TY - JOUR
T1 - Repeated cannabidiol treatment affects neuroplasticity and endocannabinoid signaling in the prefrontal cortex of the Flinders Sensitive Line (FSL) rat model of depression.
AU - Domingos, Luana Barreto
AU - Müller, Heidi Kaastrup
AU - da Silva, Nicole Rodrigues
AU - Filiou, Michaela D.
AU - Nielsen, Anders Lade
AU - Guimarães, Francisco Silveira
AU - Wegener, Gregers
AU - Joca, Sâmia
N1 - Publisher Copyright:
© 2024
PY - 2024/5/1
Y1 - 2024/5/1
N2 - Delayed therapeutic responses and limited efficacy are the main challenges of existing antidepressant drugs, thereby incentivizing the search for new potential treatments. Cannabidiol (CBD), non-psychotomimetic component of cannabis, has shown promising antidepressant effects in different rodent models, but its mechanism of action remains unclear. Herein, we investigated the antidepressant-like effects of repeated CBD treatment on behavior, neuroplasticity markers and lipidomic profile in the prefrontal cortex (PFC) of Flinders Sensitive Line (FSL), a genetic animal model of depression, and their control counterparts Flinders Resistant Line (FRL) rats. Male FSL animals were treated with CBD (10 mg/kg; i.p.) or vehicle (7 days) followed by Open Field Test (OFT) and the Forced Swimming Test (FST). The PFC was analyzed by a) western blotting to assess markers of synaptic plasticity and cannabinoid signaling in synaptosome and cytosolic fractions; b) mass spectrometry-based lipidomics to investigate endocannabinoid levels (eCB). CBD attenuated the increased immobility observed in FSL, compared to FRL in FST, without changing the locomotor behavior in the OFT. In synaptosomes, CBD increased ERK1, mGluR5, and Synaptophysin, but failed to reverse the reduced CB1 and CB2 levels in FSL rats. In the cytosolic fraction, CBD increased ERK2 and decreased mGluR5 expression in FSL rats. Surprisingly, there were no significant changes in eCB levels in response to CBD treatment. These findings suggest that CBD effects in FSL animals are associated with changes in synaptic plasticity markers involving mGluR5, ERK1, ERK2, and synaptophysin signaling in the PFC, without increasing the levels of endocannabinoids in this brain region.
AB - Delayed therapeutic responses and limited efficacy are the main challenges of existing antidepressant drugs, thereby incentivizing the search for new potential treatments. Cannabidiol (CBD), non-psychotomimetic component of cannabis, has shown promising antidepressant effects in different rodent models, but its mechanism of action remains unclear. Herein, we investigated the antidepressant-like effects of repeated CBD treatment on behavior, neuroplasticity markers and lipidomic profile in the prefrontal cortex (PFC) of Flinders Sensitive Line (FSL), a genetic animal model of depression, and their control counterparts Flinders Resistant Line (FRL) rats. Male FSL animals were treated with CBD (10 mg/kg; i.p.) or vehicle (7 days) followed by Open Field Test (OFT) and the Forced Swimming Test (FST). The PFC was analyzed by a) western blotting to assess markers of synaptic plasticity and cannabinoid signaling in synaptosome and cytosolic fractions; b) mass spectrometry-based lipidomics to investigate endocannabinoid levels (eCB). CBD attenuated the increased immobility observed in FSL, compared to FRL in FST, without changing the locomotor behavior in the OFT. In synaptosomes, CBD increased ERK1, mGluR5, and Synaptophysin, but failed to reverse the reduced CB1 and CB2 levels in FSL rats. In the cytosolic fraction, CBD increased ERK2 and decreased mGluR5 expression in FSL rats. Surprisingly, there were no significant changes in eCB levels in response to CBD treatment. These findings suggest that CBD effects in FSL animals are associated with changes in synaptic plasticity markers involving mGluR5, ERK1, ERK2, and synaptophysin signaling in the PFC, without increasing the levels of endocannabinoids in this brain region.
KW - Cannabidiol
KW - Endocannabinoids
KW - Flinders sensitive line
KW - Lipidome
KW - Neuroplasticity
KW - Synaptosome
KW - Synaptophysin/metabolism
KW - Rats
KW - Male
KW - Antidepressive Agents/pharmacology
KW - Depression/drug therapy
KW - Prefrontal Cortex
KW - Animals
KW - Neuronal Plasticity
KW - Endocannabinoids/metabolism
KW - Cannabidiol/pharmacology
KW - Disease Models, Animal
UR - http://www.scopus.com/inward/record.url?scp=85186540978&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2024.109870
DO - 10.1016/j.neuropharm.2024.109870
M3 - Journal article
C2 - 38401791
AN - SCOPUS:85186540978
SN - 0028-3908
VL - 248
JO - Neuropharmacology
JF - Neuropharmacology
M1 - 109870
ER -