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

Biochem Pharmacol. 2019 May;163:84-93. doi: 10.1016/j.bcp.2019.02.004. Epub 2019 Feb 6.

Abstract

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.

Keywords: 7,8-Dihydroxyflavone; BDNF; Cocaine; MDPV; Sensitization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzodioxoles / pharmacology*
  • Brain-Derived Neurotrophic Factor / physiology*
  • Cocaine / pharmacology*
  • Dopamine Uptake Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Flavones / pharmacology*
  • Male
  • Membrane Glycoproteins / physiology*
  • Mice
  • Motor Activity / drug effects*
  • Motor Activity / physiology
  • Protein-Tyrosine Kinases / physiology*
  • Pyrrolidines / pharmacology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • 6,7-dihydroxyflavone
  • Benzodioxoles
  • Brain-Derived Neurotrophic Factor
  • Dopamine Uptake Inhibitors
  • Flavones
  • Membrane Glycoproteins
  • Pyrrolidines
  • 3,4-methylenedioxypyrovalerone
  • Ntrk2 protein, mouse
  • Protein-Tyrosine Kinases
  • Cocaine