MDPV induces a rapid up-regulation of striatal dopamine transporter function. A comparative study with cocaine

[Speaker] Raul Lopez-Arnau:1
[Co-author] Vanessa Mosquera:1, Elena Escubedo:1, Camarasa Jordi:1, Pubill David:1
1:Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Spain

Background: New psychoactive substances, such as synthetic cathinones, have been recently identified, representing an important public health challenge. 3,4-Methylenedioxypyrovalerone (MDPV) is considered as one of the most abused synthetic cathinone and the main ingredient of «bath salts«. MDPV shows cocaine-like properties, being more potent than cocaine as a dopamine transporter (DAT) blocker and showing powerful rewarding and reinforcing effects. Acute cocaine appears to rapidly up-regulate surface expression of DAT, leading to an increase in dopamine uptake. There are evidences that DAT function is elevated by chronic cocaine users. The aim of the study was to investigate changes in dopamine clearance after MDPV or cocaine administration at different time points. Moreover, Km and Vmax values were also calculated.
Methods: Male Sprague-Dawley rats were administered with saline, MDPV (1.5 mg/kg, s.c.) or cocaine (30mg/kg, i.p.) and killed 1, 3 or 16 hours after injection and striatal synaptosomal suspensions were obtained and [3H]dopamine uptake was determined at a concentration of 200nM. To calculate Km and Vmax values, striatal synaptosomes were prepared from untreated rats and then incubated with MDPV or cocaine (1µM) for 1 hour. [3H]dopamine uptake was also determined at a concentration range of 5-500nM.
Results: Cocaine administration induced an increase in [3H]dopamine uptake (70%) only 1 hour after injection. However, MDPV administration not only produced a higher increase in dopamine clearance (120%) compared to cocaine, but also lasted 3 hours after injection. After cocaine incubation only changes in Vmax value was observed (control: Vmax = 29.57±1.73 pmol/mg*min; cocaine: Vmax = 38.38±0.36 pmol/mg*min, p<0.05) probably due to an up-regulation of surface expression of DAT. When synaptosomes were incubated in vitro with MDPV, an increase in Vmax value was also observed (MDPV: Vmax = 49.99±8.53 pmol/mg*min, p<0.01) as occurred with cocaine, but also changes in Km value was obtained (control: 0.09±0.01 µM; MDPV: 0.15±0.02 µM, p<0.01), decreasing the affinity of dopamine for being taken up.
Conclusion: These findings demonstrate, for the first time, that an acute MDPV injection is able to rapidly up-regulate DAT function to a higher and more durable extent than cocaine. Funding: SAF2016-75347-R and PNSD2016I004

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