Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
Michael FritzAnna M. KlawonnAnna NilssonAnand Kumar SinghJoanna ZajdelDaniel WilhelmsMichael LazarusAndreas LöfbergMaarit JaarolaUnn KugelbergTimothy R. BilliarDavid J. HackamChhinder P. SodhiMatthew D. BreyerJohan JakobssonMarkus SchwaningerGünther SchützJan Rodriguez ParkitnaClifford B. SaperAnders BlomqvistDavid Engblom
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Abstract:
Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type–specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.Na+-dependent binding of 3H-Cocaine is located on dopaminergic terminals and is related to the dopamine uptake system. Studies on senescent rats indicate a decrease in 3H-Cocaine binding density in the striatum. In the same tissue an increase in the Km for dopamine uptake is observed. These changes might be relevant in the age-dependent alterations in dopaminergic function.
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Dopaminergic pathways
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The synaptic deficit of brain dopaminergic activity involves a complex pattern of changes both at presynaptic and at postsynaptic level. The aged dopaminergic nuclei present a reduced number of dopamine terminals, a decreased ability to synthesize and reuptake dopamine and defective recognition sites both in terms of absolute number of D2 receptors and of transducing mechanisms linked to D1 receptors. These changes suggest that the dopaminergic system may be particularly sensitive during aging to environmental, iatrogenic and toxic factors, which may easily make the elderly develop symptoms of central dopamine deficiency.
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Many individuals with mental retardation exhibit chronic aberrant behaviors (CABs) that includes hyperactive, stereotyped, aggressive, and self-injurious behaviors. Brain imaging studies have found that several of these individuals have abnormalities in their dopaminergic neurotransmitter systems that are thought to be responsible in part, for the development of these behaviors. The present study evaluated the effects of a selective dopamine re-uptake blocker, GBR-12909 in three animal models of varying striatal dopamine concentrations. The three animal models included the neonatal 6-hydroxydopamine (6-OHDA)-lesioned rat, a model of dopamine neuronal depletion, the prenatal methylazoxymethanol (MAM)-exposed rat, a model of hyper-dopaminergic innervation and control rats, a model of normal dopaminergic function. The animals were given five daily injections of GBR-12909 and videotaped observations were conducted immediately following the injections and 6h later. The results of the study indicate that the MAM-treated rats exhibited more hyperactive behaviors than either the 6-OHDA or the control animals in response to the GBR-12909 injections. However, the 6-OHDA and control rats exhibited more self-injurious behaviors than the MAM rats. Interestingly, the topography of the self-injurious behavior exhibited differed from that we have previously observed in 6-OHDA lesioned rats following dopamine agonists and resembles the mouthing behaviors seen in some individuals with mental retardation, in particular those with Rett syndrome. These findings indicate the models of varying dopaminergic function interact differently with a dopamine re-uptake blocker than dopamine agonists and that the partially dopamine depleted model may model the behaviors seen in individuals with Rett syndrome.
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Dopamine is an intercellular messenger in both vertebrates and invertebrates. It exerts its physiological functions by binding to specific dopamine receptors. Dopaminergic systems in mammals control several important physiological functions ranging from voluntary movement and reward to general aspects of hormonal regulation and the regulation of blood pressure to name only few. Alterations in the dopaminergic system have been associated with several psychiatric and neurological disorders such as Schizophrenia and Parkinson’s disease (PD). On the contrary, the dopaminergic system in Drosophila is not well characterized. For this, characterization of the dopaminergic system in normal flies before further analyses was a basis of this study. The aim was to elucidate the expression patterns of dopamine receptors in the central nervous system (CNS) and the digestive tract and to analyze the function of these receptors at cellular and/or behavioral level in Drosophila. With this respect, I used immunohistochemical, RNAi, overexpression and pharmacological approaches. The findings from this part of study were striking. A wide distribution of four dopamine receptors present in Drosophila was apparent in the CNS and in the digestive tract. In the CNS, one receptor, DopR, was localized in dopamine producing cells, which suggests an auto-receptor function of this receptor at least in this subset of dopamine producing cells. More importantly, two receptors; DopR and DopR2 where localized in a subset of clock neurons that expresses the neuropeptide PDF (pigment dispersing factor) indicative for the hypothesis that these receptors control circadian rhythms in Drosophila melanogaster. Localization was also observed in higher order brain structures such as mushroom bodies and the central complex, regions that are implicated in controlling of learning/memory and locomotion, respectively. In the digestive tract, dopamine receptors were distributed differently in the major cells of the midgut. The wide distribution of dopamine receptors in neurons and non-neuronal tissues provides insights into the roles played by these receptors in controlling different physiological functions and behaviors in the fruit fly.
Advanced age is a major risk factor for many neurodegenerative disorders including Parkinson’s disease Preventing or stopping the development of this neurological disorder and the search for alternative treatment strategies is a major scientific challenge. Both genetic and environmental factors seem to contribute to PD development. Unfortunately, clinically relevant symptoms of PD appear when degeneration of the nigrostriatal dopamine producing (DA) neurons is at an advanced stage. For this reason, the second aim of this study focused on elucidating molecular responses involved during the asymptomatic phase of PD in-order to identify potential targets for therapeutic intervention. I used the pesticide rotenone to induce Parkinsonism in Drosophila melanogaster. Moreover, rotenone-induced Parkinsonism was combined with a focused transcriptomic analysis of DA neurons. This study provides evidences that the outcome of various highly relevant signaling pathways is modified in the dopamine producing neurons that are in an early stage of PD. Amongst these affected systems are the Wnt-, MAPK/EGFR-, TGF-β-, and TOR-signaling pathways, which are known to be important for cell survival and/or cell death in the CNS. Thus, further studies involving these pathways may provide new insights into the molecular events underlying pathogenesis and, hopefully, lead to the identification of new potential targets for neuroprotective interventions for PD.
Lastly, this study focused on the development of alternative therapeutic strategies for treatment of PD. In this, I tested whether modulation of intracellular second messenger systems by employing so-called DREADD (Designer Receptors Exclusively Activated by Designer Drugs) receptors in DA-producing neurons during rotenone treatment can prevent or delay development of the disease phenotype. Manipulation of these second messenger systems (cAMP or Ca2+) in DA-producing neurons did not prevent development of the disease phenotype induced by rotenone in the Drosophila model of PD.
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