scholarly journals Dopaminergic signalling is necessary, but not sufficient for cued fear memory destabilisation

2019 ◽  
Author(s):  
Charlotte R. Flavell ◽  
Jonathan L. C. Lee
Keyword(s):  
Therapeutic Strategy ◽  
Combined Treatment ◽  
Fear Memory ◽  
Receptor Activation ◽  
D1 Receptor ◽  
Extinction Learning ◽  
Enhancing Effect ◽  
Memory Reactivation ◽  
Therapeutic Benefits ◽  
Fear Expression

AbstractPharmacological targeting of memory reconsolidation is a promising therapeutic strategy for the treatment of fear memory-related disorders. However, the success of reconsolidation-based approaches depends upon the effective destabilisation of the fear memory by memory reactivation. Here, we show that the nootropic nefiracetam stimulates tone fear memory destabilisation to facilitate reconsolidation disruption by the glucocorticoid receptor antagonist mifepristone. Moreover, the enhancing effect of nefiracetam was dependent upon dopamine D1 receptor activation, although direct D1 receptor agonism was not sufficient to facilitate destabilisation. Finally, while the combined treatment with nefiracetam and mifepristone did not confer fear-reducing effects under conditions of extinction learning, there was some evidence that mifepristone reduces fear expression irrespective of memory reactivation parameters. Therefore, the use of combination pharmacological treatment to stimulate memory destabilisation and impair reconsolidation has potential therapeutic benefits, without risking a maladaptive increase of fear.

scholarly journals Post-reactivation mifepristone impairs generalisation of strongly-conditioned contextual fear memories

2020 ◽  
Author(s):  
Charlotte R. Flavell ◽  
Rebecca M. Gascoyne ◽  
Jonathan L. C. Lee
Keyword(s):  
Systemic Treatment ◽  
Combined Treatment ◽  
Fear Memory ◽  
Male Rats ◽  
Memory Reconsolidation ◽  
Memory Strength ◽  
Contextual Fear ◽  
Fear Expression

AbstractThe efficacy of pharmacological disruption of fear memory reconsolidation depends on several factors, including memory strength and age. We built on previous observations that systemic treatment with the nootropic nefiracetam potentiates cued fear memory destabilization to facilitate mifepristone-induced reconsolidation impairment. Here, we applied nefiratecam and mifepristone to strongly-conditioned, 1-week old contextual fear memories in male rats. Unexpectedly, the combined treatment did not result in impairment of contextual fear expression. However, mifepristone did reduce freezing to a novel context. These observations suggest that strong and established contextual fear memories do undergo destabilization without the need for pharmacological facilitation, and that impairments in strong context fear memory reconsolidation can manifest as a reduction in generalization.

scholarly journals Serine mutations in transmembrane V of the dopamine D1 receptor affect ligand interactions and receptor activation.

1992 ◽  
Vol 267 (25) ◽  
pp. 17780-17786
Author(s):  
N.J. Pollock ◽  
A.M. Manelli ◽  
C.W. Hutchins ◽  
M.E. Steffey ◽  
R.G. MacKenzie ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Ligand Interactions

scholarly journals Dopamine Transporter Genetic Reduction Induces Morpho-Functional Changes in the Enteric Nervous System

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 465
Author(s):  
Silvia Cerantola ◽  
Valentina Caputi ◽  
Gabriella Contarini ◽  
Maddalena Mereu ◽  
Antonella Bertazzo ◽  
...  
Keyword(s):  
Nervous System ◽  
Small Intestine ◽  
Enteric Nervous System ◽  
Dopamine Transporter ◽  
Myenteric Plexus ◽  
Receptor Activation ◽  
D1 Receptor ◽  
Functional Changes ◽  
Neurochemical Coding ◽  
The Impact

Antidopaminergic gastrointestinal prokinetics are indeed commonly used to treat gastrointestinal motility disorders, although the precise role of dopaminergic transmission in the gut is still unclear. Since dopamine transporter (DAT) is involved in several brain disorders by modulating extracellular dopamine in the central nervous system, this study evaluated the impact of DAT genetic reduction on the morpho-functional integrity of mouse small intestine enteric nervous system (ENS). In DAT heterozygous (DAT+/−) and wild-type (DAT+/+) mice (14 ± 2 weeks) alterations in small intestinal contractility were evaluated by isometrical assessment of neuromuscular responses to receptor and non-receptor-mediated stimuli. Changes in ENS integrity were studied by real-time PCR and confocal immunofluorescence microscopy in longitudinal muscle-myenteric plexus whole-mount preparations (). DAT genetic reduction resulted in a significant increase in dopamine-mediated effects, primarily via D1 receptor activation, as well as in reduced cholinergic response, sustained by tachykininergic and glutamatergic neurotransmission via NMDA receptors. These functional anomalies were associated to architectural changes in the neurochemical coding and S100β immunoreactivity in small intestine myenteric plexus. Our study provides evidence that genetic-driven DAT defective activity determines anomalies in ENS architecture and neurochemical coding together with ileal dysmotility, highlighting the involvement of dopaminergic system in gut disorders, often associated to neurological conditions.

scholarly journals Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct

2016 ◽  
Vol 310 (4) ◽  
pp. F284-F293 ◽  
Author(s):  
Alexis A. Gonzalez ◽  
Flavia Cifuentes-Araneda ◽  
Cristobal Ibaceta-Gonzalez ◽  
Alex Gonzalez-Vergara ◽  
Leonardo Zamora ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Critical Role ◽  
Combined Treatment ◽  
Receptor Activation ◽  
Ang Ii ◽  
Principal Cells ◽  
Protein Levels ◽  
Renin Synthesis ◽  
Renin Mrna ◽  
Creb Pathway

Renin is synthesized in the principal cells of the collecting duct (CD), and its production is increased via cAMP in angiotensin (ANG) II-dependent hypertension, despite suppression of juxtaglomerular (JG) renin. Vasopressin, one of the effector hormones of the renin-angiotensin system (RAS) via the type 2-receptor (V2R), activates the cAMP/PKA/cAMP response element-binding protein (CREB) pathway and aquaporin-2 expression in principal cells of the CD. Accordingly, we hypothesized that activation of V2R increases renin synthesis via PKA/CREB, independently of ANG II type 1 (AT1) receptor activation in CD cells. Desmopressin (DDAVP; 10−6 M), a selective V2R agonist, increased renin mRNA (∼3-fold), prorenin (∼1.5-fold), and renin (∼2-fold) in cell lysates and cell culture media in the M-1 CD cell line. Cotreatment with DDAVP+H89 (PKA inhibitor) or CREB short hairpin (sh) RNA prevented this response. H89 also blunted DDAVP-induced CREB phosphorylation and nuclear localization. In 48-h water-deprived (WD) mice, prorenin-renin protein levels were increased in the renal inner medulla (∼1.4- and 1.8-fold). In WD mice treated with an ACE inhibitor plus AT1 receptor blockade, renin mRNA and prorenin protein levels were still higher than controls, while renin protein content was not changed. In M-1 cells, ANG II or DDAVP increased prorenin-renin protein levels; however, there were no further increases by combined treatment. These results indicate that in the CD the activation of the V2R stimulates renin synthesis via the PKA/CREB pathway independently of RAS, suggesting a critical role for vasopressin in the regulation of renin in the CD.

scholarly journals Role of Amygdala-Infralimbic Cortex Circuitry in Glucocorticoid-Induced Facilitation of Auditory Fear Memory Extinction

2021 ◽  
pp. 1-22
Author(s):  
Masoomeh Dadkhah ◽  
◽  
Abbas Ali Vafaei ◽  
Ali Rashidy-Pour ◽  
Parnia Trahomi ◽  
...  
Keyword(s):  
Critical Role ◽  
Fear Memory ◽  
Fear Extinction ◽  
Freezing Behavior ◽  
Extinction Training ◽  
Male Rats ◽  
Memory Extinction ◽  
The Right ◽  
Fear Expression

Purpose: The basolateral amygdala (BLA) and infralimbic area (IL) of medial prefrontal cortex (mPFC) are two inter-connected brain structures that mediate both fear memory expression and extinction. Besides the well-known role of the BLA in the acquisition and expression of fear memory, projections from IL to BLA inhibit fear expression and have a critical role in fear extinction. However, the details of IL-BLA interaction remain unclear. Here, we aimed to investigate the role of functional reciprocal interactions between BLA and IL in mediating fear memory extinction. Methods: Using lidocaine (LID), male rats underwent unilateral or bilateral inactivation of the BLA and then unilateral intra-IL infusion of CORT, prior to extinction training of auditory fear conditioning paradigm. Freezing behavior was reported as an index for the measurement of conditioned fear. Infusions were performed before the extinction training, allowing to examine the effects on fear expression and also further extinction memory. Experiments 1-3 investigated the effects of left or right infusion of CORT into IL, and LID unilaterally into BLA on fear memory extinction. Results: Results showed that intra-IL infusion of CORT in the right hemisphere reduced freezing behavior when administrated before the extinction training. Auditory fear memory extinction was impaired by asymmetric inactivation of BLA and CORT infusion in the right IL; however, the same effect was not observed with symmetric inactivation of BLA. Conclusion: It is concluded that that the IL-BLA neural circuit may provide additional evidence to contribution of this circuit in auditory fear extinction. This study demonstrate dissociable roles for right or left BLA in subserving the auditory fear extinction. Our finding also raise the possibility that left BLA-IL circuitry may contribute in mediating auditory fear memory extinction via underlying mechanisms, however further research is required.

scholarly journals Dopamine D1 receptor activation contributes to light-adapted changes in retinal inhibition to rod bipolar cells

2018 ◽  
Vol 120 (2) ◽  
pp. 867-879 ◽  
Author(s):  
Michael D. Flood ◽  
Johnnie M. Moore-Dotson ◽  
Erika D. Eggers
Keyword(s):  
Light Adaptation ◽  
Amacrine Cell ◽  
Amacrine Cells ◽  
Receptor Activation ◽  
Bipolar Cells ◽  
D1 Receptor ◽  
D1 Receptors ◽  
Light Responses ◽  
Dopamine Modulation ◽  
Rod Bipolar Cells

Dopamine modulation of retinal signaling has been shown to be an important part of retinal adaptation to increased background light levels, but the role of dopamine modulation of retinal inhibition is not clear. We previously showed that light adaptation causes a large reduction in inhibition to rod bipolar cells, potentially to match the decrease in excitation after rod saturation. In this study, we determined how dopamine D1 receptors in the inner retina contribute to this modulation. We found that D1 receptor activation significantly decreased the magnitude of inhibitory light responses from rod bipolar cells, whereas D1 receptor blockade during light adaptation partially prevented this decline. To determine what mechanisms were involved in the modulation of inhibitory light responses, we measured the effect of D1 receptor activation on spontaneous currents and currents evoked from electrically stimulating amacrine cell inputs to rod bipolar cells. D1 receptor activation decreased the frequency of spontaneous inhibition with no change in event amplitudes, suggesting a presynaptic change in amacrine cell activity in agreement with previous reports that rod bipolar cells lack D1 receptors. Additionally, we found that D1 receptor activation reduced the amplitude of electrically evoked responses, showing that D1 receptors can modulate amacrine cells directly. Our results suggest that D1 receptor activation can replicate a large portion but not all of the effects of light adaptation, likely by modulating release from amacrine cells onto rod bipolar cells. NEW & NOTEWORTHY We demonstrated a new aspect of dopaminergic signaling that is involved in mediating light adaptation of retinal inhibition. This D1 receptor-dependent mechanism likely acts through receptors located directly on amacrine cells, in addition to its potential role in modulating the strength of serial inhibition between amacrine cells. Our results also suggest that another D2/D4 receptor-dependent or dopamine-independent mechanism must also be involved in light adaptation of inhibition to rod bipolar cells.

scholarly journals Farnesoid X receptor activation inhibits TGFBR1/TAK1-mediated vascular inflammation and calcification via miR-135a-5p

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Chao Li ◽  
Shijun Zhang ◽  
Xiaoqing Chen ◽  
Jingkang Ji ◽  
Wenqing Yang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Smooth Muscle ◽  
Vascular Calcification ◽  
Therapeutic Strategy ◽  
Vascular Inflammation ◽  
Receptor Activation ◽  
Farnesoid X Receptor ◽  
Osteogenic Medium ◽  
Aortic Smooth Muscle ◽  
High Phosphate

AbstractChronic inflammation plays a crucial role in vascular calcification. However, only a few studies have revealed the mechanisms underlying the development of inflammation under high-phosphate conditions in chronic kidney disease (CKD) patients. Here, we show that inflammation resulting from the activation of the TGFBR1/TAK1 pathway is involved in calcification in CKD rats or osteogenic medium-cultured human aortic smooth muscle cells (HASMCs). Moreover, miR-135a-5p is demonstrated to be a key regulator of the TGFBR1/TAK1 pathway, which has been reported to be decreased in CKD rats. We further reveal that farnesoid X receptor (FXR) activation increases miR-135a-5p expression, thereby inhibiting the activation of the TGFBR1/TAK1 pathway, ultimately resulting in the attenuation of vascular inflammation and calcification in CKD rats. Our findings provide advanced insights into the mechanisms underlying the development of inflammation in vascular calcification, and evidence that FXR activation could serve as a therapeutic strategy for retarding vascular calcification in CKD patients.

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