Cells
July 27, 2021
Dasiel O. Borroto‐escuela, Patrizia Ambrogini, Manuel Narváez et al.
29 citations
Heteroreceptor complexes represent a new biological principle for signal integration in the brain, with bidirectional allosteric receptor–receptor interactions offering novel targets for treating CNS diseases, including mental disorders. The existence of D2R-5-HT2AR heterocomplexes can explain the anti-schizophrenic effects of atypical antipsychotics through blocking the allosteric enhancement of D2R signaling by 5-HT2AR activation. This principle also helps understand mechanisms of 5-HT hallucinogens like psilocybin and the prosocial, anti-stress actions of MDMA. GalR1-GalR2 heterodimers and putative GalR1-GalR2-5-HT1 complexes are targets for galanin fragment Gal(1–15) in modulating emotional networks. Antidepressant drugs, including TCAs, SSRIs, and ketamine, can directly bind to the TrkB receptor, providing a novel mechanism for their actions. Astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses are relevant to major depressive disorder research.
Cells
March 22, 2023
Kevin Domanegg, Wolfgang H. Sommer, Marcus W. Meinhardt
23 citations
Alcohol use disorders remain a major public health problem, and current medications have limited success. Recent clinical trials suggest that psychedelics, especially psilocybin, combined with psychotherapy can reduce heavy drinking. This review connects two lines of research: how addiction alters metabotropic glutamate receptor 2 (mGlu2) function, and how psychedelics act through serotonin 2A receptors (2AR) to induce gene expression and neuroplasticity. Evidence indicates that mGlu2 and 2AR can regulate each other's signaling, either through crosstalk or by forming a 2AR-mGlu2 heteromer, and that 2AR activation can epigenetically modulate mGlu2 expression. The authors propose that targeting these pathways could restore mGlu2 function in AUD patients and reduce relapse risk.
Cells
April 12, 2024
Carlos Arrabal-Gómez, Rasiel Beltran-Casanueva, Aracelis Hernández-García et al.
7 citations
A single dose combining a neuropeptide Y Y1 receptor agonist with ketamine enhanced memory consolidation and increased production of new neurons (neuroblasts) in the dorsal hippocampus of male rats, without affecting quiescent neural progenitors or astrocytes. The effects were linked to brain-derived neurotrophic factor and suggested the formation of NPY1R-TrkB heteroreceptor complexes, though this interaction requires further confirmation. The findings point to a potential therapeutic approach for neurodegenerative diseases.
Cells
August 26, 2024
Tatjana Nikolić, Milica Velimirović Bogosavljević, Tihomir Stojković et al.
6 citations
In a rat model of schizophrenia created by perinatal phencyclidine (PCP) exposure, antipsychotic treatment with haloperidol or clozapine reduced altered glucocorticoid receptor (GR) sensitivity in the brain. The study measured corticosterone levels and GR-related proteins (GR, pGR, HSP70, HSP90, FKBP51, and 11β-HSD) in different brain regions of adult male rats. Six groups were treated with PCP or saline on postnatal days 2, 6, 9, and 12; some groups then received haloperidol or clozapine from day 35 to 100. The findings indicate disturbances in the HPA axis in this schizophrenia model and suggest antipsychotics may have protective effects against such dysregulation.
Cells
June 3, 2025
Marta Jóźwiak-Bębenista, Anna Wiktorowska-Owczarek, Małgorzata Siatkowska et al.
4 citations
Ketamine and its metabolites—including R-ketamine, S-ketamine, and the hydroxynorketamines (2S,6S-HNK and 2R,6R-HNK)—directly reduce markers of endoplasmic reticulum (ER) stress and inflammation in human microglial cells. In cells treated with tunicamycin to induce ER stress, all compounds lowered expression and protein levels of CHOP and GRP78, two key components of the unfolded protein response (UPR). In microglia stimulated with lipopolysaccharide (LPS), the compounds decreased levels of the inflammatory cytokine IL-6 and, to a lesser extent, IL-8. These findings point to a glia-targeted mechanism for modulating ER stress and neuroinflammation, supporting further in vivo research to develop antidepressants with fewer psychoactive side effects than current treatments.
Cells
June 19, 2025
Júlia Jarne-Ferrer, Mercè Pallàs, Christian Griñán-Ferré et al.
2 citations
Combining the psychedelic molecule N,N-Dimethyltryptamine (NN-DMT) with five plant-derived bioactive compounds—Withanone, Apigenin, Bacoside A, Baicalin, and Thymoquinone—reduces age-related mobility problems, decreases amyloid-β plaque buildup, and improves survival under oxidative stress more effectively than any single compound alone. This synergistic effect was observed in a transgenic Caenorhabditis elegans model of Alzheimer's disease. The findings suggest that multi-target therapies addressing both protein aggregation and oxidative damage may offer a more promising direction for Alzheimer's treatment than single-drug approaches.
Cells
November 26, 2025
1 citation
Psychedelic compounds that activate the 5-HT2A receptor might help treat multiple sclerosis by both calming harmful inflammation and promoting repair in the brain and spinal cord. Current MS drugs work on the immune system but do little to fix damage inside the central nervous system. Psychedelics appear to reduce pro-inflammatory signals from glial cells while increasing factors that support nerve cell health and myelin repair. However, most evidence comes from studies of general inflammation, not autoimmune disease, so it is unclear if these effects will work for MS. Major obstacles include heart and mental health risks, plus legal and ethical barriers. The authors suggest that non-hallucinogenic drugs inspired by psychedelics, which activate the same receptor without the mind-altering effects, may be a more practical path forward.
Cells
December 11, 2025
Agnieszka Pałucha-Poniewiera
The NMDA receptor antagonist (S)-ketamine produces rapid and lasting antidepressant effects in patients resistant to traditional treatments, validating the glutamatergic hypothesis of depression proposed over 20 years ago. However, (S)-ketamine also causes side effects that limit its safety. Preclinical studies suggest that low doses of mGlu2 and mGlu5 receptor antagonists can enhance ketamine's therapeutic effects while reducing its side effects. This review examines the synergistic interaction between ketamine and these glutamatergic modulators, the underlying mechanisms, and the role of mGlu2 and mGlu5 receptors in ketamine's antidepressant action.