Astrogliosis Occurs Selectively in Amygdala of Adolescent Primate and Rodent Following Daily Δ9-Tetrahydrocannabinol, Prevented by Cannabidiol Co-Treatment
Background: Adolescent-onset cannabis use confers higher risk for neuropsychiatric disorders, implicating amygdala dysfunction. However, the mechanisms that mediate Δ9-tetrahydrocannabinol (THC)–triggered neuroadaptive changes in the maturing amygdala remain unclear. Methods: Proteomic analysis of a...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
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| Series: | Biological Psychiatry Global Open Science |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667174325000503 |
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| Summary: | Background: Adolescent-onset cannabis use confers higher risk for neuropsychiatric disorders, implicating amygdala dysfunction. However, the mechanisms that mediate Δ9-tetrahydrocannabinol (THC)–triggered neuroadaptive changes in the maturing amygdala remain unclear. Methods: Proteomic analysis of amygdala tissue from male adolescent Saimiri boliviensis nonhuman primates chronically treated with THC provided leads for targeted analyses of glial fibrillary acidic protein (GFAP), stathmin-1, and neuronal cell adhesion molecule (NrCAM) in a second species of male adolescent (postnatal day [P]35) and adult (P70) Sprague-Dawley rats. Primate activity monitoring and rat behavioral testing revealed THC-disrupted sleep architecture and anxiety-related behavior, respectively. Primary rat astrocyte cultures provided mechanistic insight into THC activation of astrocyte inflammatory function. Results: THC-induced upregulation of GFAP and complement factor-B (CF-B) signified proinflammatory glial activation exclusively in the adolescent amygdala, an effect absent in other brain regions and in adults. THC attenuated synaptic plasticity enhancers, stathmin-1 and NrCAM, effects not recapitulated in adults. Co-administered cannabidiol (CBD) prevented astrogliosis but did not restore synaptic plasticity marker levels. Astrogliosis was correlated with fragmented sleep, and attenuated plasticity markers were correlated with anxiety. THC-induced GFAP and CF-B upregulation with attenuation by CBD were replicated in cultured astrocytes, requiring cannabinoid type 1 receptor (CB1R)-activated calcium signaling. Elevated CB1R expression in the maturing brain was astrocyte-localized in the amygdala, but neuronal in the cortex and striatum. Conclusions: Brain region- and age-specific regulation of CB1R in astrocytes critically links THC and unique adolescent amygdala vulnerability to inflammatory gliosis, impairing behaviors implicated in neuropsychiatric disorders. Mitigation of specific THC-induced changes by CBD offers leads for attenuating some adverse effects of THC. |
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| ISSN: | 2667-1743 |