scholarly journals AMPA receptors mediate the pro-cognitive effects of electrical and optogenetic stimulation of the medial prefrontal cortex in antidepressant non-responsive Wistar–Kyoto rats

2020 ◽  
Vol 34 (12) ◽  
pp. 1418-1430
Author(s):  
Mariusz Papp ◽  
Piotr Gruca ◽  
Magdalena Lason ◽  
Ewa Litwa ◽  
Wojciech Solecki ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Antidepressant Drugs ◽  
Mild Stress ◽  
Sucrose Intake ◽  
Wky Rats ◽  
Optogenetic Stimulation ◽  
Wistar Kyoto

Background: The chronic mild stress (CMS) procedure is a widely used animal model of depression, and its application in Wistar–Kyoto (WKY) rats has been validated as a model of antidepressant-refractory depression. While not responding to chronic treatment with antidepressant drugs, WKY rats do respond to acute deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC). In antidepressant-responsive strains there is evidence suggesting a role for AMPA subtype of glutamate receptor in the action mechanism of both antidepressants and DBS. Methods: Animals were subjected to CMS for 6 to 8 weeks; sucrose intake was monitored weekly and novel object recognition (NOR) test was conducted following recovery from CMS. Wistars were treated chronically with venlafaxine (VEN), while WKY were treated acutely with either DBS, optogenetic stimulation (OGS) of virally-transduced (AAV5-hSyn-ChR2-EYFP) mPFC or ventral hippocampus, or acute intra-mPFC injection of the AMPA receptor positive allosteric modulator CX-516. The AMPA receptor antagonist NBQX was administered, at identical sites in mPFC, immediately following the exposure trial in the NOR. Results: Sucrose intake and NOR were suppressed by CMS, and restored by VEN in Wistars and by DBS, OGS, or CX-516 in WKY. However, OGS of the ventral hippocampal afferents to mPFC was ineffective. A low dose of NBQX selectively blocked the procognitive effect of VEN, DBS and OGS. Conclusions: These results suggest that activation of AMPA receptors in the mPFC represents a common pathway for the antidepressant effects of both conventional (VEN) and novel (DBS, OGS) antidepressant modalities, in both antidepressant responsive (Wistar) and antidepressant-resistant (WKY) rats.

scholarly journals Insufficiency of ventral hippocampus to medial prefrontal cortex transmission explains antidepressant non-response

2021 ◽  
pp. 026988112110482 ◽  
Author(s):  
Mariusz Papp ◽  
Piotr Gruca ◽  
Magdalena Lason ◽  
Ewa Litwa ◽  
Wojciech Solecki ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Ventral Hippocampus ◽  
Normal Brain ◽  
Mild Stress ◽  
Sucrose Intake ◽  
Normal Behaviour ◽  
Wky Rats

Background: There is extensive evidence that antidepressant drugs restore normal brain function by repairing damage to ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). While the damage is more extensive in hippocampus, the evidence of treatments, such as deep brain stimulation, suggests that functional changes in prefrontal cortex may be more critical. We hypothesized that antidepressant non-response may result from an insufficiency of transmission from vHPC to mPFC. Method: Antidepressant non-responsive Wistar Kyoto (WKY) rats were subjected to chronic mild stress (CMS), then treated with chronic daily administration of the antidepressant drug venlafaxine (VEN) and/or repeated weekly optogenetic stimulation (OGS) of afferents to mPFC originating from vHPC or dorsal HPC (dHPC). Results: As in many previous studies, CMS decreased sucrose intake, open-arm entries on the elevated plus maze (EPM), and novel object recognition (NOR). Neither VEN nor vHPC–mPFC OGS alone was effective in reversing the effects of CMS, but the combination of chronic VEN and repeated OGS restored normal behaviour on all three measures. dHPC–mPFC OGS restored normal behaviour in the EPM and NOR test irrespective of concomitant VEN treatment, and had no effect on sucrose intake. Conclusions: The synergism between VEN and vHPC–mPFC OGS supports the hypothesis that the antidepressant non-responsiveness of WKY rats results from a failure of antidepressant treatment fully to restore transmission in the vHPC–mPFC pathway.

Rapid antidepressant effects of deep brain stimulation of the pre-frontal cortex in an animal model of treatment-resistant depression

2018 ◽  
Vol 32 (10) ◽  
pp. 1133-1140 ◽  
Author(s):  
Mariusz Papp ◽  
Piotr Gruca ◽  
Magdalena Lason ◽  
Katarzyna Tota-Glowczyk ◽  
Monika Niemczyk ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
Antidepressant Drugs ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Sucrose Intake ◽  
Treatment Resistant ◽  
Deep Brain ◽  
Stimulation Of

Background: A significant proportion of depressed patients fail to respond to treatment with antidepressant drugs. Such patients might nonetheless respond to deep brain stimulation of the prefrontal cortex. Deep brain stimulation has also been shown to normalize behaviour in the chronic mild stress (CMS) model of depression. However, these studies have involved animals that are in general treatment responsive. Thus, this is not the ideal situation in which to investigate how deep brain stimulation is effective where antidepressant drugs are not. Aims: Here, we studied the behavioural effects of deep brain stimulation in treatment-resistant animals. Methods: Wistar rats were exposed to chronic mild stress and concurrent treatment with saline or one of three antidepressant drugs, imipramine, citalopram and venlafaxine. Individuals were selected from the CMS-exposed drug-treated groups that had failed to increase their sucrose intake by week 5 of drug treatment. All animals were then implanted with deep brain stimulation electrodes in the ventro-medial prefrontal cortex, and tested for sucrose intake and in the elevated plus maze and novel object recognition test, following 2 × 2 h of deep brain stimulation. Results: The selected drug-treated animals were found to be antidepressant-resistant in all three tests. With a single exception (sucrose intake in imipramine-treated animals), deep brain stimulation reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all four conditions, with no significant differences between saline- and drug-treated animals. Conclusions: These data provide a proof of principle that deep brain stimulation of the prefrontal cortex can be effective in a rat model of resistance to chronic antidepressant treatment, replicating the clinical effect of deep brain stimulation in treatment-resistant depression.

scholarly journals Antidepressant Effect of Optogenetic Stimulation of the Medial Prefrontal Cortex

2010 ◽  
Vol 30 (48) ◽  
pp. 16082-16090 ◽  
Author(s):  
H. E. Covington ◽  
M. K. Lobo ◽  
I. Maze ◽  
V. Vialou ◽  
J. M. Hyman ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Antidepressant Effect ◽  
Optogenetic Stimulation ◽  
Stimulation Of

The role of prefrontal cortex dopamine D2 and D3 receptors in the mechanism of action of venlafaxine and deep brain stimulation in animal models of treatment-responsive and treatment-resistant depression

2019 ◽  
Vol 33 (6) ◽  
pp. 748-756 ◽  
Author(s):  
Mariusz Papp ◽  
Piotr Gruca ◽  
Magdalena Lason ◽  
Monika Niemczyk ◽  
Paul Willner
Keyword(s):  
Prefrontal Cortex ◽  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
Memory Consolidation ◽  
Wistar Rats ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Wistar Kyoto Rats ◽  
Wistar Kyoto ◽  
Deep Brain

Aims: The Wistar-Kyoto rat has been validated as an animal model of treatment-resistant depression. Here we investigated a role of dopamine D2 and D3 receptors in the ventro-medial prefrontal cortex in the mechanism of action of deep brain stimulation in Wistar-Kyoto rats and venlafaxine in Wistar rats. Methods: Wistar or Wistar-Kyoto rats were exposed chronically to chronic mild stress. Wistar rats were treated chronically with venlafaxine (10 mg/kg) beginning after two weeks of chronic mild stress; Wistar-Kyoto rats received two sessions of deep brain stimulation before behavioural tests. L-742,626 (1 µg), a D2 receptor agonist, or 7-OH DPAT (3 µg), a D3 receptor antagonist, were infused into the ventro-medial prefrontal cortex immediately following the exposure trial in the Novel Object Recognition Test, and discrimination between novel and familiar object was tested one hour later. Results: Chronic mild stress decreased sucrose intake and impaired memory consolidation; these effects were reversed by venlafaxine in Wistar rats and deep brain stimulation in Wistar-Kyoto rats. In control animals, L-742,626 and 7-OH DPAT also impaired memory consolidation. In Wistar rats, venlafaxine reversed the effect of L-742,626 in controls, but not in the chronic mild stress group, and venlafaxine did not reverse the effect of 7-OH DPAT in either group. In Wistar-Kyoto rats, deep brain stimulation reversed the effect of both L-742,626 and 7-OH DPAT in both control and chronic mild stress groups. Conclusions: We conclude that the action of venlafaxine to reverse the impairment of memory consolidation caused by chronic mild stress in Wistar rats involves D2 receptors in the ventro-medial prefrontal cortex; but the effect of deep brain stimulation to reverse the same effect in Wistar-Kyoto rats does not.

scholarly journals Modulation of extracellular d-serine content by calcium permeable AMPA receptors in rat medial prefrontal cortex as revealed by in vivo microdialysis

2013 ◽  
Vol 16 (6) ◽  
pp. 1395-1406 ◽  
Author(s):  
Sayuri Ishiwata ◽  
Asami Umino ◽  
Masakazu Umino ◽  
Kazuko Yorita ◽  
Kiyoshi Fukui ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Receptor Antagonist ◽  
Medial Prefrontal Cortex ◽  
Glutamate Receptor ◽  
Ampa Receptor ◽  
In Vivo Microdialysis ◽  
Receptor Subtype ◽  
Fluorometric Detection ◽  
Brain Functions

Abstract In mammalian brains, d-serine has been shown to be required for the regulation of glutamate neurotransmission as an endogenous co-agonist for the N-methyl-d-aspartate type glutamate receptor that is essential for the expression of higher-order brain functions. The exact control mechanisms for the extracellular d-serine dynamics, however, await further elucidation. To obtain an insight into this issue, we have characterized the effects of agents acting at the α-amino-3-hydroxy-5-methyl-4-isoxazolepropioinic acid (AMPA) type glutamate receptor on the extracellular d-serine contents in the medial prefrontal cortex of freely moving rats by an in vivo microdialysis technique in combination with high-performance liquid chromatography with fluorometric detection. In vivo experiments are needed in terms of a crucial role of d-serine in the neuron-glia communications despite the previous in vitro studies on AMPA receptor-d-serine interactions using the separated preparations of neurons or glial cells. Here, we show that the intra-cortical infusion of (S)-AMPA, an active enantiomer at the AMPA receptor, causes a significant and concentration-dependent reduction in the prefrontal extracellular contents of d-serine, which is reversed by an AMPA/kainate receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, and a calcium permeable AMPA receptor antagonist, 1-naphthyl acetyl spermine. The d-serine reducing effects of (S)-AMPA are augmented by co-infusion of cyclothiazide that prevents AMPA receptor desensitization. Our data support the view that a calcium permeable AMPA receptor subtype may exert a phasic inhibitory control on the extracellular d-serine release in the mammalian prefrontal cortex in vivo.

β-Carboline harmine reverses the effects induced by stress on behaviour and citrate synthase activity in the rat prefrontal cortex

2013 ◽  
Vol 25 (6) ◽  
pp. 328-333 ◽  
Author(s):  
Helena Mendes Abelaira ◽  
Gislaine Zilli Réus ◽  
Giselli Scaini ◽  
Emilio Luiz Streck ◽  
José Alexandre Crippa ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Energy Metabolism ◽  
Citrate Synthase ◽  
Memory Performance ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Sucrose Intake ◽  
The Brain

ObjectivesThe present study was aimed at evaluating the effects of the administration of β-carboline harmine on behaviour and citrate synthase activity in the brain of rats exposed to chronic mild stress (CMS) procedure.MethodsTo this aim, after 40 days of exposure to CMS procedure, rats were treated with harmine (15 mg/kg/day) for 7 days, then memory, anhedonia and citrate synthase activity were assessed.ResultOur findings demonstrated that stressed rats treated with saline increased the sucrose intake, and the stressed rats treated with harmine reversed this effect. Neither stress nor harmine treatment altered memory performance in rats. In addition, chronic stressful situations induced increase in citrate synthase activity in the prefrontal cortex, but not in the hippocampus and striatum. Treatment with harmine reversed the increase in citrate synthase activity in the prefrontal cortex.ConclusionThese findings support the hypothesis that harmine could be involved in controlling the energy metabolism.

scholarly journals Validation of the Wistar-kyoto Rat Kept in Solitary Housing as an Animal Model for Endogenous Depression Using Voxel-based Morphometry

2021 ◽  
Author(s):  
Takanobu Yoshii ◽  
Naoya Oishi ◽  
Yasutaka Sotozono ◽  
Anri Watanabe ◽  
Yuki Sakai ◽  
...  
Keyword(s):  
Animal Model ◽  
Cerebellar Nuclei ◽  
Endogenous Depression ◽  
Lateral Septum ◽  
Cerebellar Vermis ◽  
Mild Stress ◽  
Voxel Based Morphometry ◽  
Wky Rats ◽  
Study Results ◽  
Wistar Kyoto

Abstract Major depressive disorder is a common psychiatric condition that is often resistant to medication. The Wistar-Kyoto (WKY) rat has been suggested as an animal model of endogenous depression; however, it is challenging to translate results obtained in animal models into humans. Solitary housing is a mild stress paradigm that could simulate the environment of depressive patients with limited social activity due to symptoms. We used voxel-based morphometry to directly compare the solitary-housed WKY rat model with data from previous human studies, and validated our results with behavioural studies and correlation analyses. Atrophy in WKY rats was detected in the ventral hippocampus, caudate putamen, lateral septum, cerebellar vermis, and cerebellar nuclei (p < 0.05, corrected for family-wise error rate). Further, locomotor behaviour was negatively correlated with hippocampal atrophy and positively correlated with atrophy of the cerebellar vermis. The regions of brain atrophy validate WKY rats as an animal model for endogenous depression and can aid the translation of study results to humans. Our study also reveals the possibility of a cerebellar contribution to depression.

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