The BDNF-TrkB signaling pathway is involved differently in the development of locomotor sensitization and place conditioning by MDPV and cocaine

[Speaker] Elena Escubedo:1
[Co-author] Leticia Duart-Castells:1, Raul Lopez-Arnau:1, David Pubill:1, Jorge Camarasa:1
1:Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Spain

3,4-Methylenedioxypyrovalerone (MDPV) is a cathinone that acts as a dopamine transporter blocker and proved to increase vulnerability to cocaine abuse. Accordingly, we determined if there is also a cross-sensitization between both drugs. In addition, we evaluated the role of the brain derived neurotrophic factor (BDNF)-TrkB signaling pathway in the development of locomotor sensitization as well as on the place conditioning test (CPP), compared to cocaine.
For the cross-sensitization experiments, mice were treated with saline, MDPV (1.5 mg/kg, s.c.) or cocaine (15 mg/kg, i.p.) for 5 consecutive days. After 10 days of withdrawal, mice were challenged with MDPV (1 mg/kg, s.c.) or cocaine (8 mg/kg, s.c.) and their horizontal locomotor activity was registered. BDNF protein levels were quantified in the ventral striatum of mice sacrificed 24h or 10 days after treatment using a specific BDNF ELISA kit. We wanted to attenuate the development of locomotor sensitization by administering a TrkB agonist 7,8-dihydroxyflavone (7,8-DHF, 10 mg/kg i.p.) before injection of MDPV or cocaine. In parallel, we sought to block the development of CPP by administering 7,8-DHF or a selective TrkB antagonist ANA-12 (0.5 mg/kg i.p.), 30 or 15 min before every conditioning session in the CPP test, respectively.
Our results showed that not only MDPV and cocaine sensitize to themselves and MDPV sensitizes to cocaine, but also cocaine is able to induce a behavioral sensitization to MDPV. Furthermore, BDNF protein levels were found significantly decreased 24h after repeated treatment with MDPV (86.63±4.12%), while no changes were found after cocaine treatment. Pretreatment with the TrkB agonist attenuated MDPV sensitization (69.45±3.75%, p<0.001) while enhanced that of cocaine (121.16±4.54%, p<0.05). The agonist did not block the development of CPP to MDPV. Additionally, the effect of the antagonist on place conditioning differed between cocaine and MDPV.
In conclusion, our findings suggest that there is a cross-sensitization between MDPV and cocaine, so both drugs enhance the abuse liability to each other. However, our results support that, after a repeated treatment, the BDNF-TrkB signaling pathway is involved differently in effects between MDPV and cocaine. Therefore, a single therapeutic solution does not seem possible. Funding: SAF2016-75347-R and PNSD 2016I004.

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