Dual mechanism of TRKB activation by anandamide through CB1 and TRPV1 receptors

Author(s)

Diniz, Cassiano R. A. F. ^[1] ; Biojone, Caroline ^{[2, 3]} ; Joca, Sarnia R. L. ^{[4, 2, 5]} ; Rantamaki, Tomi ^[6] ; Castren, Eero ^[3] ; Guimaraes, Francisco S. ^[1] ; Casarotto, Plinio C. ^{[1, 3]}

Affiliation

^[1] Univ Sao Paulo, Dept Pharmacol, Ribeirao Preto Med Sch, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Sch Pharmaceut Sci, Dept Phys & Chem, Ribeirao Preto, SP - Brazil

^[3] Univ Helsinki, Neurosci Ctr, HILIFE, Helsinki - Finland

^[4] Aarhus Univ, Dept Clin Med, Translat Neuropsychiat Unit, Aarhus - Denmark

^[5] Aarhus Univ, Aarhus Inst Adv Studies, Aarhus - Denmark

^[6] Univ Helsinki, Fac Pharm, Div Pharmacol & Pharmacotherapeut, Helsinki - Finland

• Document type: Journal article
• Source: PeerJ; v. 7, FEB 21 2019.
• Web of Science Citations: 0

Abstract

Background. Administration of anandamide (AEA) or 2-arachidonoylglycerol (2AG) induces CB1 coupling and activation of TRKB receptors, regulating the neuronal migration and maturation in the developing cortex. However, at higher concentrations AEA also engages vanilloid receptor TRPV1, usually with opposed consequences on behavior. Methods and Results. Using primary cell cultures from the cortex of rat embryos (E18) we determined the effects of AEA on phosphorylated TRKB (pTRK). We observed that AEA (at 100 and 200 nM) induced a significant increase in pTRK levels. Such effect of AEA at 100 nM was blocked by pretreatment with the CBI antagonist AM251 (200 nM) and, at the higher concentration of 200 nM by the TRPV1 antagonist capsazepine (200 nM), but mildly attenuated by AM251. Interestingly, the effect of AEA or capsaicin (a TRPV1 agonist, also at 200 nM) on pTRK was blocked by TRKB.Fc (a soluble form of TRKB able to bind BDNF) or capsazepine, suggesting a mechanism dependent on BDNF release. Using the marble-burying test (MBT) in mice, we observed that the local administration of ACEA (a CBI agonist) into the prelimbic region of prefrontal cortex (PL-PFC) was sufficient to reduce the burying behavior, while capsaicin or BDNF exerted the opposite effect, increasing the number of buried marbles. In addition, both ACEA and capsaicin effects were blocked by previous administration of k252a (an antagonist of TRK receptors) into PL-PFC. The effect of systemically injected CB1 agonist WIN55,212-2 was blocked by previous administration of k252a. We also observed a partial colocalization of CBI /TRPV1 /TRKB in the PL-PFC, and the localization of TRPV1 in CaMK2+ cells. Conclusion. Taken together, our data indicate that anandamide engages a coordinated activation of TRKB, via CB1 and TRPV1. Thus, acting upon CBI. and TRPV1, AEA could regulate the TRKB-dependent plasticity in both pre- and postsynaptic compartments. (AU)

• FAPESP's process: 13/02549-0 - Involvement of plastic mechanisms associated to fluoxetine-induced neuronal turnover on the fear extinction in the cued conditioned model
• Grantee: Cassiano Ricardo Alves Faria Diniz
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/04250-5 - Study of the relevance of p75 receptor activation for the effect of antidepressants on the extinction memory
• Grantee: Cassiano Ricardo Alves Faria Diniz
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 11/02746-4 - Involvement of endocannabinoid system modulating repetitive behavior: possible participation of brain-derived neurotrophic factor (BDNF)
• Grantee: Plínio Cabrera Casarotto
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/01029-2 - Molecular interactions between CB1 and TrkB modulating repetitive behavior
• Grantee: Plínio Cabrera Casarotto
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor