CB1 cannabinoid receptor-mediated neurite remodeling in mouse neuroblastoma N1E-115 cells

The morphological remodeling of neuronal cells influences neurogenesis and brain functions. We hypothesize that psychoactive and neurotoxic effects of cannabinoids maybe mediated, at least in part, by their morphoregulatory a ctivities. In the present study, mouse neuroblastoma N1E-115 cells were use d as an in vitro model to investigate cannabinoid-induced neurite remodelin g effects and to identify the involvement of cannabinoid receptors in this neurite remodeling process. Using reverse transcription-polymerase chain re action and immunofluorescence microscopy, the endogenously expressed CB1, b ut not CB2, cannabinoid receptors were detected in morphologically differen tiated N1E-115 cells. Activation of these natively expressed CB1 cannabinoi d receptors by cannabinoid agonist HU-210 led to a concentration-dependent inhibition of adenylate cyclase activity. Importantly, HU-210 treatment ind uced neurite retraction in a concentration-dependent manner. Pretreatment o f N1E-115 cells with a CB1 antisense oligodeoxynucleotide (ODN) suppressed HU-210-induced inhibition of forskolin-stimulated CAMP accumulation, indica ting that the knocking down of functional CB1 cannabinoid receptor expressi on was achieved. Antisense ODN pretreatment also abolished HU-210-induced n eurite retraction, demonstrating the involvement of CB1 cannabinoid recepto rs in mediating the neurite remodeling effects of HU-210. In addition, reve rsing HU-210-induced intracellular cAMP declination by 8-Br-cAMP partially prevented HU-210-induced neurite retraction, indicating the involvement of cAMP-dependent signaling pathways in mediating the neurite remodeling funct ion of CB1 cannabinoid receptors in N1E-115 cells. These data demonstrate t hat neurite remodeling is a newly discovered function of CB1 cannabinoid re ceptors. This morphoregulatory function of CB1 cannabinoid receptors might be a new mechanism that mediates the psychoactive and neurotoxic effects of cannabinoids in developing and adult brain. (C) 2001 Wiley-Liss, Inc.