Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

Robichon, Katharina; Sondhauss, Sven; Jordan, T. William; Keyzers, Robert A.; Connor, Bronwen; Flamme, Anne Camille La

doi:10.1038/s41598-021-82667-6

Cited by 13 publications

(9 citation statements)

References 62 publications

(99 reference statements)

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“…In accordance with our nding, the expression of D2R on brain-resident or in ltrating immune cells in EAE was already showed to be signi cantly increasing[65]. Moreover, in the work byRobichon et al (2021) no signi cant reduction in the immunocontent of D1R on macrophages and monocytes was reported[65]…”

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confidence: 89%

Dopaminergic Receptors as Neuroimmune Mediators in Experimental Autoimmune Encephalomyelitis

et al. 2021

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The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system with the pathogenesis of multiple sclerosis (MS). Herein, we investigate the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also examined if the treatment with pramipexole (PPX) -a dopamine D2/D3 receptor-preferring agonist -would be able to prevent the EAE-induced motor and mood dysfunction, as well as the underlying mechanisms of action. Our ndings showed that D2R immunocontent upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontent was signi cantly increased in the lymph nodes during the chronic phase of EAE. Also, during this phase, oxidative damage in the spinal cord and striatum of EAE animals was signi cantly higher. During the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. In addition, PPX treatment failed to inhibit EAE progression and anhedonic-like behavior. Otherwise, PPX inhibited the depressive-like behavior. Relevantly, PPX oral treatment downregulated IL-1β levels and increased BNDF content in the spinal cord after EAE induction. Altogether, it is possible to conclude that D2R participates in crosstalk between CNS and immune system during autoimmune and neuroin ammatory response induced by EAE, mainly in the acute and chronic phase of the disease. Relevantly, a dopamine D2/D3 receptor-preferring agonist mitigated depressive-like behavior induced by EAE, which offers a new possibility for treating depressive symptoms in MS patients.

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confidence: 89%

Dopaminergic Receptors as Neuroimmune Mediators in Experimental Autoimmune Encephalomyelitis

et al. 2021

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“…Clozapine and risperidone were tested in patients with MS (CRISP, or Community ReIntegration for Socially isolated Patients, trial, ACTRN12616000178448), but the trial was halted early due to a higher incidence of adverse side effects during the titration stage (72), prompting investigations into the pharmacodynamics of these drugs. Robichon et al (73) investigated the biodistribution of clozapine in a mouse EAE model using matrix-assisted laser desorption ionization, or MALDI, imaging (73). Higher levels (fivefold) of clozapine in the serum were observed in EAE mice compared with control mice.…”

Section: Imaging Agents Based On Established Therapeutic Drugsmentioning

confidence: 99%

Opportunities for Molecular Imaging in Multiple Sclerosis Management: Linking Probe to Treatment

Thomas¹,

Barkhof²,

Bulte³

2022

Radiology

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“…Flow cytometry has not been traditionally used to measure receptor expression, but advancements in this technique have resulted in it being capable of measuring membrane-bound receptor expression in single intact cells. In fact, a procedure for measuring D2 receptor expression in rodents was recently optimised and published by the consulted research group (Robichon et al, 2021). Additionally, this group generously offered to provide both the technical support and laboratory supplies required to conduct flow cytometry.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Flow cytometry was immediately performed on a BD FACS Canto II (BD Biosciences) and analysed using FlowJo software version 10.6 (Treestar Inc., Ashland, OR, USA). This general procedure has been previously reported (Robichon et al, 2021).…”

Section: Cell Preparationmentioning

confidence: 99%

“…Flow cytometry was used to measure D2 receptor expression. Flow cytometry, like autoradiographic or immunohistochemical techniques, is used to measure protein expression (see, Benoit et al, 2018) and is capable of detecting changes in D2 expression in rodents (Robichon et al, 2021). Flow cytometry allows unfixed tissue to be extracted, processed, and analysed within a single day.…”

Section: Reversal Learningmentioning

confidence: 99%

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The Effects of Repeated Dopamine D2 Receptor Antagonism on D2 Receptor Expression and Behavioural Inflexibility

Highgate¹

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Background: Reversal learning has been shown to improve as a function of dopamine D2 receptor expression, and manipulations that downregulated D2 expression also impaired behavioural flexibility. The possibility remains that an upregulation may facilitate reversal learning. Further, D2 receptor expression and reversal learning were compromised following repeated methamphetamine exposure. It stands to reason that restoration of receptor expression following methamphetamine exposure might prevent this impairment from occurring. Objectives: Develop a procedure for measuring reversal learning and determine whether repeated D2 receptor antagonism increases D2 receptor expression and improves behavioural flexibility in rats. Further, the possibility that this treatment would ameliorate behavioural inflexibility produced by prior methamphetamine exposure was examined. Methods: A task was developed to measure reversal learning. I systematically replicated an existing procedure, but then developed a novel procedure that focused on identifying a reasonable criterion for visual discrimination. To do this, male Sprague Dawley rats completed 25 days of visual discrimination. Various criteria requiring different levels of accuracy and persistence were retrospectively applied to the data and a single criterion was selected from these. The procedure was then extended to include three reversal tasks. In the next study, male Sprague-Dawley rats received repeated daily pretreatment with the dopamine D2 antagonist, eticlopride (0.0 or 0.3 mg/kg/day, IP, 14 days). Three days after treatment, whole-brain (minus olfactory bulbs and cerebellum) dopamine D2 receptor expression was measured using flow cytometry. Another cohort was exposed to the same regimen between the second and third reversal task to determine whether this treatment improved reversal learning. The final study was then conducted, the only difference from the previous study being that methamphetamine (0.0mg/kg or 2.0mg/kg, SC, 4 injections, 2 hours apart) was administered the day before eticlopride treatment commenced in order to produce behavioural inflexibility. Results: The criterion developed for the acquisition of visual discrimination was adopted for several reasons. First, the entire sample was able to meet the criterion. Second, the number of days to acquisition was equivalent irrespective of which visual cue served as the discriminative stimulus. Finally, accuracy was persistent both within and between test sessions. Importantly, therefore, these criteria eliminated confounds that might otherwise have been expected to impact reversal learning performance. The adjunct reversal tasks were typically completed within 2-5 test days, which was important since neuroadaptations can revert over time, and individual differences in performance were consistent across tasks. As expected, eticlopride treatment increased D2 receptor expression and improved reversal learning. Further, this improvement was predicted by baseline behavioural flexibility measures, such that, the improvement produced by repeated eticlopride treatment preferentially mpacted rats that were less behaviourally flexible prior to treatment. Methamphetamine treatment impaired reversal learning, but this impairment was prevented by repeated eticlopride treatment. Conclusions: Choice of criterion impacts behavioural performance in visual discrimination learning. D2 receptor expression is also a critical determinant of behavioural flexibility, irrespective of whether the discriminative stimulus is visual or spatial. Further, pre-existing, or experimentally produced behavioural inflexibility is sensitive to a treatment that upregulated D2 expression. Collectively, these findings support the critical role of D2 expression in reversal learning and suggest it is an effective target for facilitating behavioural flexibility.

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Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

Cited by 13 publications

References 62 publications

Dopaminergic Receptors as Neuroimmune Mediators in Experimental Autoimmune Encephalomyelitis

Dopaminergic Receptors as Neuroimmune Mediators in Experimental Autoimmune Encephalomyelitis

Opportunities for Molecular Imaging in Multiple Sclerosis Management: Linking Probe to Treatment

The Effects of Repeated Dopamine D2 Receptor Antagonism on D2 Receptor Expression and Behavioural Inflexibility

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