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4. Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice

Author

Sierra, Salvador, Muchhala, Karan H., Jessup, Donald K., Contreras, Katherine M., Shah, Urjita H., Stevens, David L., Jimenez, Jennifer, Cuno Lavilla, Xiomara K., de la Fuente Revenga, Mario, Lippold, Kumiko M., Shen, Shanwei, Poklis, Justin L., Qiao, Liya Y., Dewey, William L., Akbarali, Hamid I., Damaj, M. Imad, and González-Maeso, Javier

Published
2022
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8. Differences in 5-HT2A and mGlu2 Receptor Expression Levels and Repressive Epigenetic Modifications at the 5-HT2A Promoter Region in the Roman Low- (RLA-I) and High- (RHA-I) Avoidance Rat Strains

Author

Fomsgaard, Luna, Moreno, Jose L., de la Fuente Revenga, Mario, Brudek, Tomasz, Adamsen, Dea, Rio-Alamos, Cristobal, Saunders, Justin, Klein, Anders Bue, Oliveras, Ignasi, Cañete, Toni, Blazquez, Gloria, Tobeña, Adolf, Fernandez-Teruel, Albert, Gonzalez-Maeso, Javier, and Aznar, Susana

Published
2018
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12. Expanding the HDAC druggable landscape beyond enzymatic activity

Author

Olivet, Julien, primary, Choi, Soon Gang, additional, Sierra, Salvador, additional, O’Grady, Tina M., additional, de la Fuente Revenga, Mario, additional, Laval, Florent, additional, Botchkarev, Vladimir V., additional, Gorgulla, Christoph, additional, Coote, Paul W., additional, Blavier, Jérémy, additional, Geffken, Ezekiel A., additional, Lakhani, Jimit, additional, Song, Kijun, additional, Yeoh, Zoe C., additional, Hu, Bin, additional, Varca, Anthony C., additional, Bruyr, Jonathan, additional, Ibrahim, Samira, additional, Jivanjee, Tasneem, additional, Bromley, Joshua D., additional, Nyquist, Sarah K., additional, Richardson, Aaron, additional, Yue, Hong, additional, Wang, Yang, additional, Calonghi, Natalia, additional, Stefan, Alessandra, additional, Spirohn, Kerstin, additional, Vertommen, Didier, additional, Baietti, Maria F., additional, Lemmens, Irma, additional, Seo, Hyuk-Soo, additional, Dozmorov, Mikhail G., additional, Willems, Luc, additional, Tavernier, Jan, additional, Das, Kalyan, additional, Leucci, Eleonora, additional, Hochkoeppler, Alejandro, additional, Sun, Zhen-Yu Jim, additional, Calderwood, Michael A., additional, Hao, Tong, additional, Shalek, Alex K., additional, Hill, David E., additional, Boeszoermenyi, Andras, additional, Arthanari, Haribabu, additional, Buhrlage, Sara J., additional, Dhe-Paganon, Sirano, additional, González-Maeso, Javier, additional, Dequiedt, Franck, additional, Twizere, Jean-Claude, additional, and Vidal, Marc, additional

Published
2022
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17. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice

Author

de la Fuente Revenga, Mario, primary, Zhu, Bohan, additional, Guevara, Christopher A., additional, Naler, Lynette B., additional, Saunders, Justin M., additional, Zhou, Zirui, additional, Toneatti, Rudy, additional, Sierra, Salvador, additional, Wolstenholme, Jennifer T., additional, Beardsley, Patrick M., additional, Huntley, George W., additional, Lu, Chang, additional, and González-Maeso, Javier, additional

Published
2021
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19. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice

Author

de la Fuente Revenga, Mario, Zhu, Bohan, Guevara, Christopher A., Naler, Lynette B., Saunders, Justin M., Zhou, Zirui, Toneatti, Rudy, Sierra, Salvador, Wolstenholme, Jennifer T., Beardsley, Patrick M., Huntley, George W., Lu, Chang, González-Maso, Javier, de la Fuente Revenga, Mario, Zhu, Bohan, Guevara, Christopher A., Naler, Lynette B., Saunders, Justin M., Zhou, Zirui, Toneatti, Rudy, Sierra, Salvador, Wolstenholme, Jennifer T., Beardsley, Patrick M., Huntley, George W., Lu, Chang, and González-Maso, Javier

Abstract

Clinical evidence suggests that rapid and sustained antidepressant action can be attained with a single exposure to psychedelics. However, the biological substrates and key mediators of psychedelics’ enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produces fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT2A receptor. Additionally, a single dose of DOI leads to changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly that stretch for days after the psychedelic exposure. These DOI-induced alterations in the neuronal epigenome overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder. Together, these data support that epigenomic-driven changes in synaptic plasticity sustain psychedelics’ long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.

Published
2021

21. Molecular targets of psychedelic‐induced plasticity.

Author

Jaster, Alaina M., de la Fuente Revenga, Mario, and González‐Maeso, Javier

Subjects
*DRUG target, *SEROTONIN, *SEROTONIN receptors, *NEUROPLASTICITY, *HALLUCINOGENIC drugs, *ANIMAL models in research, *NEUROPHARMACOLOGY
Abstract

Psychedelic research across different disciplines and biological levels is growing at a remarkably fast pace. In the prospect of a psychedelic drug becoming again an approved treatment, much of these efforts have been oriented toward exploring the relationship between the actual psychedelic effects and those manifestations of therapeutic interest. Considering the central role of the serotonin 5‐HT2A receptor in the distinct effects of psychedelics in human psyche, neuropharmacology sits at the center of this debate and exploratory continuum. Here we discuss some of the most recent findings in human studies and contextualize them considering previous preclinical models studying phenomena related to synaptic plasticity. A special emphasis is placed on knowledge gaps, challenges, and limitations to evaluate the underpinnings of psychedelics' potential antidepressant action. [ABSTRACT FROM AUTHOR]

Published
2022
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22. Effects of the 5-HT2A receptor antagonist volinanserin on head-twitch response and intracranial self-stimulation depression induced by different structural classes of psychedelics in rodents.

Author

Jaster, Alaina M., Elder, Harrison, Marsh, Samuel A., de la Fuente Revenga, Mario, Negus, S. Stevens, and González-Maeso, Javier

Subjects
HALLUCINOGENIC drugs, SEROTONIN receptors, G protein coupled receptors, PHENETHYLAMINES, TRYPTAMINE, PSYCHOPHARMACOLOGY
Published
2022
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25. Assessing the Psychedelic 'After-Glow' in Ayahuasca Users: Post-Acute Neurometabolic and Functional Connectivity Changes Are Associated with Enhanced Mindfulness Capacities

Author

Riba Serrano, Jordi, Sampedro, Frederic, Vilà-Canet, G., de la Fuente Revenga, Mario, Valle, Marta, Roberto, Natalia, Dominguez-Clave, Elisabet, Elices, M., Luna, Luís Eduardo, Crippa, José A. S., Hallak, Jaime E. C., de Araujo, Draulio B., Friedlander, Pablo, Barker, Steven A.., Álvarez, Enrique, Soler, Joaquim, Pascual Mateos, Juan Carlos, Feilding, Amanda, and Universitat Autònoma de Barcelona

Subjects
Adult, Male, Cingulate cortex, Hallucinogen, Magnetic Resonance Spectroscopy, Time Factors, mindfulness, Mindfulness, Glutamic Acid, Regular Research Articles, Brain mapping, Temporal lobe, 03 medical and health sciences, Imaging, Three-Dimensional, psychedelic after-effects, 0302 clinical medicine, Surveys and Questionnaires, Humans, magnetic resonance imaging, Pharmacology (medical), human, Default mode network, Cerebral Cortex, Pharmacology, Aspartic Acid, Brain Mapping, Banisteriopsis, Middle Aged, Ayahuasca, Healthy Volunteers, 030227 psychiatry, Editor's Choice, Psychiatry and Mental health, Hallucinogens, Antidepressant, Female, Psychology, IMAGEM POR RESSONÂNCIA MAGNÉTICA, Neuroscience, 030217 neurology & neurosurgery, Follow-Up Studies, ayahuasca
Abstract

Background Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network, purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here, we investigated in an open-label uncontrolled study in 16 healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications and their association with mindfulness measures. Methods Using 1H-magnetic resonance spectroscopy and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior and anterior cingulate cortex after a single ayahuasca dose. Results Magnetic resonance spectroscopy showed post-acute reductions in glutamate+glutamine, creatine, and N-acetylaspartate+N-acetylaspartylglutamate in the posterior cingulate cortex. Connectivity was increased between the posterior cingulate cortex and the anterior cingulate cortex, and between the anterior cingulate cortex and limbic structures in the right medial temporal lobe. Glutamate+glutamine reductions correlated with increases in the “nonjudging” subscale of the Five Facets Mindfulness Questionnaire. Increased anterior cingulate cortex-medial temporal lobe connectivity correlated with increased scores on the self-compassion questionnaire. Post-acute neural changes predicted sustained elevations in nonjudging 2 months later. Conclusions These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the posterior cingulate cortex, a key region within the default mode network, and increased connectivity between the anterior cingulate cortex and medial temporal lobe structures involved in emotion and memory potentially underlie the post-acute psychological effects of ayahuasca.

Published
2017

27. HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice

Author

de la Fuente Revenga, Mario, primary, Ibi, Daisuke, additional, Saunders, Justin M., additional, Cuddy, Travis, additional, Ijaz, Maryum K., additional, Toneatti, Rudy, additional, Kurita, Mitsumasa, additional, Holloway, Terrell, additional, Shen, Li, additional, Seto, Jeremy, additional, Dozmorov, Mikhail G., additional, and González-Maeso, Javier, additional

Published
2018
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32. Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects

Author

Ibi, Daisuke, primary, de la Fuente Revenga, Mario, additional, Kezunovic, Nebojsa, additional, Muguruza, Carolina, additional, Saunders, Justin M, additional, Gaitonde, Supriya A, additional, Moreno, José L, additional, Ijaz, Maryum K, additional, Santosh, Vishaka, additional, Kozlenkov, Alexey, additional, Holloway, Terrell, additional, Seto, Jeremy, additional, García-Bea, Aintzane, additional, Kurita, Mitsumasa, additional, Mosley, Grace E, additional, Jiang, Yan, additional, Christoffel, Daniel J, additional, Callado, Luis F, additional, Russo, Scott J, additional, Dracheva, Stella, additional, López-Giménez, Juan F, additional, Ge, Yongchao, additional, Escalante, Carlos R, additional, Meana, J Javier, additional, Akbarian, Schahram, additional, Huntley, George W, additional, and González-Maeso, Javier, additional

Published
2017
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34. Assessing the Psychedelic “After-Glow” in Ayahuasca Users: Post-Acute Neurometabolic and Functional Connectivity Changes Are Associated with Enhanced Mindfulness Capacities

Author

Sampedro, Frederic, primary, de la Fuente Revenga, Mario, additional, Valle, Marta, additional, Roberto, Natalia, additional, Domínguez-Clavé, Elisabet, additional, Elices, Matilde, additional, Luna, Luís Eduardo, additional, Crippa, José Alexandre S, additional, Hallak, Jaime E C, additional, de Araujo, Draulio B, additional, Friedlander, Pablo, additional, Barker, Steven A, additional, Álvarez, Enrique, additional, Soler, Joaquim, additional, Pascual, Juan C, additional, Feilding, Amanda, additional, and Riba, Jordi, additional

Published
2017
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35. Differences in 5-HT2A and mGlu2 Receptor Expression Levels and Repressive Epigenetic Modifications at the 5-HT2A Promoter Region in the Roman Low- (RLA-I) and High- (RHA-I) Avoidance Rat Strains

Author

Fomsgaard, Luna, primary, Moreno, Jose L., additional, de la Fuente Revenga, Mario, additional, Brudek, Tomasz, additional, Adamsen, Dea, additional, Rio-Alamos, Cristobal, additional, Saunders, Justin, additional, Klein, Anders Bue, additional, Oliveras, Ignasi, additional, Cañete, Toni, additional, Blazquez, Gloria, additional, Tobeña, Adolf, additional, Fernandez-Teruel, Albert, additional, Gonzalez-Maeso, Javier, additional, and Aznar, Susana, additional

Published
2017
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36. Synaptopathies:synaptic dysfunction in neurological disorders - A review from students to students

Author

Lepeta, Katarzyna, Lourenco, Mychael V, Schweitzer, Barbara C, Martino Adami, Pamela V, Banerjee, Priyanjalee, Catuara-Solarz, Silvina, de La Fuente Revenga, Mario, Guillem, Alain Marc, Haidar, Mouna, Ijomone, Omamuyovwi M, Nadorp, Bettina, Qi, Lin, Perera, Nirma D, Refsgaard, Louise K, Reid, Kimberley M, Sabbar, Mariam, Sahoo, Arghyadip, Schaefer, Natascha, Sheean, Rebecca K, Suska, Anna, Verma, Rajkumar, Vicidomini, Cinzia, Wright, Dean, Zhang, Xing-Ding, Seidenbecher, Constanze, Lepeta, Katarzyna, Lourenco, Mychael V, Schweitzer, Barbara C, Martino Adami, Pamela V, Banerjee, Priyanjalee, Catuara-Solarz, Silvina, de La Fuente Revenga, Mario, Guillem, Alain Marc, Haidar, Mouna, Ijomone, Omamuyovwi M, Nadorp, Bettina, Qi, Lin, Perera, Nirma D, Refsgaard, Louise K, Reid, Kimberley M, Sabbar, Mariam, Sahoo, Arghyadip, Schaefer, Natascha, Sheean, Rebecca K, Suska, Anna, Verma, Rajkumar, Vicidomini, Cinzia, Wright, Dean, Zhang, Xing-Ding, and Seidenbecher, Constanze

Abstract

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page 783.

Published
2016

38. Ayahuasca: Pharmacology, neuroscience and therapeutic potential

Author

Domínguez-Clavé, Elisabet, primary, Soler, Joaquim, additional, Elices, Matilde, additional, Pascual, Juan C., additional, Álvarez, Enrique, additional, de la Fuente Revenga, Mario, additional, Friedlander, Pablo, additional, Feilding, Amanda, additional, and Riba, Jordi, additional

Published
2016
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40. Synaptopathies: synaptic dysfunction in neurological disorders - A review from students to students

Author

Lepeta, Katarzyna, primary, Lourenco, Mychael V., additional, Schweitzer, Barbara C., additional, Martino Adami, Pamela V., additional, Banerjee, Priyanjalee, additional, Catuara-Solarz, Silvina, additional, de La Fuente Revenga, Mario, additional, Guillem, Alain Marc, additional, Haidar, Mouna, additional, Ijomone, Omamuyovwi M., additional, Nadorp, Bettina, additional, Qi, Lin, additional, Perera, Nirma D., additional, Refsgaard, Louise K., additional, Reid, Kimberley M., additional, Sabbar, Mariam, additional, Sahoo, Arghyadip, additional, Schaefer, Natascha, additional, Sheean, Rebecca K., additional, Suska, Anna, additional, Verma, Rajkumar, additional, Vicidomini, Cinzia, additional, Wright, Dean, additional, Zhang, Xing-Ding, additional, and Seidenbecher, Constanze, additional

Published
2016
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41. Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice.

Author

Hideshima, Kelsey S., Hojati, Ashkhan, Saunders, Justin M., On, Doan M., de la Fuente Revenga, Mario, Shin, Jong M., Sánchez-González, Ana, Dunn, Cassandra M., Pais, Alexander B., Pais, Anthony C., Miles, Michael F., Wolstenholme, Jennifer T., and González-Maeso, Javier

Subjects
CLOZAPINE, G protein coupled receptors, SEROTONIN, ANTIPSYCHOTIC agents, SCHIZOPHRENIA, HALLUCINOGENIC drugs
Abstract

Background: Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis and schizophrenia treatment. Previous findings in mGlu2 knockout (KO) mice suggested that mGlu2 is necessary for head-twitch behavior, a rodent phenotype characteristic of hallucinogenic 5-HT2A receptor agonists. However, the role of mGlu2 in the behavioral effects induced by antipsychotic drugs remains poorly understood. Here, we tested antipsychotic-like behavioral phenotypes induced by the atypical antipsychotic clozapine in mGlu2-KO mice and wild-type control littermates.Methods: Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5 mg/kg) or vehicle followed by MK801 (0.5 mg/kg), PCP (7.5 mg/kg), amphetamine (6 mg/kg), scopolamine (2 mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated.Results: The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion.Conclusion: These findings further support the existence of a functionally relevant crosstalk between 5-HT2A and mGlu2 receptors in different preclinical models of antipsychotic activity. [ABSTRACT FROM AUTHOR]

Published
2018
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42. Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential

Author

de la Fuente Revenga, Mario, primary, Fernández-Sáez, Nerea, additional, Herrera-Arozamena, Clara, additional, Morales-García, José A., additional, Alonso-Gil, Sandra, additional, Pérez-Castillo, Ana, additional, Caignard, Daniel-Henri, additional, Rivara, Silvia, additional, and Rodríguez-Franco, María Isabel, additional

Published
2015
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43. Neurogenic Potential Assessment and Pharmacological Characterization of 6-Methoxy-1,2,3,4-tetrahydro-β-carboline (Pinoline) and Melatonin–Pinoline Hybrids

Author

de la Fuente Revenga, Mario, primary, Pérez, Concepción, additional, Morales-García, José A., additional, Alonso-Gil, Sandra, additional, Pérez-Castillo, Ana, additional, Caignard, Daniel-Henri, additional, Yáñez, Matilde, additional, Gamo, Ana M., additional, and Rodríguez-Franco, María Isabel, additional

Published
2015
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46. Temperature and pH dependence of enzyme catalyzed hydrolysis of trans-methylstyrene oxide : a unifying kinetic model for observed hysteresis, cooperativity and regioselectivity

Author

Lindberg, Diana, de la Fuente Revenga, Mario, Widersten, Mikael, Lindberg, Diana, de la Fuente Revenga, Mario, and Widersten, Mikael

Abstract

The underlying enzyme kinetics behind the regioselective promiscuity shown by epoxide hydrolases towards certain epoxides has been studied. The effects of temperature and pH on regioselectivity was investigated by analyzing the stereochemistry of hydrolysis products of (1R,2R)-trans-2-methylstyrene oxide between 14 to 46 °C and pH 6.0 to 9.0, either catalyzed by the potato epoxide hydrolase StEH1 or in the absence of enzyme. In the enzyme-catalyzed reaction, a switch of preferred epoxide carbon that is subjected to nucleophilic attack is observed at pH values above 8. The enzyme also displays cooperativity in substrate saturation plots when assayed at temperatures ≤30 °C and at intermediate pH. The cooperativity is lost at higher assay temperatures. Cooperativity can originate from a kinetic mechanism involving hysteresis and will be dependent on the relationship between kcat and the rate of interconversion between two different Michaelis complexes. In the case of the studied reactions, the proposed different Michaelis complexes are enzyme-substrate complexes in which the epoxide substrate is bound in different binding modes, allowing for separate pathways towards product formation. The assumption of separated, but interacting, reaction pathways is supported by that formation of the two product enantiomers also display distinct pH dependencies of kcat/KM. The thermodynamic parameters describing the differences in activation enthalpy and entropy suggest that 1) regioselectivity is primarily dictated by differences in activation entropy with positive values of both ΔΔH and ΔΔS, and 2) the hysteretic behavior is linked to an interconversion between Michaelis complexes with rates increasing with temperature. From the collected data, we propose that hysteresis, regioselectivity and, when applicable, hysteretic cooperativity are closely linked properties, explained by the kinetic mechanism earlier introduced by our group.

Published
2010
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48. Novel N-Acetyl Bioisosteresof Melatonin: Melatonergic Receptor Pharmacology, PhysicochemicalStudies, and Phenotypic Assessment of Their Neurogenic Potential.

Author

de la Fuente Revenga, Mario, Fernández-Sáez, Nerea, Herrera-Arozamena, Clara, Morales-García, José A., Alonso-Gil, Sandra, Pérez-Castillo, Ana, Caignard, Daniel-Henri, Rivara, Silvia, and Rodríguez-Franco, María Isabel

Subjects
*BIOISOSTERES, *MELATONIN, *LABORATORY rats, *CELL differentiation, *NEURAL stem cells, *IN vitro studies, *DEVELOPMENTAL neurobiology, *THERAPEUTICS
Abstract

Herein we present a new family ofmelatonin-based compounds, inwhich the acetamido group of melatonin has been bioisosterically replacedby a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole,and 1,3,4-oxadiazole, as well as other related five-membered heterocycles,namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an1,3,4-thiadiazole. New compounds were fully characterized at melatoninreceptors (MT1R and MT2R), and results wererationalized by superimposition studies of their structures to thebioactive conformation of melatonin. We also found that several ofthese melatonin-based compounds promoted differentiation of rat neuralstem cells to a neuronal phenotype in vitro, in some cases to a higherextent than melatonin. This unique profile constitutes the startingpoint for further pharmacological studies to assess the mechanisticpathways and the relevance of neurogenesis induced by melatonin-relatedstructures. [ABSTRACT FROM AUTHOR]

Published
2015
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50. Snapshot of 5-HT 2A receptor activation in the mouse brain via IP 1 detection.

Author

de la Fuente Revenga M and González-Maeso J

Abstract

The distinct subjective effects that define psychedelics such as LSD, psilocybin or DOI as drug class are causally linked to activation of the serotonin 2A receptor (5-HT 2A R). However, some aspects of 5-HT 2A R pharmacology remain elusive, such as what molecular drivers differentiate psychedelic from non-psychedelic 5-HT 2A R agonists. We developed an ex vivo platform to obtain snapshots of drug-mediated 5-HT 2A R engagement of the canonical G q/11 pathway in native tissue. This non-radioactive methodology captures the pharmacokinetic and pharmacodynamic events leading up to changes in inositol monophosphate (IP 1 ) in the mouse brain. The specificity of this method was assessed by comparing IP 1 levels in homogenates from the frontal cortex in DOI-treated wild-type and 5-HT 2A R-KO animals compared to other brain regions, namely striatum and cerebellum. Furthermore, we encountered that head-twitch response (HTR) counts and IP 1 in the frontal cortex were correlated. We observed that IP 1 levels in frontal cortex homogenates from mice treated with LSD and lisuride vary in magnitude, consistent with LSD's 5-HT 2A R agonism and psychedelic nature, and lisuride's lack thereof. MDMA evoked an increase of IP 1 signal in the frontal cortex that were not matched by the serotonin precursor 5-HTP or the serotonin reuptake inhibitor fluoxetine. We attribute differences in the readout primarily to the indirect stimulation of 5-HT 2A R by MDMA via serotonin release from its presynaptic terminals. This methodology enables capturing a snapshot of IP 1 turnover in the mouse brain that can provide mechanistic insights in the study of psychedelics and other serotonergic agents pharmacodynamics.

Published
2024
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