Altered Signaling in CB1R-5-HT2AR Heteromers in Olfactory Neuroepithelium Cells of Schizophrenia Patients is Modulated by Cannabis Use.
D. Guinart, Estefanía Moreno, Liliana Galindo, Aida Cuenca-Royo, Marta Barrera-Conde, E. J. Pérez, Cristina Fernández-Avilés, C. Correll, Enric I. Canela, V. Casadó, Arnau Cordomí, Leonardo Pardo, Rafael de la Torre, Víctor Perez, Patricia Robledo
Schizophrenia Bulletin April 6, 2020 DOI: 10.1093/schbul/sbaa038 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Case-control study Peer reviewed |
|---|---|
| Population | Patients with schizophrenia (cannabis users and non-users) and healthy controls (cannabis users and non-users), studied via olfactory neuroepithelium cells |
| Measures | intracellular pERK, cAMP, attentional performance, neurological soft signs (NSS) |
| Topics | Cannabis Serotonin |
| Key findings | CB1R-5-HT2AR heteromer expression was enhanced in both schizophrenia groups compared with non-cannabis-using healthy controls, and across all groups higher expression correlated with worse attentional performance and more neurological soft signs. The authors report that expected heteromer signaling was absent specifically in non-cannabis-using patients treated with clozapine and was mimicked in control cells exposed to clozapine, suggesting clozapine alters heteromer structure; cannabis-using patients showed signaling similar to cannabis-using controls. |
Abstract
Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulation, but difficulty in obtaining in vivo neurological tissue has limited its exploration. We investigated CB1R-5-HT2AR heteromer expression and functionality via intracellular pERK and cAMP quantification in olfactory neuroepithelium (ON) cells of SCZ patients non-cannabis users (SCZ/nc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZ/c). Results were compared vs healthy controls non-cannabis users (HC/nc) and healthy controls cannabis users (HC/c). Further, antipsychotic effects on heteromer signaling were tested in vitro in HC/nc and HC/c. Results indicated that heteromer expression was enhanced in both SCZ groups vs HC/nc. Additionally, pooling all 4 groups together, heteromer expression correlated with worse attentional performance and more neurological soft signs (NSS), indicating that these changes may be useful markers for neurocognitive impairment. Remarkably, the previously reported signaling properties of CB1R-5-HT2AR heteromers in ON cells were absent, specifically in SCZ/nc treated with clozapine. These findings were mimicked in cells from HC/nc exposed to clozapine, suggesting a major role of this antipsychotic in altering the quaternary structure of the CB1R-5-HT2AR heteromer in SCZ/nc patients. In contrast, cells from SCZ/c showed enhanced heteromer functionality similar to HC/c. Our data highlight a molecular marker of the interaction between antipsychotic medication and cannabis use in SCZ with relevance for future studies evaluating its association with specific neuropsychiatric alterations.
Comparable studies
Other observational and cohort studies on cannabis, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| High-potency cannabis and the risk of psychosis People with first episode of psychosis and healthy controls from the local population | 2009 | Case-control study | n = 454 |
| Ayahuasca-Assisted Therapy for Addiction: Results from a Preliminary Observational Study in Canada Rural aboriginal population | 2013 | Observational study | |
| Impaired cognitive performance in drug free users of recreational ecstasy (MDMA) Otherwise healthy young people | 2000 | Observational | |
| Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study Individuals from the general population in Germany aged 14-24 at baseline | 2011 | Observational cohort | n = 1,923 |
| Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases Patients treated for cannabis-induced psychotic symptoms in Denmark between 1994 and... | 2005 | Observational cohort | n = 535 |
Citations in the library
Cited by 3
- Multimodal MRI data fusion reveals distinct structural, functional and neurochemical correlates of heavy cannabis use Addiction Biology November 22, 2021
- Repeated administration of the synthetic cannabinoid AKB48 induces serotonergic neuroadaptation in male and female mice: behavioural and immunohistochemical evidence. Neuropharmacology February 1, 2026
- Role of cyclin-dependent kinase 5 in psychosis and the modulatory effects of cannabinoids. Neurobiology of Disease 2023
Cites 4
- Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors PLoS Biology July 9, 2015
- Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway Neuropsychopharmacology April 27, 2018
- Course of cannabis use and clinical outcome in patients with non-affective psychosis: a 3-year follow-up study Psychological Medicine February 5, 2015
- Gene-environment interaction between an endocannabinoid system genetic polymorphism and cannabis use in first episode of psychosis. European Neuropsychopharmacology June 1, 2019