Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats.
Erica Zamberletti, Marina Gabaglio, Massimo Grilli, Pamela Prini, Alberto Catanese, Anna Pittaluga, Mario Marchi, Tiziana Rubino, Daniela Parolaro
Pharmacological Research September 2016 DOI: 10.1016/j.phrs.2016.07.008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experimental animal study Peer reviewed |
|---|---|
| Population | Adolescent male rats exposed to THC from postnatal day 35 to 45 and assessed in adulthood |
| Intervention | Delta-9-tetrahydrocannabinol (THC) |
| Dose | increasing doses of THC twice a day |
| Duration | THC treatment from postnatal day 35 to 45; behavioral and cellular assessments in adulthood |
| Topics | Cannabis |
| Keywords | Adolescence Astrocytes Behavior Delta-9-tetrahydrocannabinol Glutamate synapse Hippocampus |
| Key findings | Adolescent THC exposure in male rats produced lasting memory deficits and psychotic-like behaviors in adulthood, without altering emotional reactivity. In the hippocampus, THC increased glutamate receptor subunits, synaptic markers, and evoked glutamate release, and produced persistent neuroinflammatory changes; none of these changes occurred in the prefrontal cortex. The authors propose that region-specific glutamate synapse and glial alterations underlie the sex-dependent behavioral effects of adolescent THC. |
Abstract
Cannabis use has been frequently associated with sex-dependent effects on brain and behavior. We previously demonstrated that adult female rats exposed to delta-9-tetrahydrocannabinol (THC) during adolescence develop long-term alterations in cognitive performances and emotional reactivity, whereas preliminary evidence suggests the presence of a different phenotype in male rats. To thoroughly depict the behavioral phenotype induced by adolescent THC exposure in male rats, we treated adolescent animals with increasing doses of THC twice a day (PND 35-45) and, at adulthood, we performed a battery of behavioral tests to measure affective- and psychotic-like symptoms as well as cognition. Poorer memory performance and psychotic-like behaviors were present after adolescent THC treatment in male rats, without alterations in the emotional component. At cellular level, the expression of the NMDA receptor subunit, GluN2B, as well as the levels of the AMPA subunits, GluA1 and GluA2, were significantly increased in hippocampal post-synaptic fractions from THC-exposed rats compared to controls. Furthermore, increases in the levels of the pre-synaptic marker, synaptophysin, and the post-synaptic marker, PSD95, were also present. Interestingly, KCl-induced [(3)H]D-ASP release from hippocampal synaptosomes, but not gliosomes, was significantly enhanced in THC-treated rats compared to controls. Moreover, in the same brain region, adolescent THC treatment also resulted in a persistent neuroinflammatory state, characterized by increased expression of the astrocyte marker, GFAP, increased levels of the pro-inflammatory markers, TNF-α, iNOS and COX-2, as well as a concomitant reduction of the anti-inflammatory cytokine, IL-10. Notably, none of these alterations was observed in the prefrontal cortex (PFC). Together with our previous findings in females, these data suggest that the sex-dependent detrimental effects induced by adolescent THC exposure on adult behavior may rely on its ability to trigger different region-dependent changes in glutamate synapse and glial cells. The phenotype observed in males is mainly associated with marked dysregulations in the hippocampus, whereas the prevalence of alterations in the emotional sphere in females is associated with profound changes in the PFC.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 18
- The Relationship Between Cannabis, Cognition, and Schizophrenia: It’s Complicated Current Topics in Behavioral Neurosciences 2022
- Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics Frontiers in Psychiatry September 5, 2023
- Prolonged incubation with Δ9-tetrahydrocannabinol but not with cannabidiol induces synaptic alterations and mitochondrial impairment in immature and mature rat organotypic hippocampal slices. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie February 1, 2025
- Prenatal cannabinoid exposure alters excitation-inhibition balance through glutamate and GABA receptor-mediated signaling. Journal of Biological Chemistry July 2026
- The role of subcortical brain tissue iron as an indicator of dopamine neurophysiology in adolescent cannabis use. Neuropsychopharmacology June 2, 2026
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Cites 8
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- Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats. Neurobiology of Disease March 1, 2014
- Chronic URB597 treatment at adulthood reverted most depressive-like symptoms induced by adolescent exposure to THC in female rats. Neuropharmacology 2011
and 3 more in the library