korth, Carsten

    2016-01-01

    To date, unequivocal neuroanatomical features have been demonstrated neither for sporadic nor for familial schizophrenia. Here, we investigated the neuroanatomical changes in a transgenic rat model for a subset of sporadic chronic mental illness (CMI), which modestly overexpresses human full-length, non-mutant Disrupted-in-Schizophrenia 1 (DISC1), and for which aberrant dopamine homeostasis consistent with some schizophrenia phenotypes has previously been reported. Neuroanatomical analysis revealed a reduced density of dopaminergic neurons in the substantia nigra and reduced dopaminergic fibres in the striatum. Parvalbumin-positive interneuron occurrence in the somatosensory cortex was shifted from layers II/III to V/VI, and the number of calbindin-positive interneurons was slightly decreased. Reduced corpus callosum thickness confirmed trend-level observations from in vivo MRI and voxel-wise tensor based morphometry. These neuroanatomical changes help explain functional phenotypes of this animal model, some of which resemble changes observed in human schizophrenia post mortem brain tissues. Our findings also demonstrate how a single molecular factor, DISC1 overexpression or misassembly, can account for a variety of seemingly unrelated morphological phenotypes and thus provides a possible unifying explanation for similar findings observed in sporadic schizophrenia patients. Our anatomical investigation of a defined model for sporadic mental illness enables a clearer definition of neuroanatomical changes associated with subsets of human sporadic schizophrenia. PMID:27721451

  8. Laser Acupuncture at HT7 Acupoint Improves Cognitive Deficit, Neuronal Loss, Oxidative Stress, and Functions of Cholinergic and Dopaminergic Systems in Animal Model of Parkinson's Disease.

    PubMed

    Wattanathorn, Jintanaporn; Sutalangka, Chatchada

    2014-01-01

    To date, the therapeutic strategy against cognitive impairment in Parkinson's disease (PD) is still not in satisfaction level and requires novel effective intervention. Based the oxidative stress reduction and cognitive enhancement induced by laser acupuncture at HT7, the beneficial effect of laser acupuncture at HT7 against cognitive impairment in PD has been focused. In this study, we aimed to determine the effect of laser acupuncture at HT7 on memory impairment, oxidative stress status, and the functions of both cholinergic and dopaminergic systems in hippocampus of animal model of PD. Male Wistar rats, weighing 180-220 g, were induced unilateral lesion at right substantianigra by 6-OHDA and were treated with laser acupuncture continuously at a period of 14 days. The results showed that laser acupuncture at HT7 enhanced memory and neuron density in CA3 and dentate gyrus. The decreased AChE, MAO-B, and MDA together with increased GSH-Px in hippocampus of a 6-OHDA lesion rats were also observed. In conclusion, laser acupuncture at HT7 can improve neuron degeneration and memory impairment in animal model of PD partly via the decreased oxidative stress and the improved cholinergic and dopaminergic functions. More researches concerning effect of treatment duration are still required.

  9. A PET study with [11-C]raclopride in Parkinson's disease: preliminary results on the effect of amantadine on the dopaminergic system.

    PubMed

    Volonté, M A; Moresco, R M; Gobbo, C; Messa, C; Carpinelli, A; Rizzo, G; Comi, G; Fazio, F

    2001-02-01

    Amantadine has been proved to be beneficial in Parkinson's disease. Although it is still uncertain which neurochemical events are modified at therapeutic doses, an increase in dopaminergic tone secondary to NMDA receptor blockade and a direct inhibition of the glutamatergic overactivity have been suggested to be involved in its clinical effects. The aim of this study was to evaluate the effects of amantadine on the dopaminergic system by measuring the in vivo binding of [11-C]raclopride to D2 dopamine receptors in the basal ganglia of 6 patients with idiopathic Parkinson's disease. Each patient underwent a PET study, before and after 14 days of treatment with amantadine (200 mg/day). Repeated treatment with therapeutic doses of amantadine induced a moderate increase in the in vivo binding of [11C]raclopride in the putamen of PD patients. This observation indicates that in PD patients, 200 mg/day amantadine does not produce an increase in extracellular levels of dopamine sufficiently to inhibit raclopride binding or that, if present, is it masked by a concurrent increase in receptor availability, as recently reported in rat striatum.

  10. 6-Hydroxydopamine-lesioning of the nigrostriatal pathway in rats alters basal ganglia mRNA for copper, zinc- and manganese-superoxide dismutase, but not glutathione peroxidase.

    PubMed

    Kunikowska, G; Jenner, P

    2001-12-13

    The effects of nigrostriatal pathway destruction on the mRNA levels of copper, zinc-dependent superoxide dismutase (Cu,Zn-SOD), manganese-dependent superoxide dismutase (Mn-SOD), and glutathione peroxidase in basal ganglia of adult rat were investigated using in situ hybridization histochemistry and oligodeoxynucleotide (single-stranded complementary DNA) probes. The 6-hydroxydopamine (6-OHDA)-induced destruction of the nigrostriatal pathway resulted in contralateral rotation to apomorphine and a marked loss of specific [(3)H]mazindol binding in the striatum (93%; P<0.05) and of tyrosine hydroxylase mRNA in substantia nigra pars compacta (SC) (93%; P<0.05) compared with control rats. Levels of Cu,Zn-SOD mRNA were decreased in the striatum, globus pallidus, and SC on the lesioned side of 6-OHDA-lesioned rats compared with sham-lesioned rats (P<0.05). Levels of Mn-SOD mRNA were increased in the nucleus accumbens (P<0.05), but decreased in the SC (P<0.05) on the lesioned side of 6-OHDA-treated rats compared with sham-lesioned rats. Lesioning with 6-OHDA had no effect on glutathione peroxidase mRNA levels in any region of basal ganglia examined. The significant changes in Cu,Zn-SOD and Mn-SOD mRNA indicate that SOD is primarily expressed by dopaminergic neurons of the nigrostriatal pathway, and that the Mn-SOD gene appears to be inducible in rat basal ganglia in response to both physical and chemical damage 5 weeks after 6-OHDA-lesioning. These findings may clarify the status of antioxidant enzymes, particularly Mn-SOD, in patients with Parkinson's disease and their relevance to disease pathogenesis.

  11. Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder.

    PubMed

    Mehler-Wex, C; Riederer, P; Gerlach, M

    2006-12-01

    The basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system

  12. Ciliary neurotrophic factor prevents degeneration of adult rat substantia nigra dopaminergic neurons in vivo.

    PubMed Central

    Hagg, T; Varon, S

    1993-01-01

    We have investigated the neuroprotective effects of recombinant human ciliary neurotrophic factor (CNTF) for injured dopaminergic neurons of the adult rat substantia nigra compacta. Fourteen days after a unilateral transection of the nigrostriatal pathway two-thirds of the neurons (identified by retrograde labeling) had degenerated. In sharp contrast, 73% (a few cases, > 90%) of this cell loss was prevented by continuous infusion of CNTF close to the injured neurons. However, CNTF did not prevent the disappearance of the transmitter-synthesizing enzyme tyrosine hydroxylase. Thus, CNTF has potent neurotrophic effects for injured adult rat dopaminergic substantia nigra neurons, whose degeneration plays a major causative role in Parkinson disease. Images Fig. 2 Fig. 3 PMID:8101002

  13. 1,2,3,4-Tetrahydroisoquinoline protects terminals of dopaminergic neurons in the striatum against the malonate-induced neurotoxicity.

    PubMed

    Lorenc-Koci, Elzbieta; Gołembiowska, Krystyna; Wardas, Jadwiga

    2005-07-27

    Malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, is frequently used as a model neurotoxin to produce lesion of the nigrostriatal dopaminergic system in animals due to particular sensitivity of dopamine neurons to mild energy impairment. This model of neurotoxicity was applied in our study to explore neuroprotective potential of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endo- and exogenous substance whose function in the mammalian brain, despite extensive studies, has not been elucidated so far. Injection of malonate at a dose of 3 mumol unilaterally into the rat left medial forebrain bundle resulted in the 54% decrease in dopamine (DA) concentration in the ipsilateral striatum and, depending on the examined striatum regions, caused 24-44% reduction in [3H]GBR12,935 binding to the dopamine transporter (DAT). TIQ (50 mg/kg i.p.) administered 4 h before malonate infusion and next once daily for successive 7 days prevented both these effects of malonate. Such TIQ treatment restored DA content and DAT binding almost to the control level. The results of the present study indicate that TIQ may act as a neuroprotective agent in the rat brain. An inhibition of the enzymatic activities of monoamine oxidase and gamma-glutamyl transpeptidase as well as an increase in the striatal levels of glutathione and nitric oxide found after TIQ administration and reported in our earlier studies are considered to be potential factors that may be involved in the TIQ-mediated protection of dopamine terminals from malonate toxicity.

  14. Regional mRNA expression of the endogenous opioid and dopaminergic systems in brains of C57BL/6J and 129P3/J mice: Strain and heroin effects

    PubMed Central

    Schlussman, S.D.; Cassin, J.; Zhang, Y.; Levran, O.; Ho, A.; Kreek, M.J.

    2011-01-01

    We have previously shown strain and dose differences in heroin-induced behavior, reward and regional expression of somatostatin receptor mRNAs in C57BL/6J and 129P3/J mice. Using Real Time PCR we examined the effects of five doses of heroin on the levels of the transcripts of endogenous opioid peptides and their receptors and dopaminergic receptors in the mesocorticolimbic and nigrostriatal pathways in these same mice. Compared to C57BL/6J animals, 129P3/J mice had higher mRNA levels of Oprk1 in the nucleus accumbens and of Oprd1 in the nucleus accumbens and a region containing both the substantia nigra and ventral tegmental area (SN/VTA). In the cortex of 129P3/J mice, lower levels of both Oprk1 and Oprd1 mRNAs were observed. Pdyn mRNA was also lower in the caudate putamen of 129P3/J mice. Strain differences were not found in the levels of Oprm1, Penk or Pomc mRNAs in any region examined. Within strains, complex patterns of heroin dose-dependent changes in the levels of Oprm1, Oprk1 and Oprd1 mRNAs were observed in the SN/VTA. Additionally, Oprd1 mRNA was dose-dependently elevated in the hypothalamus. Also in the hypothalamus, we found higher levels of Drd1a mRNA in C57BL/6J mice than in 129P3/J animals and higher levels of DAT (Slc6a3) mRNA in the caudate putamen of C57BL/6J animals than in 129P3/J counterparts. Heroin had dose-related effects on Drd1a mRNA in the hypothalamus and on Drd2 mRNA in the caudate putamen. PMID:21807019

  15. Mesocortical dopaminergic function and human cognition

    SciTech Connect

    Weinberger, D.R.; Berman, K.F.; Chase, T.N.

    1988-01-01

    In summary, we have reviewed rCBF data in humans that suggest that mesoprefrontal dopaminergic activity is involved in human cognition. In patients with Parkinson's disease and possibly in patients with schizophrenia, prefrontal physiological activation during a cognitive task that appears to depend on prefrontal neural systems correlates positively with cognitive performance on the task and with clinical signs of dopaminergic function. It may be possible in the future to examine prefrontal dopamine metabolism directly during prefrontal cognition using positron emission tomography and tracers such as F-18 DOPA. 21 references.

  16. Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: evidence for the involvement of the dopaminergic system.

    PubMed

    Machado, D G; Neis, V B; Balen, G O; Colla, A; Cunha, M P; Dalmarco, J B; Pizzolatti, M G; Prediger, R D; Rodrigues, A L S

    2012-12-01

    Ursolic acid, a constituent from Rosmarinus officinalis, is a triterpenoid compound which has been extensively known for its anticancer and antioxidant properties. In the present study, we investigated the antidepressant-like effect of ursolic acid isolated from this plant in two predictive tests of antidepressant property, the tail suspension test (TST) and the forced swimming test (FST) in mice. Furthermore, the involvement of dopaminergic system in its antidepressant-like effect was investigated in the TST. Ursolic acid reduced the immobility time in the TST (0.01 and 0.1mg/kg, p.o.) and in the FST (10mg/kg, p.o.), similar to fluoxetine (10mg/kg, p.o.), imipramine (1mg/kg, p.o.) and bupropion (10mg/kg, p.o.). The effect of ursolic acid (0.1mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with SCH23390 (0.05mg/kg, s.c., a dopamine D(1) receptor antagonist) and sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist). The administration of a sub-effective dose of ursolic acid (0.001mg/kg, p.o.) in combination with sub-effective doses of SKF38393 (0.1mg/kg, s.c., a dopamine D(1) receptor agonist), apomorphine (0.5μg/kg, i.p., a preferential dopamine D(2) receptor agonist) or bupropion (1mg/kg, i.p., a dual dopamine/noradrenaline reuptake inhibitor) reduced the immobility time in the TST as compared with either drug alone. Ursolic acid and dopaminergic agents alone or in combination did not cause significant alterations in the locomotor and exploratory activities. These results indicate that the antidepressant-like effect of ursolic acid in the TST is likely mediated by an interaction with the dopaminergic system, through the activation of dopamine D(1) and D(2) receptors.

  17. The role of nutrition in the regulation of luteinizing hormone secretion by the opioidergic, dopaminergic, and serotonergic systems in female Mediterranean goats.

    PubMed

    Zarazaga, Luis A; Celi, Irma; Guzmán, José Luis; Malpaux, Benoît

    2011-03-01

    This study examined which neural mechanism (opioid, dopaminergic, or serotonergic system) is involved in the regulation of luteinizing hormone (LH) secretion, with and without nutritional modulation, at different times of the photoperiodic cycle. Goats were randomly distributed into two experimental groups that received either 1.1 (high group; n = 18) or 0.7 (low group; n = 18) times the nutritional maintenance requirements. The goats were exposed to alternations of 3 mo of long days and 3 mo of short days. Plasma LH concentrations were measured twice a week. The effects of intravenous injections of naloxone (endogenous opioid receptor antagonist), pimozide (dopaminergic(2) receptor antagonist), and cyproheptadine (serotonin 5-hydroxytryptamine(2) receptor antagonist) on LH secretion were assessed during challenges in three different photoperiodic situations: the onset of LH stimulation by short days (OnsetSD), the onset of LH inhibition by long days (OnsetLD), and during the LH inhibition by long days (LateLD). The role of the different neural systems was clearly modified by the level of nutrition. In the low-nutrition group, only naloxone increased LH concentrations during onsetLD (P < 0.05). However, in the high-nutrition group, naloxone increased the concentration and pulsatility of LH (P < 0.05) in onsetSD and onsetLD. Pimozide increased LH concentration and pulsatility (P < 0.05) in onsetLD and LH concentration in lateLD (P < 0.001). Finally, cyproheptadine significantly increased LH concentration at all three times (P < 0.001). These results provide evidence that all three systems are involved in the inhibition of LH release in onsetLD, and that the opioid and serotonin mechanisms are involved during the onsetSD that were enhanced by a high plane of nutrition.

  18. Behavioural, biochemical and molecular changes induced by chronic crack-cocaine inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex.

    PubMed

    Areal, Lorena B; Rodrigues, Livia C M; Andrich, Filipe; Moraes, Livia S; Cicilini, Maria A; Mendonça, Josideia B; Pelição, Fabricio S; Nakamura-Palacios, Ester M; Martins-Silva, Cristina; Pires, Rita G W

    2015-09-01

    Crack-cocaine addiction has increasingly become a public health problem worldwide, especially in developing countries. However, no studies have focused on neurobiological mechanisms underlying the severe addiction produced by this drug, which seems to differ from powder cocaine in many aspects. This study investigated behavioural, biochemical and molecular changes in mice inhaling crack-cocaine, focusing on dopaminergic and endocannabinoid systems in the prefrontal cortex. Mice were submitted to two inhalation sessions of crack-cocaine a day (crack-cocaine group) during 11 days, meanwhile the control group had no access to the drug. We found that the crack-cocaine group exhibited hyperlocomotion and a peculiar jumping behaviour ("escape jumping"). Blood collected right after the last inhalation session revealed that the anhydroecgonine methyl ester (AEME), a specific metabolite of cocaine pyrolysis, was much more concentrated than cocaine itself in the crack-cocaine group. Most genes related to the endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes were downregulated after 11-day crack-cocaine exposition. These changes may have decreased dopamine and its metabolites levels, which in turn may be related with the extreme upregulation of dopamine receptors and tyrosine hydroxylase observed in the prefrontal cortex of these animals. Our data suggest that after 11 days of crack-cocaine exposure, neuroadaptive changes towards downregulation of reinforcing mechanisms may have taken place as a result of neurochemical changes observed on dopaminergic and endocannabinoid systems. Successive changes like these have never been described in cocaine hydrochloride models before, probably because AEME is only produced by cocaine pyrolysis and this metabolite may underlie the more aggressive pattern of addiction induced by crack-cocaine.

  19. [18F]fluorodopa PET shows striatal dopaminergic dysfunction in juvenile neuronal ceroid lipofuscinosis.

    PubMed Central

    Ruottinen, H M; Rinne, J O; Haaparanta, M; Solin, O; Bergman, J; Oikonen, V J; Järvelä, I; Santavuori, P

    1997-01-01

    OBJECTIVES: To investigate whether nigrostriatal dopaminergic hypofunction is related to the extrapyramidal symptoms in patients with juvenile neuronal ceroid lipofuscinosis (JNCL). METHODS: Nine patients with JNCL and seven healthy controls were studied using [18F]fluorodopa PET. RESULTS: In the patients with JNCL [18F]fluorodopa uptake (K[i][occ]) in the putamen was 60% of the control mean and the corresponding figure in the caudate nucleus was 79%. There was a weak correlation between putamen K(i)(occ) values and extrapyramidal symptoms of the patients evaluated by the motor part of the unified Parkinson's disease rating scale (r = -0.57, P < 0.05). The overall severity of the disease also displayed a negative correlation with the K(i)(occ) values in the putamen (r = -0.71, P < 0.05). CONCLUSION: In patients with JNCL there was reduced striatal [18F]fluorodopa uptake, which had a modest correlation with extrapyramidal symptoms. Dysfunction of nigrostriatal dopaminergic neurons is therefore not the only cause of the patients' extrapyramidal symptoms, but degenerative changes in other brain areas are also contributory. Images PMID:9219750

  20. Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers.

    PubMed

    Johanson, Chris-Ellyn; Frey, Kirk A; Lundahl, Leslie H; Keenan, Pamela; Lockhart, Nancy; Roll, John; Galloway, Gantt P; Koeppe, Robert A; Kilbourn, Michael R; Robbins, Trevor; Schuster, Charles R

    2006-04-01

    Preclinical investigations have established that methamphetamine (MA) produces long-term changes in dopamine (DA) neurons in the striatum. Human studies have suggested similar effects and correlated motor and cognitive deficits. The present study was designed to further our understanding of changes in brain function in humans that might result from chronic high dose use of MA after at least 3 months of abstinence. Brain function in abstinent users was compared to controls using neuroimaging of monoamine transporters and cognitive assessment. Striatal levels of DA transporter (DAT) and vesicular monoamine transporter type-2 (VMAT2) were determined using [11C]methylphenidate and [11C]dihydrotetrabenazine positron emission tomography, respectively. Cognitive function was evaluated using tests of motor function, memory, learning, attention, and executive function. Striatal DAT was approximately 15% lower and VMAT2 was 10% lower in MA abusers across striatal subregions. The MA abusers performed within the normal range but performed more poorly compared to controls on three of the 12 tasks. Failure to find more substantial changes in transporter levels and neurocognitive function may be attributed to the length of time that MA users were abstinent (ranging from 3 months to more than 10 years, mean 3 years), although there were no correlations with length of abstinence. Persistent VMAT2 reductions support the animal literature indicating a toxic effect of MA on nigrostriatal nerve terminals. However, the magnitude of the MA effects on nigrostriatal projection integrity is sufficiently small that it is questionable whether clinical signs of DA deficiency are likely to develop.

  1. Roles of cholinergic, dopaminergic, noradrenergic, serotonergic and GABAergic systems in changes of the EEG power spectra and behavioral states in rabbits.

    PubMed

    Yamamoto, J

    1988-06-01

    In the present study, the influences of cholinergic (ACh), dopaminergic (DA), noradrenergic, serotonergic and gamma-aminobutyric acid (GABA) ergic system activation and blocking agents on the cortical (CT) and hippocampal (HC) EEG power spectra were investigated in rabbits. The AChergic agents, physostigmine and atropine, produced marked increases or decreases in peak powers, the changes of which were inversely related to each other, but similar to those of the normal behavioral states. The other agents did not always produce changes. ACh seems to play an important role in the regulation of peak powers. Apomorphine shifted the theta wave peak to higher frequencies and haloperidol shifted it to lower frequencies. The other drugs did not cause a shift. DA seems to regulate peak frequency. These findings suggest that ACh is important for the regulation of consciousness between the wakefulness and SWS states and suggest that DA is involved in the production of REM sleep.

  2. Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats

    PubMed Central

    dos Santos Pereira, Maurício; Sathler, Matheus Figueiredo; Valli, Thais da Rosa; Marques, Richard Souza; Ventura, Ana Lucia Marques; Peccinalli, Ney Ronner; Fraga, Mabel Carneiro; Manhães, Alex C.; Kubrusly, Regina

    2015-01-01

    Methylphenidate (MPD) is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i) to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii) to establish the neurochemical consequences of short- (24 hours) and long-term (10 days) MPD withdrawal after a subchronic treatment (30 days) with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally), (iii) to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC) and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p.) presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult life

  3. Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats.

    PubMed

    dos Santos Pereira, Maurício; Sathler, Matheus Figueiredo; Valli, Thais da Rosa; Marques, Richard Souza; Ventura, Ana Lucia Marques; Peccinalli, Ney Ronner; Fraga, Mabel Carneiro; Manhães, Alex C; Kubrusly, Regina

    2015-01-01

    Methylphenidate (MPD) is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i) to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii) to establish the neurochemical consequences of short- (24 hours) and long-term (10 days) MPD withdrawal after a subchronic treatment (30 days) with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally), (iii) to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC) and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p.) presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult life.

  4. The effect of Schisandra chinensis extracts on depression by noradrenergic, dopaminergic, GABAergic and glutamatergic systems in the forced swim test in mice.

    PubMed

    Yan, Tingxu; Xu, Mengjie; Wu, Bo; Liao, Zhengzheng; Liu, Zhi; Zhao, Xu; Bi, Kaishun; Jia, Ying

    2016-06-15

    Schisandra chinensis (Turcz.) Baill., as a Chinese functional food, has been widely used in neurological disorders including insomnia and Alzheimer's disease. The treatment of classical neuropsychiatric disorder depression is to be developed from Schisandra chinensis. The antidepressant-like effects of the Schisandra chinensis extracts (SCE), and their probable involvement in the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems were investigated by the forced swim test (FST). Acute administration of SCE (600 mg kg(-1), i.g.), a combination of SCE (300 mg kg(-1), i.g.) and reboxetine (a noradrenalin reuptake inhibitor, 2.5 mg kg(-1), i.p.) or imipramine (a TCA, 2 mg kg(-1), i.p.) reduced the immobility time in the FST. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, a selective noradrenergic neurotoxin, 50 mg kg(-1), i.p., 4 days), haloperidol (a non-selective D2 receptor antagonist, 0.2 mg kg(-1), i.p.), SCH 23390 (a selective D1 receptor antagonist, 0.03 mg kg(-1), i.p.), bicuculline (a competitive GABA antagonist, 4 mg kg(-1), i.p.) and N-methyl-d-aspartic acid (NMDA, an agonist at the glutamate site, 75 mg kg(-1), i.p.) effectively reversed the antidepressant-like effect of SCE (600 mg kg(-1), i.g.). However, p-chlorophenylalanine (pCPA, an inhibitor of 5-HT synthesis, 100 mg kg(-1), i.p., 4 days,) did not eliminate the reduced immobility time induced by SCE (600 mg kg(-1), i.g.). Moreover, the treatments did not change the locomotor activity. Altogether, these results indicated that SCE produced antidepressant-like activity, which might be mediated by the modification of noradrenergic, dopaminergic, GABAergic and glutamatergic systems.

  5. Dopaminergic Neuronal Loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2

    PubMed Central

    Lin, Brian M.; Stafa, Klodjan; Kim, Jaekwang; Banerjee, Rebecca; Westerlund, Marie; Pletnikova, Olga; Glauser, Liliane; Yang, Lichuan; Liu, Ying; Swing, Deborah A.; Beal, M. Flint; Troncoso, Juan C.; McCaffery, J. Michael; Jenkins, Nancy A.; Copeland, Neal G.; Galter, Dagmar; Thomas, Bobby; Lee, Michael K.; Dawson, Ted M.; Dawson, Valina L.; Moore, Darren J.

    2011-01-01

    Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD. PMID:21494637

  6. Changes of the striatal /sup 3/H-spiperone binding 3 - 6 weeks after nigrostriatal denervation and after two years

    SciTech Connect

    Guerin, B.; Silice, C.; Mouchet, P.; Feuerstein, C.; Demenge, P.

    1985-09-09

    A complete unilateral lesion of the nigrostriatal pathway by 6-hydroxydopamine injection in the substantia nigra induced a drastic increase in striatal dopaminergic binding sites labelled by /sup 3/H-spiperone, 30 days after the lesion. This increase (75% over controls) was time restricted: it was only 39% and 34% over control values at respectively 25 and 35 days after the lesion. Furthermore, 45 days after the destruction of the substantia nigra, the density of labelled sites returned close to the homolateral control values, but remained higher than the contralateral ones, according to the right-left difference found in control animals. Quite later (2 years after the lesion), there was a decrease in the density of labelled sites as compared to the respective homolateral control levels. However, such binding sites tend to remain higher in the striatum of the lesioned side than in the striatum of the intact one, although such a difference was not statistically significant, being very close the right-left asymmetry observed in control animals. Contrary to previous results with /sup 3/H-Haloperidol, the apparent dissociation constant did not vary significantly, whatever the considered delay after the lesion. These results are discussed in the light of previous results obtained by others and by the authors. 28 references, 3 figures, 1 table.

  7. Cognitive executive impairment and dopaminergic deficits in de novo Parkinson's disease.

    PubMed

    Siepel, Françoise J; Brønnick, Kolbjørn S; Booij, Jan; Ravina, Bernard M; Lebedev, Alexander V; Pereira, Joana B; Grüner, Renate; Aarsland, Dag

    2014-12-01

    Cognitive impairment in Parkinson's disease (PD) is common and does directly impact patients' everyday functioning. However, the underlying mechanisms of early cognitive decline are not known. This study explored the association between striatal dopaminergic deficits and cognitive impairment within a large cohort of early, drug-naïve PD patients and tested the hypothesis that executive dysfunction in PD is associated with striatal dopaminergic depletion. A cross-sectional multicenter cohort of 339 PD patients and 158 healthy controls from the Parkinson's Progression Markers Initiative study was analyzed. Each individual underwent cerebral single-photon emission CT (SPECT) and a standardized neuropsychological assessment with tests of memory as well as visuospatial and executive function. SPECT imaging was performed with [(123) I]FP-CIT, and specific binding ratios in left and right putamen and caudate nucleus were calculated. The association between specific binding ratios, cognitive domain scores, and age was analyzed using Pearson's correlations, partial correlation, and conditional process analysis. A small, but significant, positive association between total striatal dopamine transporter binding and the attention/executive domain was found (r = 0.141; P = 0.009) in PD, but this was not significant after adjusting for age. However, in a moderated mediation model, we found that cognitive executive differences between controls and patients with PD were mediated by an age-moderated striatal dopaminergic deficit. Our findings support the hypothesis that nigrostriatal dopaminergic deficit is associated with executive impairment, but not to memory or visuospatial impairment, in early PD.

  8. Transgenic Zebrafish Expressing mCherry in the Mitochondria of Dopaminergic Neurons.

    PubMed

    Noble, Sandra; Godoy, Rafael; Affaticati, Pierre; Ekker, Marc

    2015-10-01

    Genetic mutations and environmental toxins are known to affect mitochondrial health and have been implicated in the progressive degeneration of dopaminergic neurons in Parkinson's disease. To visualize mitochondria in dopaminergic neurons of live zebrafish, we used the regulatory elements of the dopamine transporter (dat) gene to target a reporter, mCherry, after fusion with the mitochondrial localizing signal (MLS) of Tom20. Immunoblot analysis of mitochondrial and cytosolic fractions from Tg(dat:tom20 MLS-mCherry) larvae shows that mCherry is efficiently targeted to the mitochondria. Confocal imaging of live fish was carried out from 1 day postfertilization (dpf) to 9 dpf. We also colocalized dat mRNA expression with the mCherry protein in the olfactory bulb (OB), subpallium (SP), pretectum (Pr), diencephalic clusters 2 and 3 (DC2/3), caudal hypothalamus (Hc), locus coeruleus (LC), anterior preoptic area (POa), retinal amacrine cells (RAC), caudal hypothalamus (Hc), and preoptic area (PO). Treating Tg(dat:tom20 MLS-mCherry) larvae with the dopaminergic neurotoxin MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) at 2 or 3 dpf resulted in a decrease in mCherry fluorescence in the pretectum, olfactory bulb, subpallium, diencephalic clusters 2 and 3, and the caudal hypothalamus. Labeling of mitochondria in nigrostriatal dopaminergic neurons of zebrafish could allow their visualization in vivo following genetic or pharmacological manipulations.

  9. Phosphodiesterase 7 Inhibition Preserves Dopaminergic Neurons in Cellular and Rodent Models of Parkinson Disease

    PubMed Central

    Morales-Garcia, Jose A.; Redondo, Miriam; Alonso-Gil, Sandra; Gil, Carmen; Perez, Concepción; Martinez, Ana; Santos, Angel; Perez-Castillo, Ana

    2011-01-01

    Background Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP in many cell types. This cyclic nucleotide plays a key role in signal transduction in a wide variety of cellular responses. In the brain, cAMP has been implicated in learning, memory processes and other brain functions. Methodology/Principal Findings Here we show a novel function of phosphodiesterase 7 inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, a heterocyclic small molecule inhibitor of phosphodiesterase 7, conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. S14 treatment also reduced microglial activation, protected dopaminergic neurons and improved motor function in the lipopolysaccharide rat model of Parkinson disease. Finally, S14 neuroprotective effects were reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A. Conclusions/Significance Our findings demonstrate that phosphodiesterase 7 inhibition can protect dopaminergic neurons against different insults, and they provide support for the therapeutic potential of phosphodiesterase 7 inhibitors in the treatment of neurodegenerative disorders, particularly Parkinson disease. PMID:21390306

  10. Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways

    PubMed Central

    Gombash, SE; Manfredsson, FP; Mandel, RJ; Collier, TJ; Fischer, DL; Kemp, CJ; Kuhn, NM; Wohlgenant, SL; Fleming, SM; Sortwell, CE

    2015-01-01

    Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6-hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons. PMID:24807806

  11. Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways.

    PubMed

    Gombash, S E; Manfredsson, F P; Mandel, R J; Collier, T J; Fischer, D L; Kemp, C J; Kuhn, N M; Wohlgenant, S L; Fleming, S M; Sortwell, C E

    2014-07-01

    Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6-hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons.

  12. The dopaminergic system in upper limb motor blocks (ULMB) investigated during bimanual coordination in Parkinson's disease (PD).

    PubMed

    Brown, Matt J N; Almeida, Quincy J; Rahimi, Fariborz

    2015-01-01

    Upper limb motor blocks (ULMB) (inability to initiate or sudden discontinue in voluntary movements) have been identified in both unimanual and bimanual tasks in individuals with Parkinson's disease (PD). In particular, ULMB have been observed during rhythmic bimanual coordination when switching between phase patterns which is required (e.g. between in-phase and anti-phase). While sensory-perceptual mechanisms have recently been suggested to be involved in lower limb freezing, there has been no consensus on the mechanism that evokes ULMB or whether motor blocks respond to dopamine replacement like other motor symptoms of PD. The current study investigated the occurrence of ULMB in PD participants without ('off') and with ('on') dopamine replacement using bimanual wrist flexion-extension with external auditory cues. In Experiment 1, coordination was performed in either in-phase (simultaneous flexion and extension) or anti-phase (asymmetrical flexion and extension between the limbs) in one of three sensory conditions: no vision, normal vision or augmented vision. Cycle frequency was increased within each trial across seven cycle frequencies (0.75-2 Hz). In Experiment 2, coordination was initiated in either phase pattern and participants were cued to make an intentional switch between phases in the middle of trials. Trials were performed at one of two cycle frequencies (1 or 2 Hz) and one of two sensory conditions: no vision or normal vision. Healthy age-matched control participants were also investigated in both experiments for the occurrence of motor blocks that were measured using automated detection from a computer algorithm. The results from Experiment 1 indicated that increasing cycle frequency resulted in more ULMB in individuals with PD during continuous coordinated movement, regardless of dopaminergic status, phase pattern or sensory condition. Experiment 2 also confirmed an increased occurrence of ULMB with increased cycle frequency. Furthermore, a large

  13. SPECT brain imaging of the dopaminergic system in Parkinsonism using {sup 123}I and {sup 99m}Tc labeled agents

    SciTech Connect

    Du Yong

    2004-12-01

    SPECT brain imaging of the dopaminergic system using {sup 123}I and {sup 99m}Tc labeled agents, especially the simultaneous imaging of both pre- and postsynaptic neurons, promises to provide accurate diagnosis and differentiation of Parkinsonism. However, there are many degrading factors that affect the quality and quantitative accuracy of the SPECT images. These degrading factors limit the potential clinical applications of brain SPECT imaging. In this work, we studied these degrading factors by developing and validating a Monte Carlo (MC) method that provides accurate SPECT simulation with detailed modeling of the photon interactions inside the collimator detector system. To compensate for the partial volume effect (PVE) in the SPECT images caused by finite spatial resolution, we developed a new PVE compensation method that takes into account the effects of nonlinearity in iterative reconstruction-based compensation for image degrading factors, including attenuation, scatter, and collimator detector response. Compensation using the new method greatly improved the quantitative accuracy of brain SPECT images. We have also developed model-based method that can accurately estimate the downscatter and crosstalk contamination in the {sup 123}I imaging and the simultaneous {sup 123}I/{sup 99m}Tc dual-isotope imaging. Based on the model-based method, two different approaches to model-based downscatter and crosstalk contamination compensation were proposed. Both methods are based on iterative reconstruction and include compensation for other imaging degrading factors. The model-based downscatter and crosstalk compensation method provided greatly improved accuracy of activity estimates with little effect on the precision. Finally, optimization of energy windows for simultaneous {sup 123}I/{sup 99m}Tc acquisition was performed to find the energy windows with the best trade-off between minimizing the crosstalk and maximizing the detection efficiency for simultaneous

  14. Isotopic reinforcement of essential polyunsaturated fatty acids diminishes nigrostriatal degeneration in a mouse model of Parkinson's disease.

    PubMed

    Shchepinov, Mikhail S; Chou, Vivian P; Pollock, Erik; Langston, J William; Cantor, Charles R; Molinari, Robert J; Manning-Boğ, Amy B

    2011-11-30

    noted in the number of nigral dopaminergic neurons following MPTP exposure in the D-PUFA (79.5% control) vs. H-PUFA (58.8% control) mice using unbiased stereological cell counting. Taken together, these findings indicate that dietary isotopic reinforcement with D-PUFA partially protects against nigrostriatal damage from oxidative injury elicited by MPTP in mice.

  15. Maternal separation and early stress cause long-lasting effects on dopaminergic and endocannabinergic systems and alters dendritic morphology in the nucleus accumbens and frontal cortex in rats.

    PubMed

    Romano-López, Antonio; Méndez-Díaz, Mónica; García, Fabio García; Regalado-Santiago, Citlalli; Ruiz-Contreras, Alejandra E; Prospéro-García, Oscar

    2016-08-01

    A considerable amount experimental studies have shown that maternal separation (MS) is associated with adult offspring abnormal behavior and cognition disorder. Accordingly, this experimental procedure has been proposed as a predictor for alcohol and drug dependence based on the neurodevelopmental soon after birth. Endocannabinoid system (eCBs) has been implicated in reward processes, including drug abuse and dependence. MS and associated stress causes changes in the eCBs that seem to facilitate alcohol consumption. In this study, we seek to evaluate potential morphological changes in neurons of the frontal cortex (FCx) and nucleus accumbens (NAcc), in the expression of receptors and enzymes of the endocannabinoid and dopamine systems and in second messengers, such as Akt, in adult rats subjected to MS and early stress (MS + ES; 2 × 180 min daily) vs. nonseparated rats (NMS). Results showed that MS + ES induces higher D2R expression and lower D3R, FAAH, and MAGL expression compared with NMS rats. Alterations in total dendritic length were also detected and were characterized by increases in the NAcc while there were decreases in the FCx. We believe MS + ES-induced changes in the dopaminergic and endocannabinergic systems and in the neuronal microstructure might be contributing to alcohol seeking behavior and, potential vulnerability to other drugs in rats. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 819-831, 2016.

  16. The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems.

    PubMed

    Pesarico, Ana Paula; Sampaio, Tuane Bazanella; Stangherlin, Eluza Curte; Mantovani, Anderson C; Zeni, Gilson; Nogueira, Cristina Wayne

    2014-10-03

    The aim of the present study was to investigate the role of monoaminergic system in the antidepressant-like action of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a derivative of isoquinoline class, in Swiss mice. The antidepressant-like effect of FDPI was characterized in the modified forced swimming test (FST) and the possible mechanism of action was investigated by using serotonergic, dopaminergic and noradrenergic antagonists. Monoamine oxidase (MAO) activity and [(3)H]serotonin (5-HT) uptake were determined in prefrontal cortices of mice. The results showed that FDPI (1, 10 and 20mg/kg, i.g.) reduced the immobility time and increased the swimming time but did not alter climbing time in the modified FST. These effects were similar to those of paroxetine (8mg/kg, i.p.), a positive control. Pretreatments with p-chlorophenylalanine (100mg/kg, i.p., an inhibitor of 5-HT synthesis), WAY100635 (0.1mg/kg, s.c., 5-HT1A antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), haloperidol (0.2mg/kg, i.p., a non-selective D2 receptor antagonist) and SCH23390 (0.05mg/kg, s.c., a D1 receptor antagonist) were effective to block the antidepressant-like effect of FDPI at a dose of 1mg/kg in the FST. Ritanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), sulpiride (50mg/kg, i.p., a D2 and D3 receptor antagonist), prazosin (1mg/kg, i.p., an α1 receptor antagonist), yohimbine (1mg/kg, i.p., an α2 receptor antagonist) and propranolol (2mg/kg, i.p., a β receptor antagonist) did not modify the effect of FDPI in the FST. FDPI did not change synaptosomal [(3)H]5-HT uptake. At doses of 10 and 20mg/kg FDPI inhibited MAO-A and MAO-B activities. These results suggest that antidepressant-like effect of FDPI is mediated mostly by serotonergic and dopaminergic systems.

  17. Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Schrantee, Anouk; Tamminga, Hyke G. H.; Bouziane, Cheima; Bottelier, Marco A.; Bron, Esther E.; Mutsaerts, Henk-Jan M. M.; Zwinderman, Aeilko H.; Groote, Inge R.; Rombouts, Serge A. R. B.; Lindauer, Ramon J. L.; Klein, Stefan; Niessen, Wiro J.; Opmeer, Brent C.; Boer, Frits; Lucassen, Paul J.; Andersen, Susan L.; Geurts, Hilde M.; Reneman, Liesbeth

    2017-01-01

    IMPORTANCE Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. OBJECTIVES To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain–Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment–naive status. INTERVENTIONS Treatment with either methylphenidate or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses. RESULTS Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4–12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7–14.8; P = .03). CONCLUSIONS AND RELEVANCE We

  18. Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial.

    PubMed

    Schrantee, Anouk; Tamminga, Hyke G H; Bouziane, Cheima; Bottelier, Marco A; Bron, Esther E; Mutsaerts, Henk-Jan M M; Zwinderman, Aeilko H; Groote, Inge R; Rombouts, Serge A R B; Lindauer, Ramon J L; Klein, Stefan; Niessen, Wiro J; Opmeer, Brent C; Boer, Frits; Lucassen, Paul J; Andersen, Susan L; Geurts, Hilde M; Reneman, Liesbeth

    2016-09-01

    Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function. A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain-Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment-naive status. Treatment with either methylphenidate or a matched placebo for 16 weeks. Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses. Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P = .03). We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine

  19. Flavonoids as dopaminergic neuromodulators.

    PubMed

    Meireles, Manuela; Moura, Eduardo; Vieira-Coelho, Maria Augusta; Santos-Buelga, Celestino; Gonzalez-Manzano, Susana; Dueñas, Montserrat; Mateus, Nuno; Faria, Ana; Calhau, Conceição

    2016-03-01

    The present study aimed to characterize and evaluate flavonoids effects on organic cation uptake in neuronal cells. Uptake experiments were conducted using radiolabeled methyl-4-phenylpyridinuim ([(3) H]-MPP(+) ), in human neuronal dopaminergic cells, SH-SY5Y. Catechin did not alter [(3) H]-MPP(+) uptake, however its metabolite 4'-methyl-catechin decreased it by almost 50%. Epicatechin and its methylated metabolites also decreased [(3) H]-MPP(+) uptake. Interestingly, the quercetin flavonol and its metabolite conjugated with glucuronic acid, as well as the flavanones naringenin and hesperitin, increased [(3) H]-MPP(+) uptake. These results showed that different classes of flavonoids, as well as its metabolites, differently influence neuronal organic cation uptake. Several xeno- and endobiotics, including neurotransmitters, are organic cations. Specific food recommendations may be beneficial in pathological conditions where levels of neurotransmitters, as dopamine, are either increased or decreased. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Antidepressant-like effect of 17beta-estradiol: involvement of dopaminergic, serotonergic, and (or) sigma-1 receptor systems.

    PubMed

    Dhir, Ashish; Kulkarni, S K

    2008-10-01

    -1 receptor antagonist), or BD 1047 (1 mg/kg, i.p.; a novel sigma-1 receptor antagonist) reversed the antiimmobility effects of 17beta-estradiol (20 microg/kg, i.p.). Similarly, in mice pretreated with a subthreshold dose of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A serotonin receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced an antidepressant-like effect. These findings demonstrate that 17beta-estradiol exerted an antidepressant-like effect preferentially through the modulation of dopaminergic and serotonergic receptors. This action may also involve the participation of sigma-1 receptors.

  1. Cognitive performance correlates with the degree of dopaminergic degeneration in the associative part of the striatum in non-demented Parkinson's patients.

    PubMed

    Kübler, Dorothee; Schroll, Henning; Buchert, Ralph; Kühn, Andrea A

    2017-06-22

    Parkinson's disease (PD) patients show cognitive deficits that are relevant in terms of prognosis and quality of life. Degeneration of striatal dopaminergic afferents proceeds from dorsal/caudal to anterior/ventral and is discussed to account for some of these symptoms. Treatment with dopamine (DA) has differential effects on cognitive dysfunctions, improving some and worsening others. We hypothesized that cognitive performance during the dopaminergic OFF state correlates with DAT availability in the associative striatum. 16 PD patients underwent motor and cognitive examination ON and OFF DA. Global cognition was measured using the Montréal Cognitive Assessment (MoCA) test and executive functioning using a Stroop test. Nigrostriatal dopaminergic innervation was characterized with [(123)I]FP-CIT SPECT. A connectivity atlas of the striatum was used to assess DAT availability in functionally defined striatal subregions. Correlations between imaging data and behavioral data OFF medication were calculated. Correlations between DAT availability and MoCA performance in the dopaminergic OFF state was strongest in the associative part of the striatum (r = 0.674, p = 0.004). MoCA test performance did not differ between the ON and the OFF state. There was no correlation of DAT availability with Stroop performance in the OFF state but performance was significantly better during the ON state. Not only motor but also cognitive dysfunctions in PD are associated with striatal dopaminergic depletion. Cognitive decline in non-demented PD patients goes along with nigrostriatal degeneration, most pronounced in the associative subdivision of the striatum. In addition, the present findings suggest that executive dysfunctions are ameliorated by DA whereas global cognition is not improved by dopaminergic medication.

  2. 7α-Hydroxypregnenolone, a key neuronal modulator of locomotion, stimulates upstream migration by means of the dopaminergic system in salmon.

    PubMed

    Haraguchi, Shogo; Yamamoto, Yuzo; Suzuki, Yuko; Hyung Chang, Joon; Koyama, Teppei; Sato, Miku; Mita, Masatoshi; Ueda, Hiroshi; Tsutsui, Kazuyoshi

    2015-07-29

    Salmon migrate upstream against an opposing current in their natal river. However, the molecular mechanisms that stimulate upstream migratory behavior are poorly understood. Here, we show that 7α-hydroxypregnenolone (7α-OH PREG), a newly identified neuronal modulator of locomotion, acts as a key factor for upstream migration in salmon. We first identified 7α-OH PREG and cytochrome P450 7α-hydroxylase (P4507α), a steroidogenic enzyme producing 7α-OH PREG, in the salmon brain and then found that 7α-OH PREG synthesis in the brain increases during upstream migration. Subsequently, we demonstrated that 7α-OH PREG increases upstream migratory behavior of salmon. We further found that 7α-OH PREG acts on dopamine neurons in the magnocellular preoptic nucleus during upstream migration. Thus, 7α-OH PREG stimulates upstream migratory behavior through the dopaminergic system in salmon. These findings provide new insights into the molecular mechanisms of fish upstream migration.

  3. Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP

    PubMed Central

    Filichia, Emily; Hoffer, Barry; Qi, Xin; Luo, Yu

    2016-01-01

    Accumulating evidence suggest mitochondria-mediated pathways play an important role in dopaminergic neuronal cell death in Parkinson’s disease (PD). Drp1, a key regulator of mitochondrial fission, has been shown to be activated and translocated to mitochondria under stress, leading to excessive mitochondria fission and dopaminergic neuronal death in vitro. However, whether Drp1 inhibition can lead to long term stable preservation of dopaminergic neurons in PD-related mouse models remains unknown. In this study, using a classical MPTP animal PD model, we showed for the first time Drp1 activation and mitochondrial translocation in vivo after MPTP administration. Inhibition of Drp1 activation by a selective peptide inhibitor P110, blocked MPTP-induced Drp1 mitochondrial translocation and attenuated dopaminergic neuronal loss, dopaminergic nerve terminal damage and behavioral deficits caused by MPTP. MPTP-induced microglial activation and astrogliosis were not affected by P110 treatment. Instead, inhibition of Drp1 mitochondrial translocation diminished MPTP-induced p53, BAX and PUMA mitochondrial translocation. This study demonstrates that inhibition of Drp1 hyperactivation by a Drp1 peptide inhibitor P110 is neuroprotective in a MPTP animal model. Our data also suggest that the protective effects of P110 treatment might be mediated by inhibiting the p53 mediated apoptotic pathways in neurons through inhibition of Drp1-dependent p53 mitochondrial translocation. PMID:27619562

  4. Loss of cocaine locomotor response in Pitx3-deficient mice lacking a nigrostriatal pathway.

    PubMed

    Beeler, Jeff A; Cao, Zhen Fang Huang; Kheirbek, Mazen A; Zhuang, Xiaoxi

    2009-04-01

    Both the dorsal and ventral striatum have been demonstrated to have a critical role in reinforcement learning and addiction. Dissecting the specific function of these striatal compartments and their associated nigrostriatal and mesoaccumbens dopamine pathways, however, has proved difficult. Previous studies using lesions to isolate the contribution of nigrostriatal and mesoaccumbens dopamine in mediating the locomotor and reinforcing effects of psychostimulant drugs have yielded inconsistent and inconclusive results. Using a naturally occurring mutant mouse line, aphakia, that lacks a nigrostriatal dopamine pathway but retains an intact mesoaccumbens pathway, we show that the locomotor activating effects of cocaine, including locomotor sensitization, are dependent on an intact nigrostriatal dopamine projection. In contrast, cocaine reinforcement, as measured by conditioned place preference and cocaine sensitization of sucrose preference, is intact in these mice. In light of the well-established role of the nucleus accumbens in mediating the effects of psychostimulants, these data suggest that the nigrostriatal pathway can act as a critical effector mechanism for the nucleus accumbens highlighting the importance of intrastriatal connectivity and providing insight into the functional architecture of the striatum.

  5. Manipulation of Rat Movement via Nigrostriatal Stimulation Controlled by Human Visually Evoked Potentials.

    PubMed

    Koo, Bonkon; Koh, Chin Su; Park, Hae-Yong; Lee, Hwan-Gon; Chang, Jin Woo; Choi, Seungjin; Shin, Hyung-Cheul

    2017-05-24

    Here, we report that the development of a brain-to-brain interface (BBI) system that enables a human user to manipulate rat movement without any previous training. In our model, the remotely-guided rats (known as ratbots) successfully navigated a T-maze via contralateral turning behaviour induced by electrical stimulation of the nigrostriatal (NS) pathway by a brain- computer interface (BCI) based on the human controller's steady-state visually evoked potentials (SSVEPs). The system allowed human participants to manipulate rat movement with an average success rate of 82.2% and at an average rat speed of approximately 1.9 m/min. The ratbots had no directional preference, showing average success rates of 81.1% and 83.3% for the left- and right-turning task, respectively. This is the first study to demonstrate the use of NS stimulation for developing a highly stable ratbot that does not require previous training, and is the first instance of a training-free BBI for rat navigation. The results of this study will facilitate the development of borderless communication between human and untrained animals, which could not only improve the understanding of animals in humans, but also allow untrained animals to more effectively provide humans with information obtained with their superior perception.

  6. CB2 Receptor Agonists Protect Human Dopaminergic Neurons against Damage from HIV-1 gp120

    PubMed Central

    Hu, Shuxian; Sheng, Wen S.; Rock, R. Bryan

    2013-01-01

    Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Recent work suggests that the nigrostriatal dopaminergic area is a critical brain region for the neuronal dysfunction and death seen in HAND and that human dopaminergic neurons have a particular sensitivity to gp120-induced damage, manifested as reduced function (decreased dopamine uptake), morphological changes, and reduced viability. Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes. Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model, which contains dopaminergic neurons, microglia, and astrocytes, we were able to show that the CB1/CB2 agonist WIN55,212-2 blunts gp120-induced neuronal damage as measured by dopamine transporter function, apoptosis and lipid peroxidation; these actions were mediated principally by the CB2 receptor. Adding supplementary human microglia to our cultures enhances gp120-induced damage; WIN55,212-2 is able to alleviate this enhanced damage. Additionally, WIN55,212-2 inhibits gp120-induced superoxide production by purified human microglial cells, inhibits migration of human microglia towards supernatants generated from gp120-stimulated human mesencephalic neuronal/glial cultures and reduces chemokine and cytokine production from the human mesencephalic neuronal/glial cultures. These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety

  7. Dopaminergic basis for impairments in functional connectivity across subdivisions of the striatum in Parkinson's disease.

    PubMed

    Bell, Peter T; Gilat, Moran; O'Callaghan, Claire; Copland, David A; Frank, Michael J; Lewis, Simon J G; Shine, James M

    2015-04-01

    The pathological hallmark of Parkinson's disease is the degeneration of dopaminergic nigrostriatal neurons, leading to depletion of striatal dopamine. Recent neuroanatomical work has identified pathways for communication across striatal subdivisions, suggesting that the striatum provides a platform for integration of information across parallel corticostriatal circuits. The aim of this study was to investigate whether dopaminergic dysfunction in Parkinson's disease was associated with impairments in functional connectivity across striatal subdivisions, which could potentially reflect reduced integration across corticostriatal circuits. Utilizing resting-state functional magnetic resonance imaging (fMRI), we analyzed functional connectivity in 39 patients with Parkinson's disease, both "on" and "off" their regular dopaminergic medications, along with 40 age-matched healthy controls. Our results demonstrate widespread impairments in connectivity across subdivisions of the striatum in patients with Parkinson's disease in the "off" state. The administration of dopaminergic medication significantly improved connectivity across striatal subdivisions in Parkinson's disease, implicating dopaminergic deficits in the pathogenesis of impaired striatal interconnectivity. In addition, impaired striatal interconnectivity in the Parkinson's disease "off" state was associated with pathological decoupling of the striatum from the thalamic and sensorimotor (SM) networks. Specifically, we found that although the strength of striatal interconnectivity was positively correlated with both (i) the strength of internal thalamic connectivity, and (ii) the strength of internal SM connectivity, in both healthy controls and the Parkinson's disease "on" state, these relationships were absent in Parkinson's disease when in the "off" state. Taken together our findings emphasize the central role of dopamine in integrated striatal function and the pathological consequences of striatal dopamine

  8. Endocannabinoid Modulation of Dopaminergic Motor Circuits

    PubMed Central

    Morera-Herreras, Teresa; Miguelez, Cristina; Aristieta, Asier; Ruiz-Ortega, José Ángel; Ugedo, Luisa

    2012-01-01

    There is substantial evidence supporting a role for the endocannabinoid system as a modulator of the dopaminergic activity in the basal ganglia, a forebrain system that integrates cortical information to coordinate motor activity regulating signals. In fact, the administration of plant-derived, synthetic or endogenous cannabinoids produces several effects on motor function. These effects are mediated primarily through the CB1 receptors that are densely located in the dopamine-enriched basal ganglia networks, suggesting that the motor effects of endocannabinoids are due, at least in part, to modulation of dopaminergic transmission. On the other hand, there are profound changes in CB1 receptor cannabinoid signaling in the basal ganglia circuits after dopamine depletion (as happens in Parkinson’s disease) and following l-DOPA replacement therapy. Therefore, it has been suggested that endocannabinoid system modulation may constitute an important component in new therapeutic approaches to the treatment of motor disturbances. In this article we will review studies supporting the endocannabinoid modulation of dopaminergic motor circuits. PMID:22701427

  9. GM1 enhances dopaminergic markers in the brain of aged rats.

    PubMed

    Goettl, V M; Zhang, H; Burrows, A C; Wemlinger, T A; Neff, N H; Hadjiconstantinou, M

    2003-10-01

    A number of presynaptic markers are compromised in the dopaminergic neurons of aged Sprague-Dawley rats (22 months old) compared with young rats (3 months old). Indeed, in the striatum of the aged rats there is a diminished capacity to transport dopamine (DA), to bind the dopamine transporter (DAT) marker mazindol, to bind the vesicular monoamine transporter 2 (VMAT2) marker dihydrotetrabenazine, and to release DA under basal conditions or after induction by K(+) or amphetamine. Furthermore, the expression of DAT and VMAT2 mRNA in the midbrain is suppressed. GM1 ganglioside, 30 mg/kg ip daily, administered for 30 days, restores the afore-mentioned markers to values approaching those for young rats. Taken together with our published observations that GM1 partially restores tyrosine hydroxylase activity and DA metabolism in aged nigrostriatal and mesoaccumbal neurons and improves their morphology, our work suggests that GM1 might act as a dopaminergic neurotrophic factor in the aged brain and be a useful adjuvant for treating age-associated dopaminergic deficits.

  10. Phencyclidine-induced rotation and hippocampal modulation of nigrostriatal asymmetry.

    PubMed

    Glick, S D; Meibach, R C; Cox, R D; Maayani, S

    1980-08-25

    Phencyclidine (PCP) elicited dose-related rotation in naive rats. The effect of PCP was consistent in direction and magnitude from one week to the next but was dissimilar to the rotatory effects of dopaminergic (D-amphetamine, apomorphine) or anticholinergic (scopolamine) drugs. Study of the effects of PCP on regional brain uptake of labeled 2-deoxy-D-glucose suggested that PCP-induced rotation is at least in part mediated by an action in the hippocampus. PCP elicited ipsilateral rotation following unilateral hippocampal lesions whereas such lesions did not alter the direction of either nocturnal or D-amphetamine-induced rotation. PCP appears to activate a hippocampal mechanism that normally only modulates the intensity of rotation.

  11. 7alpha-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system.

    PubMed

    Matsunaga, Masahiro; Ukena, Kazuyoshi; Baulieu, Etienne-Emile; Tsutsui, Kazuyoshi

    2004-12-07

    It is becoming clear that steroids can be synthesized de novo by the brain and other nervous systems. Such steroids are called neurosteroids, and de novo neurosteroidogenesis from cholesterol is a conserved property of vertebrate brains. In this study, we show that the newt brain actively produces 7alpha-hydroxypregnenolone, a previously undescribed amphibian neurosteroid that stimulates locomotor activity. 7alpha-hydroxypregnenolone was identified as a most abundant amphibian neurosteroid in the newt brain by using biochemical techniques combined with HPLC, TLC, and GC-MS analyses. The production of 7alpha-hydroxypregnenolone in the diencephalon and rhombencephalon was higher than that in the telencephalon and peripheral steroidogenic glands. In addition, 7alpha-hydroxypregnenolone synthesis in the brain showed marked changes during the annual breeding cycle, with a maximal level in the spring breeding period when locomotor activity of the newt increases. Behavioral analysis of newts in the nonbreeding period demonstrated that administration of this previously undescribed amphibian neurosteroid acutely increased locomotor activity. In vitro analysis further revealed that 7alpha-hydroxypregnenolone treatment resulted in a dose-dependent increase in the release of dopamine from cultured brain tissue of nonbreeding newts. The effect of this neurosteroid on locomotion also was abolished by dopamine D(2)-like receptor antagonists. These results indicate that 7alpha-hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts through the dopaminergic system. This study demonstrates a physiological function of 7alpha-hydroxypregnenolone that has not been described previously in any vertebrate class. This study also provides findings on the regulatory mechanism of locomotor activity from a unique standpoint.

  12. Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease.

    PubMed

    Liu, Zhan; Huang, Yan; Cao, Bei-Bei; Qiu, Yi-Hua; Peng, Yu-Ping

    2016-11-14

    T helper (Th)17 cells, a subset of CD4(+) T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP(+))-induced PD models. Blood-brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP(+)-treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

  13. Interleukin-4 Protects Dopaminergic Neurons In vitro but Is Dispensable for MPTP-Induced Neurodegeneration In vivo

    PubMed Central

    Hühner, Laura; Rilka, Jennifer; Gilsbach, Ralf; Zhou, Xiaolai; Machado, Venissa; Spittau, Björn

    2017-01-01

    Microglia are involved in physiological as well as neuropathological processes in the central nervous system (CNS). Their functional states are often referred to as M1-like and M2-like activation, and are believed to contribute to neuroinflammation-mediated neurodegeneration or neuroprotection, respectively. Parkinson’s disease (PD) is one the most common neurodegenerative disease and is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra resulting in bradykinesia, tremor, and rigidity. Interleukin 4 (IL4)-mediated M2-like activation of microglia, which is characterized by upregulation of alternative markers Arginase 1 (Arg1) and Chitinase 3 like 3 (Ym1) has been well studied in vitro but the role of endogenous IL4 during CNS pathologies in vivo is not well understood. Interestingly, microglia activation by IL4 has been described to promote neuroprotective and neurorestorative effects, which might be important to slow the progression of neurodegenerative diseases. In the present study, we addressed the role of endogenous and exogenous IL4 during MPP+-induced degeneration of mDA neurons in vitro and further addressed the impact of IL4-deficiency on neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD in vivo. Our results clearly demonstrate that exogenous IL4 is important to protect mDA neurons in vitro, but endogenous IL4 seems to be dispensable for development and maintenance of the nigrostriatal system as well as MPTP-induced loss of TH+ neurons in vivo. These results underline the importance of IL4 in promoting a neuroprotective microglia activation state and strengthen the therapeutic potential of exogenous IL4 for protection of mDA neurons in PD models. PMID:28337124

  14. Activation of mesolimbic dopaminergic neurons following central administration of histamine is mediated by H1 receptors.

    PubMed

    Fleckenstein, A E; Lookingland, K J; Moore, K E

    1993-01-01

    The effect of intracerebroventricular administration of histamine on the activity of mesolimbic and nigrostriatal dopaminergic (DA) neurons was determined in male rats. The activity of these neurons was estimated by measuring: (1) the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after administration of a decarboxylase inhibitor, and (2) the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens and striatum, which contain the terminals of these neurons. Central administration of histamine increased both DOPA accumulation and DOPAC concentrations in the nucleus accumbens, but was without effect in the striatum. The increase in DOPAC concentrations in the nucleus accumbens occurred within 10 min and was sustained for at least 120 min. The H1 antagonist mepyramine blocked whereas the H2 antagonist zolantidine did not affect histamine-induced increases in DOPAC concentrations in the nucleus accumbens. Neither mepyramine nor zolantidine affected basal DOPAC concentrations in the nucleus accumbens. These results indicate that central administration of histamine stimulates mesolimbic DA neurons through an action at the H1 receptor, but has no effect upon the activity of nigrostriatal DA neurons.

  15. Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats.

    PubMed

    Fujii, Hiromi; Matsubara, Kohki; Sakai, Kiyoshi; Ito, Mikako; Ohno, Kinji; Ueda, Minoru; Yamamoto, Akihito

    2015-07-10

    Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of nigrostriatal dopaminergic (DAergic) neurons and the depletion of striatal dopamine. Here we show that DAergic-neuron-like cells could be efficiently induced from stem cells derived from human exfoliated deciduous teeth (SHEDs), and that these induced cells had therapeutic benefits in a 6-OHDA-induced Parkinsonian rat model. In our protocol, EGF and bFGF signaling activated the SHED's expression of proneural genes, Ngn2 and Mash1, and subsequent treatment with brain-derived neurotrophic factor (BDNF) promoted their maturation into DAergic neuron-like SHEDs (dSHEDs). A hypoxic DAergic differentiation protocol improved cell viability and enhanced the expression of multiple neurotrophic factors, including BDNF, GDNF, NT-3, and HGF. Engrafted dSHEDs survived in the striatum of Parkinsonian rats, improved the DA level more efficiently than engrafted undifferentiated SHEDs, and promoted the recovery from neurological deficits. Our findings further suggested that paracrine effects of dSHEDs contributed to neuroprotection against 6-OHDA-induced neurodegeneration and to nigrostriatal tract restoration. In addition, we found that the conditioned medium derived from dSHEDs protected primary neurons against 6-OHDA toxicity and accelerated neurite outgrowth in vitro. Thus, our data suggest that stem cells derived from dental pulp may have therapeutic benefits for PD. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Alterations of GABAergic and dopaminergic systems in mutant mice with disruption of exons 2 and 3 of the Disc1 gene.

    PubMed

    Nakai, Tsuyoshi; Nagai, Taku; Wang, Rui; Yamada, Shinnosuke; Kuroda, Keisuke; Kaibuchi, Kozo; Yamada, Kiyofumi

    2014-07-01

    Disrupted-in-schizophrenia-1 (DISC1) has been widely associated with several psychiatric disorders, including schizophrenia, mood disorders and autism. We previously reported that a deficiency of DISC1 may induce low anxiety and/or high impulsivity in mice with disruption of exons 2 and 3 of the Disc1 gene (Disc1(Δ2-3/Δ2-3)). It remains unclear, however, if deficiency of DISC1 leads to specific alterations in distinct neuronal systems. In the present study, to understand the role of DISC1 in γ-aminobutyric acid (GABA) interneurons and mesocorticolimbic dopaminergic (DAergic) neurons, we investigated the number of parvalbumin (PV)-positive interneurons, methamphetamine (METH)-induced DA release and the expression levels of GABAA, DA transporter (DAT) and DA receptors in wild-type (Disc1(+/+)) and Disc1(Δ2-3/Δ2-3) mice. Female Disc1(Δ2-3/Δ2-3) mice showed a significant reduction of PV-positive interneurons in the hippocampus, while no apparent changes were observed in mRNA expression levels of GABAA receptor subunits. METH-induced DA release was significantly potentiated in the nucleus accumbens (NAc) of female Disc1(Δ2-3/Δ2-3) mice, although there were no significant differences in the expression levels of DAT. Furthermore, the expression levels of DA receptor mRNA were upregulated in the NAc of female Disc1(Δ2-3/Δ2-3) mice. Male Disc1(Δ2-3/Δ2-3) mice showed no apparent differences in all experiments. DISC1 may play a critical role in gender-specific developmental alteration in GABAergic inhibitory interneurons and DAergic neurons.

  17. Electrophysiological characterization of substantia nigra dopaminergic neurons in partially lesioned rats: effects of subthalamotomy and levodopa treatment.

    PubMed

    Bilbao, Gaizka; Ruiz-Ortega, Jose Angel; Miguens, Natalia; Ulibarri, Isabel; Linazasoro, Gurutz; Gómez-Urquijo, Sonia; Garibi, Jesús; Ugedo, Luisa

    2006-04-21

    Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta is the main histopathological characteristic of Parkinson's disease. We studied the electrophysiological characteristics of the spontaneous activity of substantia nigra pars compacta dopaminergic neurons in rats with a partial, unilateral, 6-hydroxydopamine lesion of the nigrostriatal pathway. In addition, the effects of subthalamotomy and prolonged levodopa treatment on the activity of dopaminergic neurons were investigated. As a result of the lesion ( approximately 50% neuronal loss), the number of spontaneously active neurons was significantly reduced. Basal firing rate, burst firing and responsiveness to intravenously administered apomorphine remained unchanged. In contrast, the variation coefficient, a measure of interspike interval regularity, was significantly increased. Ibotenic acid (10 microg) lesion of the ipsilateral subthalamic nucleus in lesioned rats did not modify the electrophysiological parameters. However, prolonged levodopa treatment (100 mg/kg/day + benserazide 25 mg/kg/day, 14 days) reversed the irregularity observed in cells from lesioned rats, while it induced an irregular firing pattern in cells from intact rats. Our results using an experimental model of moderate Parkinson's disease indicate that surviving substantia nigra pars compacta dopaminergic neurons fire irregularly. In this model, subthalamotomy does not modify the firing pattern while levodopa treatment efficiently restores normal firing of SNpc neurons and does not appear to be toxic to them.

  18. Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior.

    PubMed

    Liu, Jian-Feng; Siemian, Justin N; Seaman, Robert; Zhang, Yanan; Li, Jun-Xu

    2017-01-25

    A novel G-protein coupled receptor, trace amine-associated receptor 1 (TAAR1), has been shown to be a promising target to prevent stimulant relapse. Our recent studies showed that systemic administration of TAAR1 agonists decreased abuse-related behaviors of cocaine. However, the role of TAAR1 in specific subregions of the reward system in drug addiction is unknown. Here, using a local pharmacological activation method, we assessed the role of TAAR1 within the subregions of the mesocorticolimbic system: that is, the VTA, the prelimbic cortex (PrL), and infralimbic cortex of medial prefrontal cortex, the core and shell of NAc, BLA, and CeA, on cue- and drug-induced cocaine-seeking in the rat cocaine reinstatement model. We first showed that TAAR1 mRNA was expressed throughout these brain regions. Rats underwent cocaine self-administration, followed by extinction training. RO5166017 (1.5 or 5.0 μg/side) or vehicle was microinjected into each brain region immediately before cue- and drug-induced reinstatement of cocaine-seeking. The results showed that microinjection of RO5166017 into the VTA and PrL decreased both cue- and drug priming-induced cocaine-seeking. Microinjection of RO5166017 into the NAc core and shell inhibited cue- and drug-induced cocaine-seeking, respectively. Locomotor activity or food reinforced operant responding was unaffected by microinjection of RO5166017 into these brain regions. Cocaine-seeking behaviors were not affected by RO5166017 when microinjected into the substantia nigra, infralimbic cortex, BLA, and CeA. Together, these results indicate that TAAR1 in different subregions of the mesocorticolimbic system distinctly contributes to cue- and drug-induced reinstatement of cocaine-seeking behavior.

  19. Endorphinic neurons are contacting the tuberoinfundibular dopaminergic neurons in the rat brain

    SciTech Connect

    Morel, G.; Pelletier, G.

    1986-11-01

    The anatomical relationships between endorphinic neurons and dopaminergic neurons were evaluated in the rat hypothalamus using a combination of immunocytochemistry and autoradiography. In the arcuate nucleus, endorphinic endings were seen making contacts with dopaminergic cell bodies and dendrites. No synapsis could be observed at the sites of contacts. These results strongly suggest that the endorphinic neurons are directly acting on dopaminergic neurons to modify the release of dopamine into the pituitary portal system.

  20. Dopaminergic function and intertemporal choice

    PubMed Central

    Joutsa, J; Voon, V; Johansson, J; Niemelä, S; Bergman, J; Kaasinen, V

    2015-01-01

    The discounting of delayed rewards, also known as temporal or delay discounting, is intrinsic to everyday decisions and can be impaired in pathological states such as addiction disorders. Preclinical and human studies suggest a role for dopaminergic function in temporal discounting but this relationship has not yet been verified using molecular imaging of the living human brain. Here, we evaluated dopaminergic function in temporal discounting using positron emission tomography (PET) with two different dopaminergic ligands assessing three populations in whom temporal discounting has been shown to be impaired. First, we show using [11C]raclopride PET that in pathological gamblers, greater temporal discounting correlates with decreased ventral striatal binding potential, convergent with translational findings of lower nucleus accumbens D2/D3 receptor density in high-impulsive rodents. Temporal discounting also correlates with lower ventral striatal dopamine release in response to high-reward magnitude suggesting that dopamine-mediated devaluation of larger delayed rewards may drive choice preferences. Second, we show using [18F]fluorodopa PET that in Parkinson's disease, temporal discounting correlates with greater left caudate dopaminergic terminal function. Finally, in subjects with Parkinson's disease and dopamine medication-induced behavioral addictions, temporal discounting is further correlated with greater dopaminergic terminal function in the anterior putamen. These findings provide insights into the relationship between striatal dopamine function and temporal discounting, and its potential role in pathological disorders and mechanisms underlying treatment interventions. PMID:25562841

  1. Using High-Resolution MR Imaging at 7T to Evaluate the Anatomy of the Midbrain Dopaminergic System

    PubMed Central

    Eapen, M.; Zald, D.H.; Gatenby, J.C.; Ding, Z.; Gore, J.C.

    2011-01-01

    BACKGROUND AND PURPOSE Dysfunction of DA neurotransmission from the SN and VTA has been implicated in neuropsychiatric diseases, including Parkinson disease and schizophrenia. Unfortunately, these midbrain DA structures are difficult to define on clinical MR imaging. To more precisely evaluate the anatomic architecture of the DA midbrain, we scanned healthy participants with a 7T MR imaging system. Here we contrast the performance of high-resolution T2- and T2*-weighted GRASE and FFE MR imaging scans at 7T. MATERIALS AND METHODS Ten healthy participants were scanned by using GRASE and FFE sequences. CNRs were calculated among the SN, VTA, and RN, and their volumes were estimated by using a segmentation algorithm. RESULTS Both GRASE and FFE scans revealed visible contrast between midbrain DA regions. The GRASE scan showed higher CNRs compared with the FFE scan. The T2* contrast of the FFE scan further delineated substructures and microvasculature within the midbrain SN and RN. Segmentation and volume estimation of the midbrain SN, RN, and VTA showed individual differences in the size and volume of these structures across participants. CONCLUSIONS Both GRASE and FFE provide sufficient CNR to evaluate the anatomy of the midbrain DA system. The FFE in particular reveals vascular details and substructure information within the midbrain regions that could be useful for examining structural changes in midbrain pathologies. PMID:21183619

  2. Using high-resolution MR imaging at 7T to evaluate the anatomy of the midbrain dopaminergic system.

    PubMed

    Eapen, M; Zald, D H; Gatenby, J C; Ding, Z; Gore, J C

    2011-04-01

    Dysfunction of DA neurotransmission from the SN and VTA has been implicated in neuropsychiatric diseases, including Parkinson disease and schizophrenia. Unfortunately, these midbrain DA structures are difficult to define on clinical MR imaging. To more precisely evaluate the anatomic architecture of the DA midbrain, we scanned healthy participants with a 7T MR imaging system. Here we contrast the performance of high-resolution T2- and T2*-weighted GRASE and FFE MR imaging scans at 7T. Ten healthy participants were scanned by using GRASE and FFE sequences. CNRs were calculated among the SN, VTA, and RN, and their volumes were estimated by using a segmentation algorithm. Both GRASE and FFE scans revealed visible contrast between midbrain DA regions. The GRASE scan showed higher CNRs compared with the FFE scan. The T2* contrast of the FFE scan further delineated substructures and microvasculature within the midbrain SN and RN. Segmentation and volume estimation of the midbrain SN, RN, and VTA showed individual differences in the size and volume of these structures across participants. Both GRASE and FFE provide sufficient CNR to evaluate the anatomy of the midbrain DA system. The FFE in particular reveals vascular details and substructure information within the midbrain regions that could be useful for examining structural changes in midbrain pathologies.

  3. Is the potent 5-HT1A receptor agonist, alnespirone (S-20499), affecting dopaminergic systems in the rat brain?

    PubMed

    Dugast, C; Soulière, F; Schmitt, P; Casanovas, J M; Fattaccini, C M; Mocaër, E; Lesourd, M; Renaud, B; Artigas, F; Hamon, M; Chouvet, G

    1998-06-05

    The effects of the new methoxy-chroman 5-HT1A receptor agonist, alnespirone (S-20499), on the dopamine systems in the rat brain were assessed in vivo by means of electrophysiological and neurochemical techniques. Cumulative doses of alnespirone (0.032-4.1 mg kg(-1), i.v.) did not modify the spontaneous firing rate of dopamine neurons in the substantia nigra as well as in the ventral tegmental area. The local application of alnespirone (0.1-10 microM) by reverse microdialysis into the dorsal striatum did not affect the dopamine output but induced a moderate, although dose-independent, increase of 5-HT (5-hydroxytryptamine, serotonin) concentrations in the dialysate. As expected of a 5-HT1A receptor agonist, intraperitoneal (i.p.) administration of alnespirone at 2-32 mg kg(-1) markedly decreased 5-HT turnover in the striatum. Parallel measurements of dopamine turnover showed that alnespirone exerted no effect except at the highest dose (32 mg kg(-1), i.p.) for which a significant increase was observed. Interestingly, both alnespirone-induced reduction in 5-HT turnover and increase in dopamine turnover could be prevented by pretreatment with the selective 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexa ne carboxamide). Altogether, these data indicate that alnespirone does not exert any direct influence on central dopamine systems. The enhanced dopamine turnover due to alnespirone at high dose appeared to result from 5-HT1A receptor stimulation, further supporting the idea that this receptor type may play a key role in 5-HT-dopamine interactions in brain.

  4. Metabolic Covariant Network in Relation to Nigrostriatal Degeneration in Carbon Monoxide Intoxication-Related Parkinsonism

    PubMed Central

    Chang, Chiung-Chih; Hsu, Jung-Lung; Chang, Wen-Neng; Huang, Shu-Hua; Huang, Chi-Wei; Chang, Ya-Ting; Chen, Nai-Ching; Lui, Chun-Chung; Lee, Chen-Chang; Hsu, Shih-Wei

    2016-01-01

    Presence of parkinsonian features after carbon monoxide (CO) intoxication is well known and the severity was found to relate to the pre-synaptic dopaminergic deficits. There is no systemic study to analyse the functional network involved in CO-related Parkinsonism. Forty-five CO-related parkinsonism patients and 25 aged-matched controls completed the 3D T1-weighted imaging and 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET). Voxel-based morphometry (VBM) was performed to assess the structural and functional brain differences between the patients and controls. Spatial covariant networks responsible for distinguishing patients and controls were constructed using independent component analysis. For validation, the pre-synaptic dopaminergic functional network was established by regression model using striatal TRODAT-1 SPECT as the independent variable. The clinical significance of both networks was determined by correlation with the Unified Parkinson's Disease Rating Scale (UPDRS). Compared with controls, the spatial covariant signals of FDG-PET were significantly lower in the medial and lateral frontal, caudate nucleus, dorsomedial prefrontal areas, and temporal-parietal regions while the spatial intensities correlated significantly with UPDRS total scores. The functional network that correlated with striatum pre-synaptic dopaminergic uptakes included the midbrain, thalamus, caudate, lateral frontal cortex, ventral striatum, ventral, or dorsal anterior cingulate cortex. Both networks overlapped considerably and the topographies reflected structural damage pattern. Our study provides evidence that glucose metabolism in CO-parkinsonism patients pertains to an organized covariant pattern in the cortical regions that is spatially coherent with the cortical map of pre-synaptic dopamine deficits. As the fronto-temporal, striatum, and temporal-parietal areas were involved, the unique metabolic covariant network suggests a different pathophysiology in CO

  5. Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats

    SciTech Connect

    Porrino, L.J.; Domer, F.R.; Crane, A.M.; Sokoloff, L.

    1988-05-01

    The 2-(/sup 14/C)deoxyglucose method was used to examine the effects of acute intravenous administration of cocaine on local cerebral glucose utilization in rats. These effects were correlated with the effects of cocaine on locomotor activity assessed simultaneously in the same animals. At the lowest dose of cocaine, 0.5 mg/kg (1.47 mumol/kg), alterations in glucose utilization were restricted to the medial prefrontal cortex and nucleus accumbens. Metabolic activity at 1.0 mg/kg (2.9 mumol/kg) was altered in these structures, but in the substantia nigra reticulata and lateral habenula as well. The selectivity of cocaine's effects at low doses demonstrates the particular sensitivity of these structures to cocaine's actions in the brain. In contrast, 5.0 mg/kg (14.7 mumol/kg) produced widespread changes in glucose utilization, particularly in the extrapyramidal system. Only this dose significantly increased locomotor activity above levels in vehicle-treated controls. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, and subthalamic nucleus, and negatively correlated in the lateral habenula.

  6. Conditional Expression of Parkinson's Disease-Related R1441C LRRK2 in Midbrain Dopaminergic Neurons of Mice Causes Nuclear Abnormalities without Neurodegeneration

    PubMed Central

    Tsika, Elpida; Kannan, Meghna; Foo, Caroline Shi-Yan; Dikeman, Dustin; Glauser, Liliane; Gellhaar, Sandra; Galter, Dagmar; Knott, Graham W.; Dawson, Ted M.; Dawson, Valina L.; Moore, Darren J.

    2015-01-01

    Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). The clinical and neurochemical features of LRRK2-linked PD are similar to idiopathic disease although neuropathology is somewhat heterogeneous. Dominant mutations in LRRK2 precipitate neurodegeneration through a toxic gain-of-function mechanism which can be modeled in transgenic mice overexpressing human LRRK2 variants. A number of LRRK2 transgenic mouse models have been developed that display abnormalities in dopaminergic neurotransmission and alterations in tau metabolism yet without consistently inducing dopaminergic neurodegeneration. To directly explore the impact of mutant LRRK2 on the nigrostriatal dopaminergic pathway, we developed conditional transgenic mice that selectively express human R1441C LRRK2 in dopaminergic neurons from the endogenous murine ROSA26 promoter. The expression of R1441C LRRK2 does not induce the degeneration of substantia nigra dopaminergic neurons or striatal dopamine deficits in mice up to 2 years of age, and fails to precipitate abnormal protein inclusions containing alpha-synuclein, tau, ubiquitin or autophagy markers (LC3 and p62). Furthermore, mice expressing R1441C LRRK2 exhibit normal motor activity and olfactory function with increasing age. Intriguingly, the expression of R1441C LRRK2 induces age-dependent abnormalities of the nuclear envelope in nigral dopaminergic neurons including reduced nuclear circularity and increased invaginations of the nuclear envelope. In addition, R1441C LRRK2 mice display increased neurite complexity of cultured midbrain dopaminergic neurons. Collectively, these novel R1441C LRRK2 conditional transgenic mice reveal altered dopaminergic neuronal morphology with advancing age, and provide a useful tool for exploring the pathogenic mechanisms underlying the R1441C LRRK2 mutation in PD. PMID:25174890

  7. Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease

    PubMed Central

    Good, Cameron H.; Hoffman, Alexander F.; Hoffer, Barry J.; Chefer, Vladimir I.; Shippenberg, Toni S.; Bäckman, Cristina M.; Larsson, Nils-Göran; Olson, Lars; Gellhaar, Sandra; Galter, Dagmar; Lupica, Carl R.

    2011-01-01

    Parkinson's disease (PD) involves progressive loss of nigrostriatal dopamine (DA) neurons over an extended period of time. Mitochondrial damage may lead to PD, and neurotoxins affecting mitochondria are widely used to produce degeneration of the nigrostriatal circuitry. Deletion of the mitochondrial transcription factor A gene (Tfam) in C57BL6 mouse DA neurons leads to a slowly progressing parkinsonian phenotype in which motor impairment is first observed at ∼12 wk of age. l-DOPA treatment improves motor dysfunction in these “MitoPark” mice, but this declines when DA neuron loss is more complete. To investigate early neurobiological events potentially contributing to PD, we compared the neurochemical and electrophysiological properties of the nigrostriatal circuit in behaviorally asymptomatic 6- to 8-wk-old MitoPark mice and age-matched control littermates. Release, but not uptake of DA, was impaired in MitoPark mouse striatal brain slices, and nigral DA neurons lacked characteristic pacemaker activity compared with control mice. Also, hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel function was reduced in MitoPark DA neurons, although HCN messenger RNA was unchanged. This study demonstrates altered nigrostriatal function that precedes behavioral parkinsonian symptoms in this genetic PD model. A full understanding of these presymptomatic cellular properties may lead to more effective early treatments of PD.—Good, C. H., Hoffman, A. F., Hoffer, B. J., Chefer, V. I., Shippenberg, T. S., Bäckman, C. M., Larsson, N.-G., Olson, L., Gellhaar, S., Galter, D., Lupica, C. R. Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease. PMID:21233488

  8. Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation.

    PubMed

    Liu, Jie; Huang, Dongping; Xu, Jing; Tong, Jiabin; Wang, Zishan; Huang, Li; Yang, Yufang; Bai, Xiaochen; Wang, Pan; Suo, Haiyun; Ma, Yuanyuan; Yu, Mei; Fei, Jian; Huang, Fang

    2015-10-26

    Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative disorders such as Parkinson's disease (PD). γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has recently been shown to play an inhibitory role in the immune system. Tiagabine, a piperidine derivative, enhances GABAergic transmission by inhibiting GABA transporter 1 (GAT 1). In the present study, we found that tiagabine pretreatment attenuated microglial activation, provided partial protection to the nigrostriatal axis and improved motor deficits in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The protective function of tiagabine was abolished in GAT 1 knockout mice that were challenged with MPTP. In an alternative PD model, induced by intranigral infusion of lipopolysaccharide (LPS), microglial suppression and subsequent neuroprotective effects of tiagabine were demonstrated. Furthermore, the LPS-induced inflammatory activation of BV-2 microglial cells and the toxicity of conditioned medium toward SH-SY5Y cells were inhibited by pretreatment with GABAergic drugs. The attenuation of the nuclear translocation of nuclear factor κB (NF-κB) and the inhibition of the generation of inflammatory mediators were the underlying mechanisms. Our results suggest that tiagabine acts as a brake for nigrostriatal microglial activation and that it might be a novel therapeutic approach for PD.

  9. Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation

    PubMed Central

    Liu, Jie; Huang, Dongping; Xu, Jing; Tong, Jiabin; Wang, Zishan; Huang, Li; Yang, Yufang; Bai, Xiaochen; Wang, Pan; Suo, Haiyun; Ma, Yuanyuan; Yu, Mei; Fei, Jian; Huang, Fang

    2015-01-01

    Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative disorders such as Parkinson’s disease (PD). γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has recently been shown to play an inhibitory role in the immune system. Tiagabine, a piperidine derivative, enhances GABAergic transmission by inhibiting GABA transporter 1 (GAT 1). In the present study, we found that tiagabine pretreatment attenuated microglial activation, provided partial protection to the nigrostriatal axis and improved motor deficits in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The protective function of tiagabine was abolished in GAT 1 knockout mice that were challenged with MPTP. In an alternative PD model, induced by intranigral infusion of lipopolysaccharide (LPS), microglial suppression and subsequent neuroprotective effects of tiagabine were demonstrated. Furthermore, the LPS-induced inflammatory activation of BV-2 microglial cells and the toxicity of conditioned medium toward SH-SY5Y cells were inhibited by pretreatment with GABAergic drugs. The attenuation of the nuclear translocation of nuclear factor κB (NF-κB) and the inhibition of the generation of inflammatory mediators were the underlying mechanisms. Our results suggest that tiagabine acts as a brake for nigrostriatal microglial activation and that it might be a novel therapeutic approach for PD. PMID:26499517

  10. Involvement of serotonergic, noradrenergic and dopaminergic systems in the antidepressant-like effect of ginsenoside Rb1, a major active ingredient of Panax ginseng C.A. Meyer.

    PubMed

    Wang, Guo-Li; He, Zhong-Mei; Zhu, Hong-Yan; Gao, Yu-Gang; Zhao, Yan; Yang, He; Zhang, Lian-Xue

    2017-05-23

    mechanisms mainly mediated by central neurotransmitters of serotonergic, noradrenergic and dopaminergic systems. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  11. Involvement of dopaminergic and cholinergic systems in social isolation-induced deficits in social affiliation and conditional fear memory in mice.

    PubMed

    Okada, R; Fujiwara, H; Mizuki, D; Araki, R; Yabe, T; Matsumoto, K

    2015-07-23

    , when analyzed 30 min after the administration of the test drugs, tacrine significantly attenuated the SI-induced decrease in p-CaMKII, p-CREB, and Egr-1 in a manner reversible by scopolamine. Our results suggest that SI-induced deficits in social affiliation and conditioned fear memory were mediated by functional alterations to central dopaminergic and cholinergic systems, respectively.

  12. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

    PubMed Central

    Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan; Neal, Matthew L; Jin, Huajun; Anantharam, Vellareddy; Joseph, Joy; Brenza, Timothy; Narasimhan, Balaji; Kanthasamy, Arthi; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G.

    2016-01-01

    Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP+)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP+-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in

  13. Genetic control of midbrain dopaminergic neuron development.

    PubMed

    Blaess, Sandra; Ang, Siew-Lan

    2015-01-01

    Midbrain dopaminergic neurons are involved in regulating motor control, reward behavior, and cognition. Degeneration or dysfunction of midbrain dopaminergic neurons is implicated in several neuropsychiatric disorders such as Parkinson's disease, substance use disorders, depression, and schizophrenia. Understanding the developmental processes that generate midbrain dopaminergic neurons will facilitate the generation of dopaminergic neurons from stem cells for cell replacement therapies to substitute degenerating cells in Parkinson's disease patients and will forward our understanding on how functional diversity of dopaminergic neurons in the adult brain is established. Midbrain dopaminergic neurons develop in a multistep process. Following the induction of the ventral midbrain, a distinct dopaminergic progenitor domain is specified and dopaminergic progenitors undergo proliferation, neurogenesis, and differentiation. Subsequently, midbrain dopaminergic neurons acquire a mature dopaminergic phenotype, migrate to their final position and establish projections and connections to their forebrain targets. This review will discuss insights gained on the signaling network of secreted molecules, cell surface receptors, and transcription factors that regulate specification and differentiation of midbrain dopaminergic progenitors and neurons, from the induction of the ventral midbrain to the migration of dopaminergic neurons. For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article. © 2015 Medical Research Council.

  14. Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson's disease models.

    PubMed

    Bao, Xiu-Qi; Kong, Xiang-Chen; Kong, Li-Bing; Wu, Liang-Yu; Sun, Hua; Zhang, Dan

    2014-02-14

    Parkinson's disease (PD) is a neurodegenerative disease affecting up to 80% of dopaminergic neurons in the nigrostriatal pathway. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental PD models. In this study, we carried out a set of in vitro and in vivo experiments to address the neuroprotective effect of FLZ and related mechanism. The results showed that FLZ significantly improved motor dysfunction and dopaminergic neuronal loss of rats injured by 6-hydroxydopamine (6-OHDA). The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level and tyrosine hydroxylase (TH) activity. Mechanistic study showed that FLZ protected TH activity and dopaminergic neurons through decreasing α-synuclein (α-Syn) expression and the interaction between α-Syn and TH. Further studies indicated the involvement of phosphoinositide 3-kinases (PI3K)/Akt signaling pathway in the protective effect of FLZ since it showed that blocking PI3K/Akt signaling pathway prevented the expression of α-Syn and attenuated the neuroprotection of FLZ. In addition, FLZ treatment reduced the expression of RTP801, an important protein involved in the pathogenesis of PD. Taken together, these results revealed that FLZ suppressed α-Syn expression and elevated TH activity in dopaminergic neuron through activating Akt survival pathway in 6-OHDA-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising agent for PD treatment.

  15. Sequential Loss of LC Noradrenergic and Dopaminergic Neurons Results in a Correlation of Dopaminergic Neuronal Number to Striatal Dopamine Concentration.

    PubMed

    Szot, Patricia; Franklin, Allyn; Sikkema, Carl; Wilkinson, Charles W; Raskind, Murray A

    2012-01-01

    Noradrenergic neurons in the locus coeruleus (LC) are significantly reduced in Parkinson's disease (PD) and the LC exhibits neuropathological changes early in the disease process. It has been suggested that a loss of LC neurons can enhance the susceptibility of dopaminergic neurons to damage. To determine if LC noradrenergic innervation protects dopaminergic neurons from damage, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered to adult male C57Bl/6 mice 3 days after bilateral LC administration of 6-hydroxydopamine (6OHDA), a time when there is a significant reduction in LC neuronal number and innervation to forebrain regions. To assess if LC loss can affect dopaminergic loss four groups of animals were studied: control, 6OHDA, MPTP, and 6OHDA + MPTP; animals sacrificed 3 weeks after MPTP administration. The number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and noradrenergic neurons in the LC were determined. Catecholamine levels in striatum were measured by high-pressure liquid chromatography. The loss of LC neurons did not affect the number of dopaminergic neurons in the SN and VTA compared to control; however, LC 6OHDA significantly reduced striatal dopamine (DA; 29% reduced) but not norepinephrine (NE) concentration. MPTP significantly reduced SN and VTA neuronal number and DA concentration in the striatum compared to control; however, there was not a correlation of striatal DA concentration with SN or VTA neuronal number. Administration of 6OHDA prior to MPTP did not enhance MPTP-induced damage despite an effect of LC loss on striatal DA concentration. However, the loss of LC neurons before MPTP resulted now in a correlation between SN and VTA neuronal number to striatal DA concentration. These results demonstrate that the loss of either LC or DA neurons can affect the function of each others systems, indicating the importance of both the noradrenergic and

  16. Sequential Loss of LC Noradrenergic and Dopaminergic Neurons Results in a Correlation of Dopaminergic Neuronal Number to Striatal Dopamine Concentration

    PubMed Central

    Szot, Patricia; Franklin, Allyn; Sikkema, Carl; Wilkinson, Charles W.; Raskind, Murray A.

    2012-01-01

    Noradrenergic neurons in the locus coeruleus (LC) are significantly reduced in Parkinson’s disease (PD) and the LC exhibits neuropathological changes early in the disease process. It has been suggested that a loss of LC neurons can enhance the susceptibility of dopaminergic neurons to damage. To determine if LC noradrenergic innervation protects dopaminergic neurons from damage, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered to adult male C57Bl/6 mice 3 days after bilateral LC administration of 6-hydroxydopamine (6OHDA), a time when there is a significant reduction in LC neuronal number and innervation to forebrain regions. To assess if LC loss can affect dopaminergic loss four groups of animals were studied: control, 6OHDA, MPTP, and 6OHDA + MPTP; animals sacrificed 3 weeks after MPTP administration. The number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and noradrenergic neurons in the LC were determined. Catecholamine levels in striatum were measured by high-pressure liquid chromatography. The loss of LC neurons did not affect the number of dopaminergic neurons in the SN and VTA compared to control; however, LC 6OHDA significantly reduced striatal dopamine (DA; 29% reduced) but not norepinephrine (NE) concentration. MPTP significantly reduced SN and VTA neuronal number and DA concentration in the striatum compared to control; however, there was not a correlation of striatal DA concentration with SN or VTA neuronal number. Administration of 6OHDA prior to MPTP did not enhance MPTP-induced damage despite an effect of LC loss on striatal DA concentration. However, the loss of LC neurons before MPTP resulted now in a correlation between SN and VTA neuronal number to striatal DA concentration. These results demonstrate that the loss of either LC or DA neurons can affect the function of each others systems, indicating the importance of both the noradrenergic and

  17. Characterization of the dopamine system in the brain of the túngara frog, Physalaemus pustulosus.

    PubMed

    O'Connell, Lauren A; Matthews, Bryan J; Ryan, Michael J; Hofmann, Hans A

    2010-01-01

    Dopamine is an evolutionarily ancient neurotransmitter that plays an essential role in mediating behavior. In vertebrates, dopamine is central to the mesolimbic reward system, a neural network concerned with the valuation of stimulus salience, and to the nigrostriatal motor system and hypothalamic nuclei involved in the regulation of locomotion and social behavior. In amphibians, dopaminergic neurons have been mapped out in several species, yet the distribution of dopaminoreceptive cells is unknown. The túngara frog, Physalaemus pustulosus, is an excellent model system for the study of neural mechanisms by which valuations of stimuli salience and social decisions are made, especially in the context of mate choice. In order to better understand where dopamine acts to regulate social decisions in this species, we have determined the distribution of putative dopaminergic cells (using tyrosine hydroxylase immunohistochemistry) and cells receptive to dopaminergic signaling (using DARPP-32 immunohistochemistry) throughout the brain of P. pustulosus. The distribution of dopaminergic cells was comparable to other anurans. DARPP-32 immunoreactivity was identified in key brain regions known to modulate social behavior in other vertebrates including the proposed anuran homologues of the mammalian amygdalar complex, nucleus accumbens, hippocampus, striatum, preoptic area, anterior hypothalamus, ventromedial hypothalamus, and ventral tegmental area/substantia nigra pars compacta. Due to its widespread distribution, DARPP-32 likely also plays many roles in non-limbic brain regions that mediate non-social information processing. These results significantly extend our understanding of the distribution of the dopaminergic system in the anuran brain and beyond. Copyright © 2010 S. Karger AG, Basel.

  18. beta-Naphthoflavone and benzo(a)pyrene alter dopaminergic, noradrenergic, and serotonergic systems in brain and pituitary of rainbow trout (Oncorhynchus mykiss).

    PubMed

    Gesto, Manuel; Tintos, Adrián; Soengas, José L; Míguez, Jesús M

    2009-01-01

    In the present study we evaluate for the first time the potential of the flavonoid compound beta-naphthoflavone (BNF) and the high molecular weight- Polycyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (BaP) to alter brain neurotransmitter metabolism in fish. Fish of three different groups were intraperitoneally (i.p.) injected (2 microl g(-1)) with vegetable oil alone (control) or containing BNF or BaP (10 mg kg(-1)) and sacrificed 3, 24, and 72 h after treatment. Contents of dopamine (DA), noradrenaline (NA) and serotonin (5HT), as well as the amine oxidative metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole-3-acetic acid (5HIAA) were assayed in telencephalon, hypothalamus, preoptic region, optic tectum, and brain stem, as well as the pituitary. Fish treated with PAHs showed after 3h decreases in 5HT content in telencephalon, hypothalamus, preoptic region (with both BNF and BaP), and pituitary (with BaP), resulting in increased 5HIAA/5HT ratio. An increased ratio was also observed in hypothalamus 24h after BaP, and in preoptic region 72 h after BNF, in both cases due to an increased 5HIAA content. In other brain regions PAHs effects on 5-HT metabolism were less consistent. With respect to the dopaminergic system, changes induced by PAHs mainly occurred after 24 and 72 h of treatment, with increased DOPAC/DA ratio in preoptic region and brain stem. In hypothalamus, tectum, and pituitary, changes in DA metabolism showed strong variability. Finally, a decreased content of NA was evident in preoptic region (3h) and in telencephalon (24h) after both BNF and BaP treatments. Therefore, both BNF and BaP seem to act in rainbow trout brain by impairing 5HT availability at short term (3h) and increasing neuronal metabolic utilization of both 5HT and DA after 24 and 72 h. Data collected in the present study suggest that brain monoamine neurotransmitters are potential targets of BNF and BaP, and their alteration could have a role in known effects of PAHs

  19. Regeneration of dopaminergic neurons after 6-hydroxydopamine-induced lesion in planarian brain.

    PubMed

    Nishimura, Kaneyasu; Inoue, Takeshi; Yoshimoto, Kanji; Taniguchi, Takashi; Kitamura, Yoshihisa; Agata, Kiyokazu

    2011-12-01

    Planarians have robust regenerative ability dependent on X-ray-sensitive pluripotent stem cells, called neoblasts. Here, we report that planarians can regenerate dopaminergic neurons after selective degeneration of these neurons caused by treatment with a dopaminergic neurotoxin (6-hydroxydopamine; 6-OHDA). This suggests that planarians have a system to sense the degeneration of dopaminergic neurons and to recruit stem cells to produce dopaminergic neurons to recover brain morphology and function. We confirmed that X-ray-irradiated planarians do not regenerate brain dopaminergic neurons after 6-OHDA-induced lesioning, suggesting that newly generated dopaminergic neurons are indeed derived from pluripotent stem cells. However, we found that the majority of regenerated dopaminergic neurons were 5-bromo-2'-deoxyuridine-negative cells. Therefore, we carefully analyzed when proliferating stem cells became committed to become dopaminergic neurons during regeneration by a combination of 5-bromo-2'-deoxyuridine pulse-chase experiments, immunostaining/in situ hybridization, and 5-fluorouracil treatment. The results strongly suggested that G(2) -phase stem cells become committed to dopaminergic neurons in the mesenchymal space around the brain, after migration from the trunk region following S-phase. These new findings obtained from planarian regeneration provide hints about how to conduct cell-transplantation therapy for future regenerative medicine. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  20. Nigrostriatal lesion induces D2-modulated phase-locked activity in the basal ganglia of rats.

    PubMed

    Zold, Camila L; Ballion, Bérangère; Riquelme, Luis A; Gonon, François; Murer, M Gustavo

    2007-04-01

    There is a debate as to what modifications of neuronal activity underlie the clinical manifestations of Parkinson's disease and the efficacy of antiparkinsonian pharmacotherapy. Previous studies suggest that release of GABAergic striatopallidal neurons from D2 receptor-mediated inhibition allows spreading of cortical rhythms to the globus pallidus (GP) in rats with 6-hydroxydopamine-induced nigrostriatal lesions. Here this abnormal spreading was thoroughly investigated. In control urethane-anaesthetized rats most GP neurons were excited during the active part of cortical slow waves ('direct-phase' neurons). Two neuronal populations having opposite phase relationships with cortical and striatal activity coexisted in the GP of 6-hydroxydopamine-lesioned rats. 'Inverse-phase' GP units exhibited reduced firing coupled to striatal activation during slow waves, suggesting that this GP oscillation was driven by striatopallidal hyperactivity. Half of the pallidonigral neurons identified by antidromic stimulation exhibited inverse-phase activity. Therefore, spreading of inverse-phase oscillations through pallidonigral axons might contribute to the abnormal direct-phase cortical entrainment of basal ganglia output described previously. Systemic administration of the D2 agonist quinpirole to 6-hydroxydopamine-lesioned rats reduced GP inverse-phase coupling with slow waves, and this effect was reversed by the D2 antagonist eticlopride. Because striatopallidal hyperactivity was only slightly reduced by quinpirole, other mechanisms might have contributed to the effect of quinpirole on GP oscillations. These results suggest that antiparkinsonian efficacy may rely on other actions of D2 agonists on basal ganglia activity. However, abnormal slow rhythms may promote enduring changes in functional connectivity along the striatopallidal axis, contributing to D2 agonist-resistant clinical signs of parkinsonism.

  1. NADPH Oxidase and the Degeneration of Dopaminergic Neurons in Parkinsonian Mice

    PubMed Central

    Hernandes, Marina S.; Café-Mendes, Cecília C.; Britto, Luiz R. G.

    2013-01-01

    Several lines of investigation have implicated oxidative stress in Parkinson's disease (PD) pathogenesis, but the mechanisms involved are still unclear. In this study, we characterized the involvement of NADPH oxidase (Nox), a multisubunit enzyme that catalyzes the reduction of oxygen, in the 6-hydroxydopamine- (6-OHDA-) induced PD mice model and compared for the first time the effects of this neurotoxin in mice lacking gp91phox−/−, the catalytic subunit of Nox2, and pharmacological inhibition of Nox with apocynin. Six-OHDA induced increased protein expression of p47phox, a Nox subunit, in striatum. gp91phox−/− mice appear to be completely protected from dopaminergic cell loss, whereas the apocynin treatment conferred only a limited neuroprotection. Wt mice treated with apocynin and gp91phox−/− mice both exhibited ameliorated apomorphine-induced rotational behavior. The microglial activation observed within the striatum and the substantia nigra pars compacta (SNpc) of 6-OHDA-injected Wt mice was prevented by apocynin treatment and was not detected in gp91phox−/− mice. Apocynin was not able to attenuate astrocyte activation in SN. The results support a role for Nox2 in the 6-OHDA-induced degeneration of dopaminergic neurons and glial cell activation in the nigrostriatal pathway and reveal that no comparable 6-OHDA effects were observed between apocynin-treated and gp91phox−/− mice groups. PMID:24379900

  2. Nigro-caudate dopaminergic deafferentation: a marker of REM sleep behavior disorder?

    PubMed

    Arnaldi, Dario; De Carli, Fabrizio; Picco, Agnese; Ferrara, Michela; Accardo, Jennifer; Bossert, Irene; Famà, Francesco; Girtler, Nicola; Morbelli, Silvia; Sambuceti, Gianmario; Nobili, Flavio

    2015-12-01

    Forty-nine consecutive, drug naïve outpatients with de novo Parkinson's disease (PD) and 12 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) underwent clinical examination and dopamine transporter single photon emission computed tomography with [(123)I]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane as a biomarker of nigro-striatal function. PD patients were grouped into rapid eye movement sleep behavior disorder (RBD) negative (PD-RBD-) and RBD positive (PD-RBD+). Repeated measures and univariate analysis of variance were used to compare dopaminergic and clinical impairment among groups. The variations of dopamine transporter-single photon emission computed tomography specific binding ratios (SBR) as a function of group belonging were significantly different (p = 0.0013) at caudate with respect to putamen level. Indeed, putamen SBR progressively decreased from iRBD to PD-RBD- and PD-RBD+ groups while caudate SBR were higher in PD-RBD- group than in PD-RBD+ and even than in iRBD group. Motor impairment was more severe in PD patients with RBD than in those without RBD. Our data suggest that a more severe nigro-caudate dopaminergic deafferentation is related to RBD, both in its idiopathic form and in PD patients.

  3. NADPH oxidase and the degeneration of dopaminergic neurons in parkinsonian mice.

    PubMed

    Hernandes, Marina S; Café-Mendes, Cecília C; Britto, Luiz R G

    2013-01-01

    Several lines of investigation have implicated oxidative stress in Parkinson's disease (PD) pathogenesis, but the mechanisms involved are still unclear. In this study, we characterized the involvement of NADPH oxidase (Nox), a multisubunit enzyme that catalyzes the reduction of oxygen, in the 6-hydroxydopamine- (6-OHDA-) induced PD mice model and compared for the first time the effects of this neurotoxin in mice lacking gp91(phox-/-), the catalytic subunit of Nox2, and pharmacological inhibition of Nox with apocynin. Six-OHDA induced increased protein expression of p47(phox), a Nox subunit, in striatum. gp91(phox-/-) mice appear to be completely protected from dopaminergic cell loss, whereas the apocynin treatment conferred only a limited neuroprotection. Wt mice treated with apocynin and gp91(phox-/-) mice both exhibited ameliorated apomorphine-induced rotational behavior. The microglial activation observed within the striatum and the substantia nigra pars compacta (SNpc) of 6-OHDA-injected Wt mice was prevented by apocynin treatment and was not detected in gp91(phox-/-) mice. Apocynin was not able to attenuate astrocyte activation in SN. The results support a role for Nox2 in the 6-OHDA-induced degeneration of dopaminergic neurons and glial cell activation in the nigrostriatal pathway and reveal that no comparable 6-OHDA effects were observed between apocynin-treated and gp91(phox-/-) mice groups.

  4. Protective effects of cholecystokinin-8 on methamphetamine-induced behavioral changes and dopaminergic neurodegeneration in mice.

    PubMed

    Gou, Hongyan; Wen, Di; Ma, Chunling; Li, Ming; Li, Yingmin; Zhang, Wenfang; Liu, Li; Cong, Bin

    2015-04-15

    We investigated whether pretreatment with the neuropeptide cholecystokinin-8 affected methamphetamine (METH)-induced behavioral changes and dopaminergic neurodegeneration in male C57/BL6 mice. CCK-8 pretreatment alone had no effect on locomotion and stereotypic behavior and could not induce behavioral sensitization; however, it attenuated, in a dose-dependent manner, hyperlocomotion and behavioral sensitization induced by a low dose of METH (1mg/kg). CCK-8 attenuated METH-induced stereotypic behavior at a dose of 3mg/kg but not at 10mg/kg. CCK-8 pretreatment attenuated METH (10mg/kg)-induced hyperthermia, the decrease of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum, and TH in the substantia nigra. CCK-8 alone had no effect on rectal temperature, TH and DAT expression in the nigrostriatal region. In conclusion, our study demonstrated that pretreatment with CCK-8 inhibited changes typically induced by repeated exposure to METH, such as hyperlocomotion, behavioral sensitization, stereotypic behavior, and dopaminergic neurotoxicity. These findings make CCK-8 a potential therapeutic agent for the treatment of multiple symptoms associated with METH abuse.

  5. α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage

    PubMed Central

    Bordia, Tanuja; Perez, Xiomara A.; McIntosh, J. Michael; Decker, Michael W.; Quik, Maryka

    2015-01-01

    Background ABT-126 is a novel, safe and well-tolerated α7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. Here we test the antidyskinetic effect of ABT-126 in MPTP-treated squirrel monkeys with moderate and more severe nigrostriatal damage. Methods Monkeys (n=21, Set 1) were lesioned with MPTP 1-2×. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n=5), or treated with vehicle (n=6) or ABT-126 (n=10) twice daily orally 30 min before levodopa. Set 1 was then re-lesioned 1-2 times for a total of 3-4 MPTP injections. The antidyskinetic effect of ABT-126, nicotine and the β2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n=23, Set 2) was lesioned with MPTP only 1-2×. They were treated with levodopa/carbidopa, administered the α7 agonist ABT-107 (n=6), ABT-894 (n=6), nicotine (n=5) or vehicle (n=6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured. Results With moderate nigrostriatal damage (MPTP 1-2×), ABT-126 dose-dependently decreased dyskinesias (~60%), with similar results with ABT-894 (~60%) or nicotine (~60%). With more severe damage (MPTP 3-4×), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism. Conclusion The novel α7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early and later stage Parkinson's disease. PMID:26573698

  6. Wnt5a Regulates Midbrain Dopaminergic Axon Growth and Guidance

    PubMed Central

    Blakely, Brette D.; Bye, Christopher R.; Fernando, Chathurini V.; Horne, Malcolm K.; Macheda, Maria L.; Stacker, Steven A.; Arenas, Ernest; Parish, Clare L.

    2011-01-01

    During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway). Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a−/− mice, where fasciculation of the medial forebrain bundle (MFB) as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance. PMID:21483795

  7. Antiallodynic Activity of Ceftriaxone and Clavulanic Acid in Acute Administration is Associated with Serum TNF-α Modulation and Activation of Dopaminergic and Opioidergic Systems.

    PubMed

    Ochoa-Aguilar, A; Sotomayor-Sobrino, M A; Jaimez, R; Rodríguez, R; Plancarte-Sánchez, R; Ventura-Martinez, R

    2017-03-26

    Preclinical Research The aim of this study was to determine the antiallodynic effect of acute administration of the β-lactam antimicrobials, ceftriaxone (CFX) and clavulanic acid (CLAV), for the control of established pain on a model of neuropathic pain (NP). We also investigated the involvement of dopaminergic and opioidergic pathways as well as alterations in serum concentrations of TNF-α in the antiallodynic actions of these drugs. CFX, CLAV, or gabapentin (GAP), a reference drug, were administered i.p. twelve days after constriction of the sciatic nerve in rats. Mechanic and cold allodynia were evaluated for 3 h and alterations in serum concentration of TNF-α determined. Both CFX and CLAV had antiallodynic effects in response to mechanical and cold stimulation, similar to GAP. The antiallodynic effects of CFX and CLAV were blocked by haloperidol (HAL), a D2 receptor antagonist, and by naloxone (NLX), an opioid receptor antagonist. Additionally, serum TNF-α levels were attenuated following CFX and CLAV administration. These results suggest that acute administration of CFX and CLAV may represent a promising approach for treating the acute allodynia of NP, and that the mechanisms involved in these effects involve activation of dopaminergic and opioidergic pathways as well as modulation of TNF-α production. Drug Dev Res, 2017. © 2017 Wiley Periodicals, Inc.

  8. The role of the dopaminergic system in mood, motivation and cognition in Parkinson's disease: a double blind randomized placebo-controlled experimental challenge with pramipexole and methylphenidate.

    PubMed

    Drijgers, Rosa L; Verhey, Frans R J; Tissingh, Gerrit; van Domburg, Peter H M F; Aalten, Pauline; Leentjens, Albert F G

    2012-09-15

    In Parkinson's disease (PD) reduced dopaminergic activity in the mesocorticolimbic pathway is implied in the pathophysiology of several non-motor symptoms related to mood, motivation and cognition. Insight in the pathophysiology of these syndromes may pave the way for more rational treatments. In a double-blind, randomized, placebo controlled, crossover design with three arms, we studied the effects of a direct dopaminergic challenge with the dopamine 2 receptor agonist pramipexole, an indirect challenge with the dopamine reuptake inhibitor methylphenidate, and placebo on measures of mood, motivation and cognition in 23 agonist-naïve PD patients and 23 healthy controls. Acute challenge with pramipexole had a negative effect on mood and fatigue in both patients and controls. In addition, challenge with pramipexole led to increased anger, fatigue, vigor and tension in healthy control subjects, but not in PD patients. Challenge with methylphenidate had a positive effect on anhedonia and vigor in PD patients. Due to its side effects after a single administration, pramipexole is probably less suitable for acute challenge studies. The acute effects of a methylphenidate challenge on anhedonia and vigor in PD patients make this drug an interesting choice for further studies of the treatment of mood and motivational disorders in this population.

  9. Anterograde transport of horseradish peroxidase in the nigrostriatal pathway after neostriatal kainic acid lesions.

    PubMed

    Walker, P D; McAllister, J P

    1986-08-01

    We used the anterograde transport of HRP to analyze the nigrostriatal pathway after intrastriatal injections of kainic acid. A total volume of 1 microliter kainic acid (3 nM) was injected unilaterally into the neostriatum of adult rats. After 5, 10, or 35 days, HRP was injected into the ipsilateral substantia nigra. Sections stained for Nissl substance revealed that kainic acid damaged as much as three-quarters of the neostriatum. Lesion sites were characterized by gliosis and the absence of neurons. Alternate sections processed for HRP histochemistry and analyzed with bright- and dark-field microscopy revealed labeled axons and terminals in the lesion site. These findings were consistent in all three time periods. Much of the labeling was similar to that seen in neostriatal of control animals. However, the normal homogeneous pattern of the nigrostriatal terminal field was disrupted in all experimental groups, illustrated by changes in some labeling characteristics in the lesion site. These findings provide morphologic evidence for the preservation of much of the nigrostriatal pathway but indicate that some axons and their terminals may be altered after kainic acid injection.

  10. Dopaminergic Contributions to Vocal Learning

    PubMed Central

    Hoffmann, Lukas A.; Saravanan, Varun; Wood, Alynda N.; He, Li

    2016-01-01

    Although the brain relies on auditory information to calibrate vocal behavior, the neural substrates of vocal learning remain unclear. Here we demonstrate that lesions of the dopaminergic inputs to a basal ganglia nucleus in a songbird species (Bengalese finches, Lonchura striata var. domestica) greatly reduced the magnitude of vocal learning driven by disruptive auditory feedback in a negative reinforcement task. These lesions produced no measureable effects on the quality of vocal performance or the amount of song produced. Our results suggest that dopaminergic inputs to the basal ganglia selectively mediate reinforcement-driven vocal plasticity. In contrast, dopaminergic lesions produced no measurable effects on the birds' ability to restore song acoustics to baseline following the cessation of reinforcement training, suggesting that different forms of vocal plasticity may use different neural mechanisms. SIGNIFICANCE STATEMENT During skill learning, the brain relies on sensory feedback to improve motor performance. However, the neural basis of sensorimotor learning is poorly understood. Here, we investigate the role of the neurotransmitter dopamine in regulating vocal learning in the Bengalese finch, a songbird with an extremely precise singing behavior that can nevertheless be reshaped dramatically by auditory feedback. Our findings show that reduction of dopamine inputs to a region of the songbird basal ganglia greatly impairs vocal learning but has no detectable effect on vocal performance. These results suggest a specific role for dopamine in regulating vocal plasticity. PMID:26888928

  11. Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: a self-perpetuating crosstalk?

    PubMed

    Vairetti, Mariapia; Ferrigno, Andrea; Rizzo, Vittoria; Ambrosi, Giulia; Bianchi, Alberto; Richelmi, Plinio; Blandini, Fabio; Armentero, Marie-Therese

    2012-02-01

    In Parkinson's disease (PD), aside from the central lesion, involvement of visceral organs has been proposed as part of the complex clinical picture of the disease. The issue is still poorly understood and relatively unexplored. In this study we used a classic rodent model of nigrostriatal degeneration, induced by the intrastriatal injection of 6-hydroxydopamine (6-OHDA), to investigate whether and how a PD-like central dopaminergic denervation may influence hepatic functions. Rats received an intrastriatal injection of 6-OHDA or saline (sham), and blood, cerebrospinal fluid, liver and brain samples were obtained for up to 8 weeks after surgery. Specimens were analyzed for changes in cytokine and thyroid hormone levels, as well as liver mitochondrial alterations. Hepatic mitochondria isolated from animals bearing extended nigrostriatal lesion displayed increased ROS production, while membrane potential (ΔΨ) and ATP production were significantly decreased. Reduced ATP production correlated with nigral neuronal loss. Thyroid hormone levels were significantly increased in serum of PD rats compared to sham animals while steady expression of selected cytokines was detected in all groups. Hepatic enzyme functions were comparable in all animals. Our study indicates for the first time that in a rodent model of PD, hepatic mitochondria dysfunctions arise as a consequence of nigrostriatal degeneration, and that thyroid hormone represents a key interface in this CNS-liver interaction. Liver plays a fundamental detoxifying function and a better understanding of PD-related hepatic mitochondrial alterations, which might further promote neurodegeneration, may represent an important step for the development of novel therapeutic strategies.

  12. Effect of dopaminergic medication on speech dysfluency in Parkinson's disease: a longitudinal study.

    PubMed

    Tykalová, Tereza; Rusz, Jan; Čmejla, Roman; Klempíř, Jiří; Růžičková, Hana; Roth, Jan; Růžička, Evžen

    2015-08-01

    Although speech dysfluencies have been hypothesized to be associated with abnormal function of dopaminergic system, the effects of dopaminergic medication on speech fluency in Parkinson's disease (PD) have not been systematically studied. The aim of the present study was, therefore, to investigate the long-term effect of dopaminergic medication on speech fluency in PD. Fourteen de novo PD patients with no history of developmental stuttering and 14 age- and sex-matched healthy controls (HC) were recruited. PD subjects were examined three times; before the initiation of dopaminergic treatment and twice in following 6 years. The percentage of dysfluent words was calculated from reading passage and monolog. The amount of medication was expressed by cumulative doses of L-dopa equivalent. After 3-6 years of dopaminergic therapy, PD patients exhibited significantly more dysfluent events compared to healthy subjects as well as to their own speech performance before the introduction of dopaminergic therapy (p < 0.05). In addition, we found a strong positive correlation between the increased occurrence of dysfluent words and the total cumulative dose of L-dopa equivalent (r = 0.75, p = 0.002). Our findings indicate an adverse effect of prolonged dopaminergic therapy contributing to the development of stuttering-like dysfluencies in PD. These findings may have important implication in clinical practice, where speech fluency should be taken into account to optimize dopaminergic therapy.

  13. Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration

    PubMed Central

    Paumier, Katrina L.; Luk, Kelvin C.; Manfredsson, Fredric P.; Kanaan, Nicholas M.; Lipton, Jack W.; Collier, Timothy J.; Steece-Collier, Kathy; Kemp, Christopher J.; Celano, Stephanie; Schulz, Emily; Sandoval, Ivette M.; Fleming, Sheila; Dirr, Elliott; Polinski, Nicole K.; Trojanowski, John Q.; Lee, Virginia M.; Sortwell, Caryl E.

    2015-01-01

    Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson’s disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the

  14. Correlation between automated writing movements and striatal dopaminergic innervation in patients with Wilson's disease.

    PubMed

    Hermann, Wieland; Eggers, Birk; Barthel, Henryk; Clark, Daniel; Villmann, Thomas; Hesse, Swen; Grahmann, Friedrich; Kühn, Hans-Jürgen; Sabri, Osama; Wagner, Armin

    2002-08-01

    Handwriting defects are an early sign of motor impairment in patients with Wilson's disease. The basal ganglia being the primary site of copper accumulation in the brain suggests a correlation with lesions in the nigrostiatal dopaminergic system. We have analysed and correlated striatal dopaminergic innervation using [(123)I]beta-CIT-SPECT and automated handwriting movements in 37 patients with Wilson's disease. There was a significant correlation of putaminal dopaminergic innervation with fine motor ability (p < 0,05 for NIV [number of inversion in velocity], NIA [number of inversion in acceleration], frequency). These data suggest that loss of dorsolateral striatal dopaminergic innervation has a pathophysiological function for decreased automated motor control in Wilson's disease. Furthermore analysis of automated handwriting movements could be useful for therapy monitoring and evaluation of striatal dopaminergic innervation.

  15. Histone Hyperacetylation Up-regulates Protein Kinase Cδ in Dopaminergic Neurons to Induce Cell Death

    PubMed Central

    Jin, Huajun; Kanthasamy, Arthi; Harischandra, Dilshan S.; Kondru, Naveen; Ghosh, Anamitra; Panicker, Nikhil; Anantharam, Vellareddy; Rana, Ajay; Kanthasamy, Anumantha G.

    2014-01-01

    The oxidative stress-sensitive protein kinase Cδ (PKCδ) has been implicated in dopaminergic neuronal cell death. However, little is known about the epigenetic mechanisms regulating PKCδ expression in neurons. Here, we report a novel mechanism by which the PKCδ gene can be regulated by histone acetylation. Treatment with histone deacetylase (HDAC) inhibitor sodium butyrate (NaBu) induced PKCδ expression in cultured neurons, brain slices, and animal models. Several other HDAC inhibitors also mimicked NaBu. The chromatin immunoprecipitation analysis revealed that hyperacetylation of histone H4 by NaBu is associated with the PKCδ promoter. Deletion analysis of the PKCδ promoter mapped the NaBu-responsive element to an 81-bp minimal promoter region. Detailed mutagenesis studies within this region revealed that four GC boxes conferred hyperacetylation-induced PKCδ promoter activation. Cotransfection experiments and Sp inhibitor studies demonstrated that Sp1, Sp3, and Sp4 regulated NaBu-induced PKCδ up-regulation. However, NaBu did not alter the DNA binding activities of Sp proteins or their expression. Interestingly, a one-hybrid analysis revealed that NaBu enhanced transcriptional activity of Sp1/Sp3. Overexpression of the p300/cAMP-response element-binding protein-binding protein (CBP) potentiated the NaBu-mediated transactivation potential of Sp1/Sp3, but expressing several HDACs attenuated this effect, suggesting that p300/CBP and HDACs act as coactivators or corepressors in histone acetylation-induced PKCδ up-regulation. Finally, using genetic and pharmacological approaches, we showed that NaBu up-regulation of PKCδ sensitizes neurons to cell death in a human dopaminergic cell model and brain slice cultures. Together, these results indicate that histone acetylation regulates PKCδ expression to augment nigrostriatal dopaminergic cell death, which could contribute to the progressive neuropathogenesis of Parkinson disease. PMID:25342743

  16. Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring.

    PubMed

    Kirsten, Thiago Berti; Chaves-Kirsten, Gabriela P; Bernardes, Suene; Scavone, Cristoforo; Sarkis, Jorge E; Bernardi, Maria Martha; Felicio, Luciano F

    2015-01-01

    Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism.

  17. Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring

    PubMed Central

    Kirsten, Thiago Berti; Chaves-Kirsten, Gabriela P.; Bernardes, Suene; Scavone, Cristoforo; Sarkis, Jorge E.; Bernardi, Maria Martha; Felicio, Luciano F.

    2015-01-01

    Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism. PMID:26218250

  18. Adolescent exposure to MDMA induces dopaminergic toxicity in substantia nigra and potentiates the amyloid plaque deposition in the striatum of APPswe/PS1dE9 mice.

    PubMed

    Abad, Sonia; Ramon, Carla; Pubill, David; Camarasa, Jorge; Camins, Antonio; Escubedo, Elena

    2016-09-01

    MDMA is one of the most used drugs by adolescents and its consumption has been associated with many psychobiological problems, among them psychomotor problems. Moreover, some authors described that early exposure to MDMA may render the dopaminergic neurons more vulnerable to the effects of future neurotoxic insults. Alzheimer disease (AD) is the main cause of dementia in the elderly and a percentage of the patients have predisposition to suffer nigrostriatal alterations, developing extrapyramidal signs. Nigrostriatal dysfunction in the brain of aged APPswe/PS1dE9 (APP/PS1), a mouse model of familiar AD (FAD), has also been described. The aim of the present study was to investigate the consequences of adolescent exposure to MDMA in APP/PS1 mice, on nigrostriatal function on early adulthood. We used a MDMA schedule simulating weekend binge abuse of this substance. Our MDMA schedule produced a genotype-independent decrease in dopaminergic neurons in the substantia nigra that remained at least 3months. Shortly after the injury, wild-type animals showed a decrease in the locomotor activity and apparent DA depletion in striatum, however in the APP/PS1 mice neither the locomotor activity nor the DA levels were modified, but a reduction in dopamine transporter (DAT) expression and a higher levels of oxidative stress were observed. We found that these disturbances are age-related characteristics that this APP/PS1 mice develops spontaneously much later. Therefore, MDMA administration seems to anticipate the striatal dopaminergic dysfunction in this FAD model. The most important outcome lies in a potentiation, by MDMA, of the amyloid beta deposition in the striatum. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Dietary administration of diquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice.

    PubMed

    Minnema, Daniel J; Travis, Kim Z; Breckenridge, Charles B; Sturgess, Nicholas C; Butt, Mark; Wolf, Jeffrey C; Zadory, Dan; Herberth, Mark T; Watson, Scott L; Cook, Andrew R; Botham, Philip A

    2016-03-01

    Male and female C57BL/6J mice were administered diquat dibromide (DQ∙Br2) in their diets at concentrations of 0 (control), 12.5 and 62.5 ppm for 13 weeks to assess the potential effects of DQ on the nigrostriatal dopaminergic system. Achieved dose levels at 62.5 ppm were 6.4 and 7.6 mg DQ (ion)/kg bw/day for males and females, respectively. A separate group of mice was administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) ip as a positive control. The comparative effects of DQ and MPTP on the substantia nigra pars compacta (SNpc) and/or striatum were assessed using neurochemical, neuropathological and stereological endpoints. Morphological and stereological assessments were performed by investigators who were "blinded" to dose group. DQ had no effect on striatal dopamine concentration or dopamine turnover. There was no evidence of neuronal degeneration, astrocytic or microglial activation, or a reduction in the number of tyrosine hydroxylase positive (TH(+)) neurons in the SNpc or neuronal processes in the striatum of DQ-treated mice. These results are consistent with the rapid clearance of DQ from the brain following a single dose of radiolabeled DQ. In contrast, MPTP-treated mice exhibited decreased striatal dopamine concentration, reduced numbers of TH(+) neurons in the SNpc, and neuropathological changes, including neuronal necrosis, as well as astrocytic and microglial activation in the striatum and SNpc. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Treadmill exercise facilitates synaptic plasticity on dopaminergic neurons and fibers in the mouse model with Parkinson's disease.

    PubMed

    Shin, Mal-Soon; Jeong, Ho-Young; An, Da-In; Lee, Hye-Yun; Sung, Yun-Hee

    2016-05-16

    Exercise for patients with Parkinson's disease (PD) helps to alleviate clinical symptoms such as tremor, balance instability, gait dysfunction, and rigidity. However, molecular mechanism about effect of exercise is poorly unknown. In this study, we investigated effect of exercise in synapse and dendritic spine of nigrostriatal dopaminergic neurons on mice with PD. The C57BL/6J male mice (n=40) were divided by sham group, sham-exercise treated group, 1-Methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) treated group, and MPTP-exercise treated group. For exercise treatment, the mice were put on the treadmill to run for 8m/min, 30min/day, and 5 times/week for 2 weeks. Coordination ability was checked by rota rod test. Expression of tyrosine hydroxylase (TH), synaptophysin, and post-synaptic density protein 95 (PSD-95) was confirmed at substantia nigra pars compacta (SNpc) or striatum using western blotting, or immunohistochemistry. To check dendritic spine in striatum, we used Golgi staining. The results revealed that MPTP treated group displayed poor coordination ability compared with sham group. However, MPTP-exercise treated group showed good coordination ability compared with MPTP treated group. As well as, we also found that MPTP-exercise group increases expression of synaptophysin, PSD-95, TH, and dendritic spine in nigrostriatal dopaminergic neurons and fibers than MPTP treated group (p<0.05). Our findings suggest that exercise may give beneficial effects to patients with PD by facilitating synaptic plasticity and increasing dendritic spines. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Epothilone D Prevents Binge Methamphetamine-Mediated Loss of Striatal Dopaminergic Markers

    PubMed Central

    Killinger, Bryan A.; Moszczynska, Anna

    2016-01-01

    Exposure to binge methamphetamine (METH) can result in a permanent or transient loss of dopaminergic (DAergic) markers such as dopamine (DA), dopamine transporter (DAT), and tyrosine hydroxylase (TH) in the striatum. We hypothesized that the METH-induced loss of striatal DAergic markers was, in part, due to destabilization of microtubules (MTs) in the nigrostriatal DA pathway that ultimately impedes anterograde axonal transport of these markers. To test this hypothesis, adult male Sprague Dawley rats were treated with binge METH or saline in the presence or absence of epothilone D (EpoD), a MT-stabilizing compound, and assessed for the levels of several DAergic markers as well as for the levels of tubulins and their posttranslational modifications (PMTs) at 3 days after the treatments. Binge METH induced a loss of stable long-lived MTs within the striatum but not within the SNpc. Treatment with a low dose of EpoD increased the levels of markers of stable MTs and prevented METH-mediated deficits in several DAergic markers in the striatum. By contrast, administration of a high dose of EpoD appeared to destabilize MTs and potentiated the METH-induced deficits in several DAergic markers. The low-dose EpoD also prevented the METH-induced increase in striatal DA turnover and increased behavioral stereotypy during METH treatment. Together, these results demonstrate that MT dynamics plays a role in the development of METH-induced losses of several DAergic markers in the striatum and may mediate METH-induced degeneration of terminals in the nigrostriatal DA pathway. Our study also demonstrates that MT-stabilizing drugs, such as EpoD have a potential to serve as useful therapeutic agents to restore function of DAergic nerve terminals following METH exposure when administered at low doses. PMID:26465779

  2. Dopaminergic Input to the Inferior Colliculus in Mice

    PubMed Central

    Nevue, Alexander A.; Elde, Cameron J.; Perkel, David J.; Portfors, Christine V.

    2016-01-01

    The response of sensory neurons to stimuli can be modulated by a variety of factors including attention, emotion, behavioral context, and disorders involving neuromodulatory systems. For example, patients with Parkinson’s disease (PD) have disordered speech processing, suggesting that dopamine alters normal representation of these salient sounds. Understanding the mechanisms by which dopamine modulates auditory processing is thus an important goal. The principal auditory midbrain nucleus, the inferior colliculus (IC), is a likely location for dopaminergic modulation of auditory processing because it contains dopamine receptors and nerve terminals immunoreactive for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. However, the sources of dopaminergic input to the IC are unknown. In this study, we iontophoretically injected a retrograde tracer into the IC of mice and then stained the tissue for TH. We also immunostained for dopamine beta-hydroxylase (DBH), an enzyme critical for the conversion of dopamine to norepinephrine, to differentiate between dopaminergic and noradrenergic inputs. Retrogradely labeled neurons that were positive for TH were seen bilaterally, with strong ipsilateral dominance, in the subparafascicular thalamic nucleus (SPF). All retrogradely labeled neurons that we observed in other brain regions were TH-negative. Projections from the SPF were confirmed using an anterograde tracer, revealing TH-positive and DBH-negative anterogradely labeled fibers and terminals in the IC. While the functional role of this dopaminergic input to the IC is not yet known, it provides a potential mechanism for context dependent modulation of auditory processing. PMID:26834578

  3. Dopaminergic influences on formation of a motor memory.

    PubMed

    Flöel, Agnes; Breitenstein, Caterina; Hummel, Friedhelm; Celnik, Pablo; Gingert, Christian; Sawaki, Lumy; Knecht, Stefan; Cohen, Leonardo G

    2005-07-01

    The ability of the central nervous system to form motor memories, a process contributing to motor learning and skill acquisition, decreases with age. Dopaminergic activity, one of the mechanisms implicated in memory formation, experiences a similar decline with aging. It is possible that restoring dopaminergic function in elderly adults could lead to improved formation of motor memories with training. We studied the influence of a single oral dose of levodopa (100mg) administered preceding training on the ability to encode an elementary motor memory in the primary motor cortex of elderly and young healthy volunteers in a randomized, double-blind, placebo-controlled design. Attention to the task and motor training kinematics were comparable across age groups and sessions. In young subjects, encoding a motor memory under placebo was more prominent than in older subjects, and the encoding process was accelerated by intake of levodopa. In the elderly group, diminished motor memory encoding under placebo was enhanced by intake of levodopa to levels present in younger subjects. Therefore, upregulation of dopaminergic activity accelerated memory formation in young subjects and restored the ability to form a motor memory in elderly subjects; possible mechanisms underlying the beneficial effects of dopaminergic agents on motor learning in neurorehabilitation.

  4. Protective effect of resveratrol against nigrostriatal pathway injury in striatum via JNK pathway.

    PubMed

    Li, Dan; Liu, Nan; Zhao, Liang; Tong, Lei; Kawano, Hitoshi; Yan, Hong-Jing; Li, Hong-Peng

    2017-01-01

    Nigrostriatal pathway injury is one of the traumatic brain injury models that usually lead to neurological dysfunction or neuron necrosis. Resveratrol-induced benefits have recently been demonstrated in several models of neuronal degeneration diseases. However, the protective properties of resveratrol against neurodegeneration have not been explored definitely. Thus, we employ the nigrostriatal pathway injury model to mimic the insults on the brain. Resveratrol decreased the p-ERK expression and increased the p-JNK expression compared to the DMSO group, but not alter the p38 MAPK proteins around the lesion site by Western blot. Prior to the injury, mice were infused with resveratrol intracerebroventricularly with or without JNK-IN-8, a specific c-JNK pathway inhibitor for JNK1, JNK2 and JNK4. The study assessed modified improved neurological function score (mNSS) and beam/walking test, the level of inflammatory cytokines IL-1β, IL-6 and TNF-α, and striatal expression of Bax and Bcl-2 proteins associated with neuronal apoptosis. The results revealed that resveratrol exerted a neuroprotective effect as shown by the improved mNSS and beam latency, anti-inflammatory effects as indicated by the decreased level of IL-1β, TNF-α and IL-6. Furthermore, resveratrol up-regulated the protein expression of p-JNK and Bcl-2, down-regulated the expression of Bax and the number of Fluoro-Jade C (FJC) positive neurons. However, these advantages of resveratrol were abolished by JNK-IN-8 treatment. Overall, we demonstrated that resveratrol treatment attenuates the nigrostriatal pathway injury-induced neuronal apoptosis and inflammation via activation of c-JNK signaling. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Axon responses of embryonic stem cell-derived dopaminergic neurons to Semaphorins 3A and 3C

    PubMed Central

    Tamariz, Elisa; Díaz-Martínez, N. Emmanuel; Díaz, Néstor F.; García-Peña, Claudia M.; Velasco, Iván; Varela-Echavarría, Alfredo

    2010-01-01

    Class 3 Semaphorins are a subfamily of chemotropic molecules implicated in the projection of dopaminergic neurons from the ventral mesencephalon and in the formation of the nigrostriatal pathway (NSP) during embryonic development. In humans, loss of mesencephalic dopaminergic neurons leads to Parkinson’s disease (PD). Cell replacement therapy with dopaminergic neurons generated from embryonic stem cells (ES-TH+) is being actively explored in models of PD. Among several requisites for this approach to work are the adequate reconstruction of the NSP and the correct innervation of normal striatal targets by dopaminergic axons. In this work, we characterized the response of ES-TH+ neurons to Semaphorins 3A, 3C, and 3F, and compared it with that of tyrosine hidroxylase-positive neurons (TH+) obtained from embryonic ventral mesencephalon (VM-TH+). We observed that similar proportions of ES-TH+ and VM-TH+ neurons express Semaphorin receptors Neuropilin 1 and 2. Furthermore, the axons of both populations responded very similarly to Semaphorin exposure: Semaphorin 3A increased axon length, and Semaphorin 3C attracted axons and increased their length. These effects were mediated by Neuropilins, since addition of blocking antibodies against these proteins reduced the effects on axonal growth and attraction, and only TH+ axons expressing Neuropilins responded to the Semaphorins analyzed. The observations reported here show phenotypic similarities between VM-TH+ and ES-TH+ neurons, and suggest that Semaphorins 3A and 3C could be employed to guide axons of grafted ES-TH+ in therapeutic protocols for PD. PMID:19859963

  6. Non-exercise physical activity attenuates motor symptoms in Parkinson disease independent from nigrostriatal degeneration

    PubMed Central

    Snider, Jon; Müller, Martijn L.T.M; Kotagal, Vikas; Koeppe, Robert A; Scott, Peter J.H.; Frey, Kirk A; Albin, Roger L.; Bohnen, Nicolaas I.

    2015-01-01

    Objective To investigate the relationship between time spent in non-exercise and exercise physical activity and severity of motor functions in Parkinson disease (PD). Background Increasing motor impairments of PD incline many patients to a sedentary lifestyle. We investigated the relationship between duration of both non-exercise and exercise physical activity over a 4-week period using the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire and severity of clinical motor symptoms in PD. We accounted for the magnitude of nigrostriatal degeneration. Methods Cross-sectional study. PD subjects, n=48 (40M); 69.4±7.4 (56–84) years old; 8.4±4.2 (2.5–20) years motor disease duration, mean UPDRS motor score 27.5 ± 10.3 (7–53) and mean MMSE score 28.4 ± 1.9 (22–30) underwent [11C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation and completed the CHAMPS questionnaire and clinical assessment. Results Bivariate correlations showed an inverse relationship between motor UPDRS severity scores and duration of non-exercise physical activity (R= −0.37, P=0.0099) but not with duration of exercise physical activity (R= −0.05, P= 0.76) over 4 weeks. Multiple regression analysis using UPDRS motor score as outcome variable demonstrated a significant regressor effect for duration of non-exercise physical activity (F=6.15, P=0.017) while accounting for effects of nigrostriatal degeneration (F=4.93, P=0.032), levodopa-equivalent dose (LED; F=1.07, P=0.31), age (F=4.37, P=0.043) and duration of disease (F=1.46, P=0.23; total model (F=5.76, P=0.0004). Conclusions Non-exercise physical activity is a correlate of motor symptom severity in PD independent of the magnitude of nigrostriatal degeneration. Non-exercise physical activity may have positive effects on functional performance in PD. PMID:26330028

  7. Prevalence of impaired odor identification in Parkinson disease with imaging evidence of nigrostriatal denervation.

    PubMed

    Haugen, Jacob; Müller, Martijn L T M; Kotagal, Vikas; Albin, Roger L; Koeppe, Robert A; Scott, Peter J H; Frey, Kirk A; Bohnen, Nicolaas I

    2016-04-01

    There is wide variability in the reported prevalence rates of abnormal smell in Parkinson disease (PD). This study assessed the prevalence of abnormal smell, using the University of Pennsylvania Smell Identification Test (UPSIT), in 183 patients with PD with confirmed PET imaging evidence of nigrostriatal denervation. Impaired olfaction in this sample was nearly universal (97.8 %). Wide-ranging prior olfactory impairment estimates may reflect not only uncertainty regarding diagnostic classification, but also the use of inaccurate normative data and differences in olfactory tests used.

  8. α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage.

    PubMed

    Zhang, Danhui; McGregor, Matthew; Bordia, Tanuja; Perez, Xiomara A; McIntosh, J Michael; Decker, Michael W; Quik, Maryka

    2015-12-01

    ABT-126 is a novel, safe, and well-tolerated α7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. We tested the antidyskinetic effect of ABT-126 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated squirrel monkeys with moderate and more severe nigrostriatal damage. Monkeys (n = 21, set 1) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-2×. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n = 5), or treated with vehicle (n = 6) or ABT-126 (n = 10) twice daily orally 30 min before levodopa. Set 1 was then re-lesioned 1 to 2 times for a total of 3 to 4 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections. The antidyskinetic effect of ABT-126, nicotine, and the β2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n = 23, set 2) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only 1× to 2×. They were treated with levodopa/carbidopa, administered the α7 agonist ABT-107 (n = 6), ABT-894 (n = 6), nicotine (n = 5), or vehicle (n = 6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured. With moderate nigrostriatal damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1×-2×), ABT-126 dose-dependently decreased dyskinesias (∼60%), with similar results seen with ABT-894 (∼60%) or nicotine (∼60%). With more severe damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 3-4×), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control, with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism. The novel α7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early- and later-stage Parkinson's disease. © 2015 International

  9. Non-exercise physical activity attenuates motor symptoms in Parkinson disease independent from nigrostriatal degeneration.

    PubMed

    Snider, Jonathan; Müller, Martijn L T M; Kotagal, Vikas; Koeppe, Robert A; Scott, Peter J H; Frey, Kirk A; Albin, Roger L; Bohnen, Nicolaas I

    2015-10-01

    To investigate the relationship between time spent in non-exercise and exercise physical activity and severity of motor functions in Parkinson disease (PD). Increasing motor impairments of PD incline many patients to a sedentary lifestyle. We investigated the relationship between duration of both non-exercise and exercise physical activity over a 4-week period using the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire and severity of clinical motor symptoms in PD. We accounted for the magnitude of nigrostriatal degeneration. Cross-sectional study. PD subjects, n = 48 (40 M); 69.4 ± 7.4 (56-84) years old; 8.4 ± 4.2 (2.5-20) years motor disease duration, mean UPDRS motor score 27.5 ± 10.3 (7-53) and mean MMSE score 28.4 ± 1.9 (22-30) underwent [(11)C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation and completed the CHAMPS questionnaire and clinical assessment. Bivariate correlations showed an inverse relationship between motor UPDRS severity scores and duration of non-exercise physical activity (R = -0.37, P = 0.0099) but not with duration of exercise physical activity (R = -0.05, P = 0.76) over 4 weeks. Multiple regression analysis using UPDRS motor score as outcome variable demonstrated a significant regressor effect for duration of non-exercise physical activity (F = 6.15, P = 0.017) while accounting for effects of nigrostriatal degeneration (F = 4.93, P = 0.032), levodopa-equivalent dose (LED; F = 1.07, P = 0.31), age (F = 4.37, P = 0.043) and duration of disease (F = 1.46, P = 0.23; total model (F = 5.76, P = 0.0004). Non-exercise physical activity is a correlate of motor symptom severity in PD independent of the magnitude of nigrostriatal degeneration. Non-exercise physical activity may have positive effects on functional performance in PD. Published by Elsevier Ltd.

  10. Non-dopaminergic treatments for motor control in Parkinson's disease.

    PubMed

    Fox, Susan H

    2013-09-01

    The pathological processes underlying Parkinson's disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non-selective N-methyl D-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR₅) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M4 cholinergic antagonists (anticholinergics), but

  11. DeltaA/DeltaD regulate multiple and temporally distinct phases of notch signaling during dopaminergic neurogenesis in zebrafish.

    PubMed

    Mahler, Julia; Filippi, Alida; Driever, Wolfgang

    2010-12-08

    Dopaminergic neurons develop at distinct anatomical sites to form some of the major neuromodulatory systems in the vertebrate brain. Despite their relevance in neurodegenerative diseases and the interests in reconstitutive therapies from stem cells, mechanisms of the neurogenic switch from precursor populations to dopaminergic neurons are not well understood. Here, we investigated neurogenesis of different dopaminergic and noradrenergic neuron populations in the zebrafish embryo. Birth-dating analysis by EdU (5-ethynyl-2'-deoxyuridine) incorporation revealed temporal dynamics of catecholaminergic neurogenesis. Analysis of Notch signaling mutants and stage-specific pharmacological inhibition of Notch processing revealed that dopaminergic neurons form by temporally distinct mechanisms: dopaminergic neurons of the posterior tuberculum derive directly from neural plate cells during primary neurogenesis, whereas other dopaminergic groups form in continuous or wavelike neurogenesis phases from proliferating precursor pools. Systematic analysis of Notch ligands revealed that the two zebrafish co-orthologs of mammalian Delta1, DeltaA and DeltaD, control the neurogenic switch of all early developing dopaminergic neurons in a partially redundant manner. DeltaA/D may also be involved in maintenance of dopaminergic precursor pools, as olig2 expression in ventral diencephalic dopaminergic precursors is affected in dla/dld mutants. DeltaA/D act upstream of sim1a and otpa during dopaminergic specification. However, despite the fact that both dopaminergic and corticotropin-releasing hormone neurons derive from sim1a- and otpa-expressing precursors, DeltaA/D does not act as a lineage switch between these two neuronal types. Rather, DeltaA/D limits the size of the sim1a- and otpa-expressing precursor pool from which dopaminergic neurons differentiate.

  12. Protection of dichlorvos induced oxidative stress and nigrostriatal neuronal death by chronic Coenzyme Q{sub 10} pretreatment

    SciTech Connect

    Binukumar, BK; Gupta, Nidhi; Bal, Amanjit; Gill, Kiran Dip

    2011-10-01

    Numerous epidemiological studies have shown an association between pesticide exposure and increased risk of developing Parkinson's diseases. Oxidative stress generated as a result of mitochondrial dysfunction has been implicated as an important factor in the etiology of Parkinson's disease. Previously, we reported that chronic dichlorvos exposure causes mitochondrial impairments and nigrostriatal neuronal death in rats. The present study was designed to test whether Coenzyme Q{sub 10} (CoQ{sub 10}) administration has any neuroprotective effect against dichlorvos mediated nigrostriatal neuronal death, {alpha}-synuclein aggregation, and motor dysfunction. Male albino rats were administered dichlorvos by subcutaneous injection at a dose of 2.5 mg/kg body weight over a period of 12 weeks. Results obtained there after showed that dichlorvos exposure leads to enhanced mitochondrial ROS production, {alpha}-synuclein aggregation, decreased dopamine and its metabolite levels resulting in nigrostriatal neurodegeneration. Pretreatment by Coenzyme Q{sub 10} (4.5 mg/kg ip for 12 weeks) to dichlorvos treated animals significantly attenuated the extent of nigrostriatal neuronal damage, in terms of decreased ROS production, increased dopamine and its metabolite levels, and restoration of motor dysfunction when compared to dichlorvos treated animals. Thus, the present study shows that Coenzyme Q{sub 10} administration may attenuate dichlorvos induced nigrostriatal neurodegeneration, {alpha}-synuclein aggregation and motor dysfunction by virtue of its antioxidant action. - Highlights: > CoQ{sub 10} administration attenuates dichlorvos induced nigrostriatal neurodegenaration. > CoQ{sub 10} pre treatment leads to preservation of TH-IR neurons. > CoQ{sub 10} may decrease oxidative damage and {alpha}-synuclin aggregation. > CoQ{sub 10} treatment enhances motor function and protects rats from catalepsy.

  13. Spatial and Temporal Distribution of Dopaminergic Neurons during Development in Zebrafish.

    PubMed

    Du, Yuchen; Guo, Qiang; Shan, Minghui; Wu, Yongmei; Huang, Sizhou; Zhao, Haixia; Hong, Huarong; Yang, Ming; Yang, Xi; Ren, Liyi; Peng, Jiali; Sun, Jing; Zhou, Hongli; Li, Shurong; Su, Bingyin

    2016-01-01

    As one of the model organisms of Parkinson's disease (PD) research, the zebrafish has its advantages, such as the 87% homology with human genome and transparent embryos which make it possible to observe the development of dopaminergic neurons in real time. However, there is no midbrain dopaminergic system in zebrafish when compared with mammals, and the location and projection of the dopaminergic neurons are seldom reported. In this study, Vmat2:GFP transgenic zebrafish was used to observe the development and distribution of dopaminergic neurons in real time. We found that diencephalons (DC) 2 and DC4 neuronal populations were detected at 24 h post fertilization (hpf). All DC neuronal populations as well as those in locus coeruleus (LC), raphe nuclei (Ra) and telencephalon were detected at 48 hpf. Axons were detected at 72 hpf. At 96 hpf, all the neuronal populations were detected. For the first time we reported axons from the posterior tubercle (PT) of ventral DC projected to subpallium in vivo. However, when compared with results from whole mount tyrosine hydroxylase (TH) immunofluorescence staining in wild type (WT) zebrafish, we found that DC2 and DC4 neuronal populations were mainly dopaminergic, while DC1, DC3, DC5 and DC6 might not. Neurons in pretectum (Pr) and telencephalon were mainly dopaminergic, while neurons in LC and Ra might be noradrenergic. Our study makes some corrections and modifications on the development, localization and distribution of zebrafish dopaminergic neurons, and provides some experimental evidences for the construction of the zebrafish PD model.

  14. Renalase regulates peripheral and central dopaminergic activities.

    PubMed

    Quelhas-Santos, Janete; Serrão, Maria Paula; Soares-Silva, Isabel; Fernandes-Cerqueira, Cátia; Simões-Silva, Liliana; Pinho, Maria João; Remião, Fernando; Sampaio-Maia, Benedita; Desir, Gary V; Pestana, Manuel

    2015-01-15

    Renalase is a recently identified FAD/NADH-dependent amine oxidase mainly expressed in kidney that is secreted into blood and urine where it was suggested to metabolize catecholamines. The present study evaluated central and peripheral dopaminergic activities in the renalase knockout (KO) mouse model and examined the changes induced by recombinant renalase (RR) administration on plasma and urine catecholamine levels. Compared with wild-type (WT) mice, KO mice presented increased plasma levels of epinephrine (Epi), norepinephrine (NE), and dopamine (DA) that were accompanied by increases in the urinary excretion of Epi, NE, DA. In addition, the KO mice presented an increase in urinary DA-to-l-3,4-dihydroxyphenylalanine (l-DOPA) ratios without changes in renal tubular aromatic-l-amino acid decarboxylase (AADC) activity. By contrast, the in vivo administration of RR (1.5 mg/kg sc) to KO mice was accompanied by significant decreases in plasma levels of Epi, DA, and l-DOPA as well as in urinary excretion of Epi, DA, and DA-to-l-DOPA ratios notwithstanding the accompanied increase in renal AADC activity. In addition, the increase in renal DA output observed in renalase KO mice was accompanied by an increase in the expression of the L-type amino acid transporter like (LAT) 1 that is reversed by the administration of RR in these animals. These results suggest that the overexpression of LAT1 in the renal cortex of the renalase KO mice might contribute to the enhanced l-DOPA availability/uptake and consequently to the activation of the renal dopaminergic system in the presence of renalase deficiency.

  15. Renalase regulates peripheral and central dopaminergic activities

    PubMed Central

    Serrão, Maria Paula; Soares-Silva, Isabel; Fernandes-Cerqueira, Cátia; Simões-Silva, Liliana; Pinho, Maria João; Remião, Fernando; Sampaio-Maia, Benedita; Desir, Gary V.; Pestana, Manuel

    2014-01-01

    Renalase is a recently identified FAD/NADH-dependent amine oxidase mainly expressed in kidney that is secreted into blood and urine where it was suggested to metabolize catecholamines. The present study evaluated central and peripheral dopaminergic activities in the renalase knockout (KO) mouse model and examined the changes induced by recombinant renalase (RR) administration on plasma and urine catecholamine levels. Compared with wild-type (WT) mice, KO mice presented increased plasma levels of epinephrine (Epi), norepinephrine (NE), and dopamine (DA) that were accompanied by increases in the urinary excretion of Epi, NE, DA. In addition, the KO mice presented an increase in urinary DA-to-l-3,4-dihydroxyphenylalanine (l-DOPA) ratios without changes in renal tubular aromatic-l-amino acid decarboxylase (AADC) activity. By contrast, the in vivo administration of RR (1.5 mg/kg sc) to KO mice was accompanied by significant decreases in plasma levels of Epi, DA, and l-DOPA as well as in urinary excretion of Epi, DA, and DA-to-l-DOPA ratios notwithstanding the accompanied increase in renal AADC activity. In addition, the increase in renal DA output observed in renalase KO mice was accompanied by an increase in the expression of the L-type amino acid transporter like (LAT) 1 that is reversed by the administration of RR in these animals. These results suggest that the overexpression of LAT1 in the renal cortex of the renalase KO mice might contribute to the enhanced l-DOPA availability/uptake and consequently to the activation of the renal dopaminergic system in the presence of renalase deficiency. PMID:25411385

  16. Catecholamine/Serotonin interactions: systems thinking for brain function and disease.

    PubMed

    Hensler, Julie G; Artigas, Francesc; Bortolozzi, Analía; Daws, Lynette C; De Deurwaerdère, Philippe; Milan, Léa; Navailles, Sylvia; Koek, Wouter

    2013-01-01

    This chapter brings together the work of several leading laboratories, each an outstanding example of integrative approaches to complex diseases of the central nervous system. Cognitive dysfunction and negative symptoms associated with schizophrenia are believed to result from hypofunction of the mesocortical dopaminergic projections to prefrontal cortex (PFC). Noradrenergic targets for the augmentation of dopaminergic function in PFC show promise to improve cognitive deficits as well as negative symptoms. Serotonergic targets for the modulation of mesocortical dopaminergic neurotransmission include 5-HT2A and 5-HT1A receptors. The hallmark of Parkinson's disease is the destruction of nigrostriatal dopaminergic neurons. l-DOPA, a metabolic precursor of dopamine, is the standard of treatment. However, the ectopic release of dopamine (DA) from serotonin neurons and the clearance of extracellular DA by the norepinephrine transporter in areas enriched with noradrenergic terminals contribute to extracellular DA produced by l-DOPA and offer opportunities to improve l-DOPA therapy. The high-affinity transporters for monoamines are the primary targets for antidepressant drugs. However, many patients experience suboptimal therapeutic benefit or fail to respond to treatment. Organic cation transporters and plasma membrane monoamine transporter serve an important function in regulating monoamine neurotransmission and hold potential utility as targets for the development of therapeutic drugs. Improved therapeutic approaches will arise from not only understanding how monoamines influence one another within the central nervous system as an integrated whole but also addressing the pathophysiology of specific core symptoms or distinct syndromal dimensions (cognitive impairment, motor slowing, and negative affect) regardless of disease classification, for example, psychotic, affective, and neurodegenerative.

  17. Catecholamine/Serotonin Interactions: Systems Thinking for Brain Function and Disease

    PubMed Central

    Hensler, Julie G.; Artigas, Francesc; Bortolozzi, Analía; Daws, Lynette C.; Deurwaerdère, Philippe De; Milan, Léa; Navailles, Sylvia; Koek, Wouter

    2013-01-01

    This chapter brings together the work of several leading laboratories, each an outstanding example of integrative approaches to complex diseases of the central nervous system. Cognitive dysfunction and negative symptoms associated with schizophrenia are believed to result from hypofunction of the mesocortical dopaminergic projections to prefrontal cortex (PFC). Noradrenergic targets for the augmentation of dopaminergic function in PFC show promise to improve cognitive deficits as well as negative symptoms. Serotonergic targets for the modulation of mesocortical dopaminergic neurotransmission include 5-HT2A and 5-HT1A receptors. The hallmark of Parkinson’s disease is the destruction of nigrostriatal dopaminergic neurons. L-DOPA, a metabolic precursor of dopamine, is the standard of treatment. However, the ectopic release of dopamine (DA) from serotonin neurons and the clearance of extracellular DA by the norepinephrine transporter in areas enriched with noradrenergic terminals contribute to extracellular DA produced by L-DOPA and offer opportunities to improve L-DOPA therapy. The high-affinity transporters for monoamines are the primary targets for antidepressant drugs. However, many patients experience suboptimal therapeutic benefit or fail to respond to treatment. Organic cation transporters and plasma membrane monoamine transporter serve an important function in regulating monoamine neurotransmission and hold potential utility as targets for the development of therapeutic drugs. Improved therapeutic approaches will arise from not only understanding how monoamines influence one another within the central nervous system as an integrated whole but also addressing the pathophysiology of specific core symptoms or distinct syndromal dimensions (cognitive impairment, motor slowing, and negative affect) regardless of disease classification, for example, psychotic, affective, and neurodegenerative. PMID:24054145

  18. Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice

    SciTech Connect

    Bardullas, U.; Limon-Pacheco, J.H.; Giordano, M.; Carrizales, L.; Mendoza-Trejo, M.S.; Rodriguez, V.M.

    2009-09-01

    Arsenic (As) is a toxic metalloid widely present in the environment. Human exposure to As has been associated with the development of skin and internal organ cancers and cardiovascular disorders, among other diseases. A few studies report decreases in intelligence quotient (IQ), and sensory and motor alterations after chronic As exposure in humans. On the other hand, studies of rodents exposed to high doses of As have found alterations in locomotor activity, brain neurochemistry, behavioral tasks, and oxidative stress. In the present study both male and female C57Bl/6J mice were exposed to environmentally relevant doses of As such as 0.05, 0.5, 5.0, or 50 mg As/L of drinking water for 4 months, and locomotor activity was assessed every month. Male mice presented hyperactivity in the group exposed to 0.5 mg As/L and hypoactivity in the group exposed to 50 mg As/L after 4 months of As exposure, whereas female mice exposed to 0.05, 0.5, and 5.0 mg As/L exhibited hyperactivity in every monthly test during As exposure. Furthermore, striatal and hypothalamic dopamine content was decreased only in female mice. Also decreases in tyrosine hydroxylase (TH) and cytosolic thioredoxin (Trx-1) mRNA expression in striatum and nucleus accumbens were observed in male and female mice, respectively. These results indicate that chronic As exposure leads to gender-dependent alterations in dopaminergic markers and spontaneous locomotor activity, and down-regulation of the antioxidant capacity of the brain.

  19. Glial cell-line derived neurotrophic factor (GDNF) replacement attenuates motor impairments and nigrostriatal dopamine deficits in 12-month-old mice with a partial deletion of GDNF

    PubMed Central

    Littrell, Ofelia M.; Granholm, Ann-Charlotte; Gerhardt, Greg A.; Boger, Heather A.

    2013-01-01

    Glial cell-line derived neurotrophic factor (GDNF) has been established as a growth factor for the survival and maintenance of dopamine (DA) neurons. In phase I clinical trials, GDNF treatment in Parkinson’s disease patients led to improved motor function and GDNF has been found to be down regulated in Parkinson’s disease patients. Studies using GDNF heterozygous (Gdnf+/−) mice have demonstrated that a partial reduction of GDNF leads to an age-related accelerated decline in nigrostriatal DA system- and motor-function and increased neuro-inflammation and oxidative stress in the substantia nigra (SN). Therefore, the purpose of the current studies was to determine if GDNF replacement restores motor function and functional markers within the nigrostriatal DA system in middle-aged Gdnf+/− mice. At 11 months of age, male Gdnf+/− and wildtype (WT) mice underwent bilateral intra-striatal injections of GDNF (10 μg) or vehicle. Locomotor activity was assessed weekly 1–4 weeks after treatment. Four weeks after treatment, their brains were processed for analysis of GDNF levels and various DAergic and oxidative stress markers. An intrastriatal injection of GDNF increased motor activity in Gdnf+/− mice to levels comparable to WT mice (1 week after injection) and this effect was maintained through the 4-week time point. This increase in locomotion was accompanied by a 40% increase in striatal GDNF protein levels and SN GDNF expression in Gdnf+/− mice. Additionally, GDNF treatment significantly increased the number of tyrosine hydroxylase (TH)-positive neurons in the SN of middle-aged Gdnf+/− mice, but not WT mice, which was coupled with reduced oxidative stress in the SN. These studies further support that long-term changes related to the dysfunction of the nigrostriatal pathway are influenced by GDNF expression and add that this dysfunction appears to be responsive to GDNF treatment. Additionally, these studies suggest that long-term GDNF depletion alters the

  20. Nigrostriatal dopamine-independent resting-state functional networks in Parkinson's disease.

    PubMed

    Ham, Jee Hyun; Cha, Jungho; Lee, Jae Jung; Baek, Gwang-Min; Sunwoo, Mun Kyung; Hong, Jin Yong; Shin, Na-Young; Sohn, Young Ho; Lee, Jong-Min; Lee, Phil Hyu

    2015-10-01

    As an indicator of synchronous neural activity, resting-state functional networks are influenced by neuropathological and neurochemical changes in degenerative diseases. To further advance understanding about neurochemical and neuropathological basis for resting-state functional maps, we performed a comparative analysis of resting-state functional connectivity in patients with Parkinson's disease (PD) and drug induced parkinsonism (DIP). Resting-state neuroimaging data were analyzed with a seed-based approach to investigate striatocortical functional connectivity and cortical functional connectivity within the default mode network, executive control network, and the dorsal attention network. The striatal subregions were divided into the more or less affected sides in terms of dopamine transporter uptake. Compared with DIP, PD exhibited an increased cerebellar connectivity from the more affected side of the caudate and the less affected sides of the anterior and the posterior putamen. Additionally, PD showed increased functional connectivity in the anterior prefrontal areas from the more affected side of the anterior putamen and from the less affected side of the posterior putamen. However, PD exhibited decreased cortical functional connectivity from the posterior cingulate cortex in the left temporal area. Finally, DIP patients showed decreased cortical functional connectivity from the dorsolateral prefrontal cortex in frontal and parietal areas compared with PD patients. In summary, the present study demonstrates that PD patients exhibited a unique resting state functional connectivity that may be associated with PD-related pathological changes beyond the dopaminergic system, whereas DIP patients showed altered functional connectivity within executive control network.

  1. The adenosinergic system is involved in sensitization to morphine withdrawal signs in rats-neurochemical and molecular basis in dopaminergic system.

    PubMed

    Listos, Joanna; Baranowska-Bosiacka, Irena; Wąsik, Agnieszka; Talarek, Sylwia; Tarnowski, Maciej; Listos, Piotr; Łupina, Małgorzata; Antkiewicz-Michaluk, Lucyna; Gutowska, Izabela; Tkacz, Marta; Pilutin, Anna; Orzelska-Górka, Jolanta; Chlubek, Dariusz; Fidecka, Sylwia

    2016-06-01

    Experimental data informs that not only do the dose and time duration of dependent drugs affect the severity of withdrawal episodes. Previous withdrawal experiences may intensify this process, which is referred as sensitization to withdrawal signs. Adenosine and dopamine (DA) receptors may be involved in this sensitization. Rats were continuously and sporadically treated with increasing doses of morphine for 8 days. In rats, sporadically treated with morphine, morphine administration was modified by adding three morphine-free periods. Adenosine agonists were given during each of the morphine-free periods (six injections in total). On the 9th day, morphine was injected. One hour later, naloxone was administered to induce morphine withdrawal signs. Then, the animals were placed into cylinders and the number of jumpings was recorded. Next, the rats were decapitated and brain and brain structures (striatum, hippocampus, and prefrontal cortex) were dissected for neurochemical, molecular, and immunohistochemical experiments within DAergic pathways. We demonstrated that previous experiences of opioid withdrawal intensified subsequent withdrawal signs. Adenosine ligands attenuated the sensitization to withdrawal signs. In a neurochemical study, the release of DA and its metabolites was impaired in all structures. Significant alterations were also observed in mRNA and protein expression of DA receptors. Results demonstrate that intermittent treatment with morphine induces alterations in the DAergic system which may be responsible for sensitization to morphine withdrawal signs. Although adenosine ligands attenuate this type of sensitization, they are not able to fully restore the physiological brain status.

  2. New developments of dopaminergic imaging in Parkinson's disease.

    PubMed

    Varrone, A; Halldin, C

    2012-03-09

    The development of radioligands for the dopaminergic system has provided suitable imaging biomarkers for clinical research in Parkinson's disease (PD) and related movement disorders. Single photon emission tomography (SPECT) has played an important role as main molecular imaging modality because of the availability of imaging tools such as dopamine transporter (DAT) radioligands for wide clinical use. At present, SPECT imaging of the DAT is the main diagnostic imaging procedure for the assessment of patients with parkinsonism. However, in the recent years positron emission tomography (PET) has become an important clinical diagnostic modality, mainly in oncology, due to the wide availability of PET/CT systems with improved imaging performance and to the use of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) as main diagnostic agent. In this context, further development of 18F-radioligands is of high interest for their potential utility in the clinical setting. This review will give a general overview on the development of SPECT and PET radioligands for the dopaminergic system and describe the potential advantages of developing 18F-labelled radioligands for imaging of the dopaminergic system in PD and related movement disorders.

  3. New developments of dopaminergic imaging in Parkinson's disease.

    PubMed

    Varrone, A; Halldin, C

    2012-02-01

    The development of radioligands for the dopaminergic system has provided suitable imaging biomarkers for clinical research in Parkinson's disease (PD) and related movement disorders. Single photon emission tomography (SPECT) has played an important role as main molecular imaging modality because of the availability of imaging tools such as dopamine transporter (DAT) radioligands for wide clinical use. At present, SPECT imaging of the DAT is the main diagnostic imaging procedure for the assessment of patients with parkinsonism. However, in the recent years positron emission tomography (PET) has become an important clinical diagnostic modality, mainly in oncology, due to the wide availability of PET/CT systems with improved imaging performance and to the use of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) as main diagnostic agent. In this context, further development of 18F-radioligands is of high interest for their potential utility in the clinical setting. This review will give a general overview on the development of SPECT and PET radioligands for the dopaminergic system and describe the potential advantages of developing 18F-labelled radioligands for imaging of the dopaminergic system in PD and related movement disorders.

  4. Escin, a novel triterpene, mitigates chronic MPTP/p-induced dopaminergic toxicity by attenuating mitochondrial dysfunction, oxidative stress, and apoptosis.

    PubMed

    Selvakumar, Govindasamy Pushpavathi; Manivasagam, Thamilarasan; Rekha, Karamkolly R; Jayaraj, Richard L; Elangovan, Namasivayam

    2015-01-01

    Parkinson's disease (PD) is a common, chronic, and debilitating neurodegenerative disorder characterized by progressive loss of nigrostriatal dopaminergic neurons due to unknown factors. In the present study, we have evaluated if escin, a triterpene saponin from seeds of horse chestnut tree (Aesculus hippocastanum), offers neuroprotection against chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced toxicity using a mouse model. Chronic administration of MPTP/p deteriorated the loss of TH immunoreactivity in striatum. Subsequently, MPTP/p also enhanced oxidative stress by mitochondrial complex I inhibition, thereby ensuing dopaminergic denervation via modulation of Bcl-2, Bax, Cyto-C, and cleaved caspases expressions. However, we observed that pretreatment with escin (4 mg/kg) significantly attenuated MPTP/p-induced mitochondrial dysfunction, oxidative stress, and apoptosis. Furthermore, behavioral studies and ultrastructural analysis of mitochondria and intracellular components were in support of these findings. Therefore, we speculate that escin might be a promising candidate for the prevention of mitochondrial dysfunction-induced apoptosis in neurodegenerative disorders such as PD.

  5. Pre-synaptic striatal dopaminergic function in people at high risk of psychosis

    PubMed Central

    Howes, Oliver D; Montgomery, Andrew J; Asselin, Marie-Claude; Murray, Robin M; Grasby, Paul M; McGuire, Philip K

    2013-01-01

    Background The dopamine hypothesis has been the major pathophysiological theory of psychosis in recent decades. Molecular imaging studies have provided in vivo evidence of increased dopamine synaptic availability and increased pre-synaptic dopamine synthesis in the striata of people with psychotic illnesses. These studies support the predictions of the dopamine hypothesis, but it remains to be determined whether dopaminergic abnormalities pre-date or are secondary to the development of psychosis. Method We selectively review the molecular imaging studies of the striatal dopaminergic system in psychosis and link this to models of psychosis and the functional sub-divisions of the striatum to make predictions for dopaminergic system in the prodromal phase of psychosis. Results A fairly consistent body of evidence indicates that pre-synaptic dopamine synthesis and synaptic dopamine availability is increased in the striata of people with psychotic illnesses. There may also be a small increase in striatal D2 dopamine receptor levels, although the evidence is less consistent. No studies to date have investigated striatal dopaminergic function longitudinally in people with psychosis or who are in the prodromal phase of psychosis. Evidence indicates that people with psychosis and at risk of psychosis show characteristic cognitive biases which support models of psychosis that link cognitive processes underlying appraisal to the development of delusions. Conclusions Current findings indicate an association between dopaminergic abnormalities and psychosis, which supports the dopamine hypothesis. However it is not possible to infer a causal relationship from these data. Studies of the dopaminergic system in the prodromal phase of psychosis and over the course of the developing psychotic illness are needed to determine whether dopaminergic abnormalities are secondary or primary, and whether dopaminergic abnormalities underlie the cognitive biases and impairments associated with

  6. The role of parkin in the differential susceptibility of tuberoinfundibular and nigrostriatal dopamine neurons to acute toxicant exposure.

    PubMed

    Benskey, Matthew J; Manfredsson, Fredric P; Lookingland, Keith J; Goudreau, John L

    2015-01-01

    Parkinson disease causes degeneration of nigrostriatal dopamine (DA) neurons, while tuberoinfundibular DA neurons remain unaffected. A similar pattern is observed following exposure to 1-methy-4-phenyl-1,2,3,6-tetrahydropyradine (MPTP). The mechanism of tuberoinfundibular neuronal recovery from MPTP is associated with up-regulation of parkin protein. Here we tested if parkin mediates tuberoinfundibular neuronal recovery from MPTP by knocking-down parkin in tuberoinfundibular neurons using recombinant adeno-associated virus (rAAV), expressing a short hairpin RNA (shRNA) directed toward parkin. Following knockdown, axon terminal DA and tyrosine hydroxylase (TH) concentrations were analyzed 24h post-MPTP administration. rAAV-shRNA-mediated knockdown of endogenous parkin rendered tuberoinfundibular neurons susceptible to MPTP induced terminal DA loss, but not TH loss, within 24h post-MPTP. To determine if the neuroprotective benefits of parkin up-regulation could be translated to nigrostriatal neurons, rAAV expressing human parkin was injected into the substantia nigra of mice and axon terminal DA and TH concentrations were analyzed 24h post-MPTP. Nigral parkin over-expression prevented loss of TH in the axon terminals and soma of nigrostriatal neurons, but had no effect on terminal DA loss within 24h post-MPTP. These data show that parkin is necessary for the recovery of terminal DA concentrations within tuberoinfundibular neurons following acute MPTP administration, and parkin can rescue MPTP-induced decreases in TH within nigrostriatal neurons.

  7. Extraversion and striatal dopaminergic receptor availability in young adults: an [18F]fallypride PET study.

    PubMed

    Baik, Sang-hyun; Yoon, Heung Sik; Kim, Sang Eun; Kim, Sang Hee

    2012-03-07

    Extraversion is a core personality trait associated with individual differences in reward sensitivity and has been linked to the dopaminergic brain system. We investigated whether dopaminergic receptor availability in the striatum was directly associated with individual differences in extraversion using the high-affinity radiotracer [¹⁸F]fallypride and PET. Seventeen healthy male and female participants completed an [¹⁸F]fallypride PET scan at rest. Extraversion was assessed using the revised Eysenck Personality Questionnaire. Dopamine receptor availability in predefined striatal regions of interest was assessed as [¹⁸F]fallypride binding potential using a reference tissue model for [¹⁸F]fallypride. Both region of interest and voxel-based whole-brain analyses showed that extraversion was significantly correlated with dopaminergic receptor availability in the striatum bilaterally. This finding contributes to our understanding of the dopaminergic neural mechanisms underlying individual differences in extraversion.

  8. Enhanced Sensitivity to Hyperpolarizing Inhibition in Mesoaccumbal Relative to Nigrostriatal Dopamine Neuron Subpopulations

    PubMed Central

    2017-01-01

    Midbrain dopamine neurons recorded in vivo pause their firing in response to reward omission and aversive stimuli. While the initiation of pauses typically involves synaptic or modulatory input, intrinsic membrane properties may also enhance or limit hyperpolarization, raising the question of how intrinsic conductances shape pauses in dopamine neurons. Using retrograde labeling and electrophysiological techniques combined with computational modeling, we examined the intrinsic conductances that shape pauses evoked by current injections and synaptic stimulation in subpopulations of dopamine neurons grouped according to their axonal projections to the nucleus accumbens or dorsal striatum in mice. Testing across a range of conditions and pulse durations, we found that mesoaccumbal and nigrostriatal neurons differ substantially in rebound properties with mesoaccumbal neurons displaying significantly longer delays to spiking following hyperpolarization. The underlying mechanism involves an inactivating potassium (IA) current with decay time constants of up to 225 ms, and small-amplitude hyperpolarization-activated currents (IH), characteristics that were most often observed in mesoaccumbal neurons. Pharmacological block of IA completely abolished rebound delays and, importantly, shortened synaptically evoked inhibitory pauses, thereby demonstrating the involvement of A-type potassium channels in prolonging pauses evoked by GABAergic inhibition. Therefore, these results show that mesoaccumbal and nigrostriatal neurons display differential responses to hyperpolarizing inhibitory stimuli that favors a higher sensitivity to inhibition in mesoaccumbal neurons. These findings may explain, in part, observations from in vivo experiments that ventral tegmental area neurons tend to exhibit longer aversive pauses relative to SNc neurons. SIGNIFICANCE STATEMENT Our study examines rebound, postburst, and synaptically evoked inhibitory pauses in subpopulations of midbrain dopamine

  9. Neurochemical evidence that cocaine- and amphetamine-regulated transcript (CART) 55-102 peptide modulates the dopaminergic reward system by decreasing the dopamine release in the mouse nucleus accumbens.

    PubMed

    Rakovska, Angelina; Baranyi, Maria; Windisch, Katalin; Petkova-Kirova, Polina; Gagov, Hristo; Kalfin, Reni

    2017-09-01

    CART (Cocaine- and Amphetamine-Regulated Transcript) peptide is a neurotransmitter naturally occurring in the CNS and found mostly in nucleus accumbens, ventrotegmental area, ventral pallidum, amygdalae and striatum, brain regions associated with drug addiction. In the nucleus accumbens, known for its significant role in motivation, pleasure, reward and reinforcement learning, CART peptide inhibits cocaine and amphetamine-induced dopamine-mediated increases in locomotor activity and behavior, suggesting a CART peptide interaction with the dopaminergic system. Thus in the present study, we examined the effect of CART (55-102) peptide on the basal, electrical field stimulation-evoked (EFS-evoked) (30V, 2Hz, 120 shocks) and returning basal dopamine (DA) release and on the release of the DA metabolites 3,4-dihydroxyphenyl acetaldehyde (DOPAL), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3,4-dihydroxyphenylethanol (DOPET), 3-methoxytyramine (3-MT) as well as on norepinephrine (NE) and dopamine-o-quinone (Daq) in isolated mouse nucleus accumbens, in a preparation, in which any CART peptide effects on the dendrites or soma of ventral tegmental projection neurons have been excluded. We further extended our study to assess the effect of CART (55-102) peptide on basal cocaine-induced release of dopamine and its metabolites DOPAL, DOPAC, HVA, DOPET and 3-MT as well as on NE and Daq. To analyze the amount of [(3)H]dopamine, dopamine metabolites, Daq and NE in the nucleus accumbens superfusate, a high-pressure liquid chromatography (HPLC), coupled with electrochemical, UV and radiochemical detections was used. CART (55-102) peptide, 0.1μM, added alone, exerted: (i) a significant decrease in the basal and EFS-evoked levels of extracellular dopamine (ii) a significant increase in the EFS-evoked and returning basal levels of the dopamine metabolites DOPAC and HVA, major products of dopamine degradation and (iii) a significant decrease in the returning basal

  10. N-oleoyldopamine modulates activity of midbrain dopaminergic neurons through multiple mechanisms.

    PubMed

    Sergeeva, Olga A; De Luca, Roberto; Mazur, Karolina; Chepkova, Aissa N; Haas, Helmut L; Bauer, Andreas

    2017-04-09

    N-oleoyl-dopamine (OLDA) is an amide of dopamine and oleic acid, synthesized in catecholaminergic neurons. The present study investigates OLDA targets in midbrain dopaminergic (DA) neurons. Substantia Nigra compacta (SNc) DA neurons recorded in brain slices were excited by OLDA in wild type mice. In transient receptor potential vanilloid 1 (TRPV1) knockout (KO) mice, however, SNc DA neurons displayed sustained inhibition of firing. In the presence of the dopamine type 2 receptor (D2R) antagonist sulpiride or the dopamine transporter blocker nomifensine no such inhibition was observed. Under sulpiride OLDA slightly excited SNc DA neurons, an action abolished upon combined application of the cannabinoid1 and 2 receptor antagonists AM251 and AM630. In ventral tegmental area (VTA) DA neurons from TRPV1 KO mice a transient inhibition of firing by OLDA was observed. Thus OLDA modulates the firing of nigrostriatal DA neurons through interactions with TRPV1, cannabinoid receptors and dopamine uptake. These findings suggest further development of OLDA-like tandem molecules for the treatment of movement disorders including Parkinson's disease.

  11. Organochlorine pesticides dieldrin and lindane induce cooperative toxicity in dopaminergic neurons: role of oxidative stress.

    PubMed

    Sharma, Heera; Zhang, Ping; Barber, David S; Liu, Bin

    2010-03-01

    Elevated environmental exposure to pesticides has been implicated as a contributing factor in the pathogenesis of Parkinson's disease (PD), a progressive movement disorder resulted from degeneration of the nigrostriatal dopaminergic (DA) pathway. Organochlorine pesticides (OCPs) including dieldrin and lindane remain ubiquitous in the environment and food supply due to their resistance to degradation and bioaccumulation along the food chain. While prior studies have gained insight into the neurotoxic effects of individual OCPs such as dieldrin, the effect of combinations of coexisting OCPs is lacking. In this study, we determined the combined effect of dieldrin and lindane on DA neurons and potential mechanism of action. Combinations of dieldrin and lindane (5-25 microM) were more effective in causing toxicity in immortalized rat N27 DA neurons than when used alone. Mechanistically, dieldrin and lindane combination induced a rapid increase in the levels of intracellular reactive oxygen species, a decrease in mitochondrial membrane potential and activation of caspase 3/7. Pretreatment with antioxidant N-acetyl cysteine blocked the effect of dieldrin and lindane on ROS generation and mitochondrial membrane potential and protected against dieldrin- and lindane-induced neurotoxicity. These results demonstrate that dieldrin and lindane work cooperatively to induce DA neurotoxicity through the induction of oxidative stress and mitochondrial dysfunction. These findings may advance understanding of the role of pesticides in the multi-factorial etiology of PD. Copyright (c) 2009 Elsevier Inc. All rights reserved.

  12. Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function.

    PubMed

    Oaks, Adam W; Frankfurt, Maya; Finkelstein, David I; Sidhu, Anita

    2013-01-01

    Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8-12 months of age. In younger, pre-symptomatic animals, altered motor activity and anxiety-like behaviors have also been reported. These behavioral changes, which precede severe neuropathology, may stem from non-pathological functions of alpha-synuclein, including modulation of monoamine neurotransmission. Our analysis over the adult life-span of motor activity, anxiety-like, and depressive-like behaviors identifies perturbations both before and after the onset of disease. Young A53T mice had increased distribution of the dopamine transporter (DAT) to the membrane that was associated with increased striatal re-uptake function. DAT function decreased with aging, and was associated with neurochemical alterations that included increased expression of beta-synuclein and gamma synuclein. Prior to normalization of dopamine uptake, transient activation of Tau kinases and hyperphosphorylation of Tau in the striatum were also observed. Aged A53T mice had reduced neuron counts in the substantia nigra pars compacta, yet striatal medium spiny neuron dendritic spine density was largely maintained. These findings highlight the involvement of the synuclein family of proteins and phosphorylation of Tau in the response to dopaminergic dysfunction of the nigrostriatal pathway.

  13. Isoforms of the Erythropoietin receptor in dopaminergic neurons of the Substantia Nigra.

    PubMed

    Marcuzzi, Federica; Zucchelli, Silvia; Bertuzzi, Maria; Santoro, Claudio; Tell, Gianluca; Carninci, Piero; Gustincich, Stefano

    2016-11-01

    Erythropoietin receptor (EpoR) regulates erythrocytes differentiation in blood. In the brain, EpoR has been shown to protect several neuronal cell types from cell death, including the A9 dopaminergic neurons (DA) of the Substantia Nigra (SN). These cells form the nigrostriatal pathway and are devoted to the control of postural reflexes and voluntary movements. Selective degeneration of A9 DA neurons leads to Parkinson's disease. By the use of nanoCAGE, a technology that allows the identification of Transcription Start Sites (TSSs) at a genome-wide level, we have described the promoter-level expression atlas of mouse A9 DA neurons purified with Laser Capture Microdissection (LCM). Here, we identify mRNA variants of the Erythropoietin Receptor (DA-EpoR) transcribed from alternative TSSs. Experimental validation and full-length cDNA cloning is integrated with gene expression analysis in the FANTOM5 database. In DA neurons, the EpoR gene encodes for a N-terminal truncated receptor. Based on STAT5 phosphorylation assays, we show that the new variant of N-terminally truncated EpoR acts as decoy when co-expressed with the full-length form. A similar isoform is also found in human. This work highlights new complexities in the regulation of Erythropoietin (EPO) signaling in the brain.

  14. Neurofeedback-mediated self-regulation of the dopaminergic midbrain.

    PubMed

    Sulzer, James; Sitaram, Ranganatha; Blefari, Maria Laura; Kollias, Spyros; Birbaumer, Niels; Stephan, Klaas Enno; Luft, Andreas; Gassert, Roger

    2013-12-01

    The dopaminergic system is involved in reward encoding and reinforcement learning. Dopaminergic neurons from this system in the substantia nigra/ventral tegmental area complex (SN/VTA) fire in response to unexpected reinforcing cues. The goal of this study was to investigate whether individuals can gain voluntary control of SN/VTA activity, thereby potentially enhancing dopamine release to target brain regions. Neurofeedback and mental imagery were used to self-regulate the SN/VTA. Real-time functional magnetic resonance imaging (rtfMRI) provided abstract visual feedback of the SN/VTA activity while the subject imagined rewarding scenes. Skin conductance response (SCR) was recorded as a measure of emotional arousal. To examine the effect of neurofeedback, subjects were assigned to either receiving feedback directly proportional (n=15, veridical feedback) or inversely proportional (n=17, inverted feedback) to SN/VTA activity. Both groups of subjects were able to up-regulate SN/VTA activity initially without feedback. Veridical feedback improved the ability to up-regulate SN/VTA compared to baseline while inverted feedback did not. Additional dopaminergic regions were activated in both groups. The ability to self-regulate SN/VTA was differentially correlated with SCR depending on the group, suggesting an association between emotional arousal and neurofeedback performance. These findings indicate that SN/VTA can be voluntarily activated by imagery and voluntary activation is further enhanced by neurofeedback. The findings may lead the way towards a non-invasive strategy for endogenous control of dopamine.

  15. Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesions.

    PubMed

    Arias-Carrión, O; Verdugo-Díaz, L; Feria-Velasco, A; Millán-Aldaco, D; Gutiérrez, A A; Hernández-Cruz, A; Drucker-Colín, R

    2004-10-01

    Neurogenesis continues at least in two regions of the mammalian adult brain, the subventricular zone (SVZ) and the subgranular zone in hippocampal dentate gyrus. Neurogenesis in these regions is subjected to physiological regulation and can be modified by pharmacological and pathological events. Here we report the induction of neurogenesis in the SVZ and the differentiation after nigrostriatal pathway lesion along with transcranial magnetic field stimulation (TMFS) in adult rats. Significant numbers of proliferating cells demonstrated by bromodeoxyuridine-positive reaction colocalized with the neuronal marker NeuN were detected bilaterally in the SVZ, and several of these cells also expressed tyrosine hydroxylase. Transplanted chromaffin cells into lesioned animals also induced bilateral appearance of subependymal cells. These results show for the first time that unilateral lesion, transplant, and/or TMFS induce neurogenesis in the SVZ of rats and also that TMFS prevents the motor alterations induced by the lesion. Copyright 2004 Wiley-Liss, Inc.

  16. Inhibition of p38 pathway-dependent MPTP-induced dopaminergic neurodegeneration in estrogen receptor alpha knockout mice.

    PubMed

    Hwang, Chul Ju; Choi, Dong-Young; Jung, Yu Yeon; Lee, Young-Jung; Yun, Jae Suk; Oh, Ki-Wan; Han, Sang-Bae; Oh, Seikwan; Park, Mi Hee; Hong, Jin Tae

    2016-04-01

    Approximately, 7-10 million people in the world suffer from Parkinson's disease (PD). Recently, increasing evidence has suggested the protective effect of estrogens against nigrostriatal dopaminergic damage in PD. In this study, we investigated whether estrogen affects 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment in estrogen receptor alpha (ERα)-deficient mice. MPTP (15mg/kg, four times with 1.5-h interval)-induced dopaminergic neurodegeneration was evaluated in ERα wild-type (WT) and knockout (KO) mice. Larger dopamine depletion, behavioral impairments (Rotarod test, Pole test, and Gait test), activation of microglia and astrocytes, and neuroinflammation after MPTP injection were observed in ERα KO mice compared to those in WT mice. Immunostaining for tyrosine hydroxylase (TH) after MPTP injection showed fewer TH-positive neurons in ERα KO mice than WT mice. Levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC, metabolite of dopamine) were also lowered in ERα KO mice after MPTP injection. Interestingly, a higher immunoreactivity for monoamine oxidase (MAO) B was found in the substantia nigra and striatum of ERα KO mice after MPTP injection. We also found an increased activation of p38 kinase (which positively regulates MAO B expression) in ERα KO mice. In vitro estrogen treatment inhibited neuroinflammation in 1-methyl-4-phenyl pyridium (MPP+)-treated cultured astrocyte cells; however, these inhibitory effects were removed by p38 inhibitor. These results indicate that ERα might be important for dopaminergic neuronal survival through inhibition of p38 pathway.

  17. Purified Wnt-5a increases differentiation of midbrain dopaminergic cells and dishevelled phosphorylation.

    PubMed

    Schulte, Gunnar; Bryja, Vítezslav; Rawal, Nina; Castelo-Branco, Goncalo; Sousa, Kyle M; Arenas, Ernest

    2005-03-01

    The Wnt family of lipoproteins regulates several aspects of the development of the nervous system. Recently, we reported that Wnt-3a enhances the proliferation of midbrain dopaminergic precursors and that Wnt-5a promotes their differentiation into dopaminergic neurones. Here we report the purification of hemagglutinin-tagged Wnt-5a using a three-step purification method similar to that previously described for Wnt-3a. Haemagglutinin-tagged Wnt-5a was biologically active and induced the differentiation of immature primary midbrain precursors into tyrosine hydroxylase-positive dopaminergic neurones. Using a substantia nigra-derived dopaminergic cell line (SN4741), we found that Wnt-5a, unlike Wnt-3a, did not promote beta-catenin phosphorylation or stabilization. However, both Wnt-5a and Wnt-3a activated dishevelled, as assessed by a phosphorylation-dependent mobility shift. Moreover, the activity of Wnt-5a on dishevelled was blocked by pre-treatment with acyl protein thioesterase-1, indicating that palmitoylation of Wnt-5a is necessary for its function. Thus, our results suggest that Wnt-3a and Wnt-5a, respectively, activate canonical and non-canonical Wnt signalling pathways in ventral midbrain dopaminergic cells. Furthermore, we identify dishevelled as a key player in transducing both Wnt canonical and non-canonical signals in dopaminergic cells.

  18. Simultaneous activation of mitophagy and autophagy by staurosporine protects against dopaminergic neuronal cell death.

    PubMed

    Ha, Ji-Young; Kim, Ji-Soo; Kim, Seo-Eun; Son, Jin H

    2014-02-21

    Abnormal autophagy is frequently observed during dopaminergic neurodegeneration in Parkinson's disease (PD). However, it is not yet firmly established whether active autophagy is beneficial or pathogenic with respect to dopaminergic cell loss. Staurosporine, a common inducer of apoptosis, is often used in mechanistic studies of dopaminergic cell death. Here we report that staurosporine activates both autophagy and mitophagy simultaneously during dopaminergic neuronal cell death, and evaluate the physiological significance of these processes during cell death. First, staurosporine treatment resulted in induction of autophagy in more than 75% of apoptotic cells. Pharmacological inhibition of autophagy by bafilomycin A1 decreased significantly cell viability. In addition, staurosporine treatment resulted in activation of the PINK1-Parkin mitophagy pathway, of which deficit underlies some familial cases of PD, in the dopaminergic neuronal cell line, SN4741. The genetic blockade of this pathway by PINK1 null mutation also dramatically increa