Astrogliosis Occurs Selectively in Amygdala of Adolescent Primate and Rodent Following Daily Δ9-Tetrahydrocannabinol, Prevented by Cannabidiol Co-Treatment.

Adolescent cannabis use increases risk for neuropsychiatric disorders, possibly through amygdala dysfunction. Chronic THC treatment in male adolescent nonhuman primates and rats disrupted sleep and increased anxiety-related behavior. THC activated proinflammatory glial cells (astrocytes) exclusively in the adolescent amygdala, upregulating GFAP and complement factor-B, effects absent in adults or other brain regions. THC also reduced synaptic plasticity markers stathmin-1 and NrCAM. Co-administered cannabidiol prevented astrocyte inflammation but did not restore plasticity markers. Astrogliosis correlated with fragmented sleep, attenuated plasticity markers with anxiety. Elevated CB1R expression in the maturing brain was astrocyte-localized in the amygdala, linking THC to unique adolescent amygdala vulnerability.

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Abstract

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. 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. 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. 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.