7,8-Dihydroxyflavone blocks the development of behavioral sensitization to MDPV, but not to cocaine: Differential role of the BDNF-TrkB pathway

• Published in: Biochemical pharmacology 2019-05, Vol.163, p.84-93
• Main Authors: Duart-Castells, L., López-Arnau, R., Vizcaíno, S., Camarasa, J., Pubill, D., Escubedo, E.
• Format: Article
• Language: English
• Subjects: 7,8-Dihydroxyflavone; Animals; BDNF; Benzodioxoles - pharmacology; Brain-Derived Neurotrophic Factor - physiology; Cocaine; Cocaine - pharmacology; Cocaïna; Dopamina; Dopamine; Dopamine Uptake Inhibitors - pharmacology; Dose-Response Relationship, Drug; Flavones - pharmacology; Male; MDPV; Membrane Glycoproteins - physiology; Mice; Motor Activity - drug effects; Motor Activity - physiology; Neurofarmacologia; Neuropharmacology; Protein-Tyrosine Kinases - physiology; Pyrrolidines - pharmacology; Sensitization; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2019.02.004

[Display omitted] 3,4-Methylenedioxypyrovalerone (MDPV) acts as a dopamine transporter blocker and exerts powerful psychostimulant effects. In this study we aimed to investigate the bidirectional cross-sensitization between MDPV and cocaine, as well as to evaluate the role of the BDNF-TrkB signaling pathway in the development of locomotor sensitization to both drugs. Mice were treated with MDPV (1.5 mg/kg) or cocaine (10 or 15 mg/kg) once daily for 5 days. After withdrawal (10 days), animals were challenged with cocaine (8 mg/kg) or MDPV (1 mg/kg). For biochemical determinations, MDPV (1.5 mg/kg) or cocaine (15 mg/kg) were administered acutely or repeatedly, and BDNF, D3R and G9a transcription levels as well as pro- and mature BDNF protein levels were determined. Our results demonstrate that repeated administration of MDPV or cocaine sensitizes to cocaine and MDPV locomotor effects. After an acute or a repeated exposure to MDPV, cortical mRNA BDNF levels were increased, while a decrease in mBDNF protein levels in the nucleus accumbens 2 h after repeated exposure was evidenced. Interestingly, such decline was involved in the development of locomotor sensitization, thus the pretreatment with 7,8-dihydroxyflavone (10 mg/kg), a TrkB agonist, blocked the development of sensitization to MDPV but not to cocaine, for which no changes in the BDNF-TrkB signaling pathway were observed at early withdrawal. In conclusion, a bidirectional cross-sensitization between MDPV and cocaine was evidenced. Our findings suggest that decreased BDNF-TrkB signaling has an important role in the behavioral sensitization to MDPV, pointing TrkB modulation as a target to prevent MDPV sensitization.