OPEN Foundation

G. Wegener

Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin

January 3, 2022 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychopharmacology / Leave a Comment / By / , , ,

Abstract

Background: Psilocybin is a serotonergic psychedelic found in “magic mushrooms” with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and addiction. In rodents, psilocybin acutely induces plasticity-related immediate early genes in cortical tissue; however, studies into the effects on subcortical regions, of different doses, and the subsequent translation of corresponding proteins are lacking.

Methods: We examined the acute effects of a single administration of psilocybin (0.5-20 mg/kg) on the expression of selected genes in the prefrontal cortex and hippocampus. In total, 46 target genes and eight reference genes were assessed using real-time quantitative polymerase chain reaction. Corresponding protein levels of the three most commonly regulated genes were assessed using Western blotting.

Results: In the prefrontal cortex, psilocybin increased the expression of Cebpb, c-Fos, Dups1, Fosb, Junb, Iκβ-α, Nr4a1, P11, Psd95, and Sgk1, and decreased the expression of Clk1. In the hippocampus, psilocybin strongly increased the expression of Arrdc2, Dusp1, Iκβ-α, and Sgk1 in a dose-dependent manner, and decreased the expression of Arc, Clk1, Egr2, and Ptgs2. Protein levels of Sgk1, Dusp1, and Iκβ-α showed only partial agreement with transcriptional patterns, stressing the importance of assessing downstream translation when investigating rapid gene responses.

Conclusion: The present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. Our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.

Jefsen, O. H., Elfving, B., Wegener, G., & Müller, H. K. (2021). Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. Journal of psychopharmacology (Oxford, England), 35(4), 483–493. https://doi.org/10.1177/0269881120959614O.

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Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat.

May 20, 2019 / Depression, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , , , , , ,

Abstract

OBJECTIVE:
Psilocybin is a serotonin receptor agonist with a therapeutic potential for treatment-resistant depression and other psychiatric illnesses. We investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression.
METHODS:
Using the Flinders Sensitive Line (FSL) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (FST). We measured locomotor activity in an open field test (OFT) to control for stimulant properties of the drugs. We performed a set of experiments to test different doses, treatment paradigms, and timing of the tests in relation to the drug administration.
RESULTS:
Psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the FST and no effect on locomotor activity in the OFT. FSL rats did show significantly more immobility than their control strain, the Flinders Resistant Line, as expected.
CONCLUSION:
Psilocin and psilocybin showed no antidepressant-like effect in the FSL rats, despite a positive effect in humans. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.
Jefsen, O., Højgaard, K., Christiansen, S. L., Elfving, B., Nutt, D. J., Wegener, G., & Müller, H. K. (2019). Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat. Acta neuropsychiatrica, 1-7., https://doi.org/10.1017/neu.2019.15
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Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

February 8, 2017 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , ,

Abstract

BACKGROUND AND PURPOSE: Astroglia contribute to the pathophysiology of major depression and antidepressant drugs act by modulating synaptic plasticity; therefore, the present study investigated whether the fast antidepressant action of ketamine is reflected in a rapid alteration of the astrocytes’ morphology in a genetic animal model of depression.

EXPERIMENTAL APPROACH: S-Ketamine (15 mg·kg-1 ) or saline was administered as a single injection to Flinders Line (FSL/ FRL) rats. Twenty-four hours after the treatment, perfusion fixation was carried out and the morphology of glial fibrillary acid protein (GFAP)-positive astrocytes in the CA1 stratum radiatum (CA1.SR) and the molecular layer of the dentate gyrus (GCL) of the hippocampus was investigated by applying stereological techniques and analysis with Imaris software. The depressive-like behaviour of animals was also evaluated using forced swim test.

KEY RESULTS: FSL rats treated with ketamine exhibited a significant reduction in immobility time in comparison with the FSL-vehicle group. The volumes of the hippocampal CA1.SR and GCL regions were significantly increased 1 day after ketamine treatment in the FSL rats. The size of astrocytes in the ketamine-treated FSL rats was larger than those in the FSL-vehicle group. Additionally, the number and length of the astrocytic processes in the CA1.SR region were significantly increased 1 day following ketamine treatment.

CONCLUSIONS AND IMPLICATIONS: Our results support the hypothesis that astroglial atrophy contributes to the pathophysiology of depression and a morphological modification of astrocytes could be one mechanism by which ketamine rapidly improves depressive behaviour.

Ardalan, M., Rafati, A. H., Nyengaard, J. R., & Wegener, G. (2017). Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. British Journal of Pharmacology, 174(6), 483-492. 10.1111/bph.13714
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Neurovascular Plasticity of the Hippocampus One Week after a Single Dose of Ketamine in Genetic Rat Model of Depression

July 21, 2016 / Depression, Ketamine, Neuroscience, Papers, Psychopharmacology, Publications / By / , , , ,

Abstract

Glutamatergic system and the structural plasticity hypothesis are principal components for rapid and sustained antidepressant effects of novel antidepressant therapeutics. This study represents the first investigation of the structural plasticity of the hippocampus as one of the main contributed mechanisms to the sustained anti-depressive effect of ketamine. Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats were given a single intraperitoneal injection of ketamine (15 mg/kg) or saline 7 days before perfusion-fixed. The optical fractionator method was used to estimate the total number of neurons in the granular cell layer. Microvessel length in the molecular layer of DG was evaluated with global spatial sampling method. By use of the physical disector method, the number of synapses was estimated. The volume of the hippocampus was larger in the FRL-vehicle rats compared with FSL-vehicle group and in FSL-ketamine versus FSL-vehicle rats (P < 0.05). The number of non-perforated synapses was significantly higher in the FSL-ketamine versus FSL-vehicle group, (P = 0.01). A significant effect of ketamine on enhancement of the number of neurons in DG in FSL rats was observed (P = 0.01). The total length of the microvessels 1 week after ketamine treatment in the FSL rats significantly increased (P  < 0.05). Our results indicate that neurovascular changes of hippocampus could be one of the possible mechanisms underlying the sustained antidepressant effect of ketamine by reversing alteration of the number of the excitatory synapses, neuronal number and length of the microvessels in the hippocampus.

Ardalan, M., Wegener, G., Polsinelli, B., Madsen, T. M., & Nyengaard, J. R. (2016). Neurovascular Plasticity of the Hippocampus One Week after a Single Dose of Ketamine in Genetic Rat Model of Depression. Hippocampus. http://dx.doi.org/10.1002/hipo.22617
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Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: A critical review

June 2, 2016 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , ,

Abstract

A single i.v. infusion of ketamine, classified as an N-methyl-d-aspartate (NMDA) receptor antagonist, may alleviate depressive symptoms within hours of administration in treatment resistant depressed patients, and the antidepressant effect may last for several weeks. These unique therapeutic properties have prompted researchers to explore the mechanisms mediating the antidepressant effects of ketamine, but despite many efforts, no consensus on its antidepressant mechanism of action has been reached. Recent preclinical reports have associated the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) with the antidepressant-like action of ketamine. Here, we review the current evidence for a serotonergic role in ketamine’s antidepressant effects.

The pharmacological profile of ketamine may include equipotent activity on several non-NMDA targets, and the current hypotheses for the mechanisms responsible for ketamine’s antidepressant activity do not appear to preclude the possibility that non-glutamate neurotransmitters are involved in the antidepressant effects. At multiple levels, the serotonergic and glutamatergic systems interact, and such crosstalk could support the notion that changes in serotonergic neurotransmission may impact ketamine’s antidepressant potential. In line with these prospects, ketamine may increase 5-HT levels in the prefrontal cortex of rats, plausibly via hippocampal NMDA receptor inhibition and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In addition, a number of preclinical studies suggest that the antidepressant-like effects of ketamine may depend on endogenous activation of 5-HT receptors. Recent imaging and behavioral data predominantly support a role for 5-HT1A or 5-HT1B receptors, but the full range of 5-HT receptors has currently not been systematically investigated in this context. Furthermore, the nature of any 5-HT dependent mechanism in ketamine’s antidepressant effect is currently not understood, and therefore, more studies are warranted to confirm this hypothesis and explore the specific pathways that might implicate 5-HT.

du Jardin, K. G., Müller, H. K., Elfving, B., Dale, E., Wegener, G., & Sanchez, C. (2016). Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: A critical review. Progress in Neuro-Psychopharmacology and Biological Psychiatry. http://dx.doi.org/10.1016/j.pnpbp.2016.05.007
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Potential involvement of serotonergic signaling in ketamine's antidepressant actions: A critical review

June 2, 2016 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , ,

Abstract

A single i.v. infusion of ketamine, classified as an N-methyl-d-aspartate (NMDA) receptor antagonist, may alleviate depressive symptoms within hours of administration in treatment resistant depressed patients, and the antidepressant effect may last for several weeks. These unique therapeutic properties have prompted researchers to explore the mechanisms mediating the antidepressant effects of ketamine, but despite many efforts, no consensus on its antidepressant mechanism of action has been reached. Recent preclinical reports have associated the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) with the antidepressant-like action of ketamine. Here, we review the current evidence for a serotonergic role in ketamine’s antidepressant effects.

The pharmacological profile of ketamine may include equipotent activity on several non-NMDA targets, and the current hypotheses for the mechanisms responsible for ketamine’s antidepressant activity do not appear to preclude the possibility that non-glutamate neurotransmitters are involved in the antidepressant effects. At multiple levels, the serotonergic and glutamatergic systems interact, and such crosstalk could support the notion that changes in serotonergic neurotransmission may impact ketamine’s antidepressant potential. In line with these prospects, ketamine may increase 5-HT levels in the prefrontal cortex of rats, plausibly via hippocampal NMDA receptor inhibition and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In addition, a number of preclinical studies suggest that the antidepressant-like effects of ketamine may depend on endogenous activation of 5-HT receptors. Recent imaging and behavioral data predominantly support a role for 5-HT1A or 5-HT1B receptors, but the full range of 5-HT receptors has currently not been systematically investigated in this context. Furthermore, the nature of any 5-HT dependent mechanism in ketamine’s antidepressant effect is currently not understood, and therefore, more studies are warranted to confirm this hypothesis and explore the specific pathways that might implicate 5-HT.

du Jardin, K. G., Müller, H. K., Elfving, B., Dale, E., Wegener, G., & Sanchez, C. (2016). Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: A critical review. Progress in Neuro-Psychopharmacology and Biological Psychiatry. http://dx.doi.org/10.1016/j.pnpbp.2016.05.007
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30 April - Q&A with Rick Strassman

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