Selective neuronal death following exposure to methylenedioxypyrovalerone is accompanied by an inhibition of NMDA receptor NR2B subunit expression.

In a previous study, methylenedioxypyrovalerone (MDPV), a designer drug of the cathinone family, caused selective enhancement of Caspase3 immunoreactive (Casp3+) apoptotic cells in the nucleus accumbens (NAc) of 7­day­old mice. To further elaborate on the mechanism underlying MDPV­elicited apoptosis, here, we investigated the appearance of Casp3+ cells in developing neural tube explants of E12.5 mice, following MDPV treatment in vitro. Apoptotic cells appeared in large number in the pallium as radial progenitor cells and multipolar neurons, and in the subpallium including the future NAc, both in control and MDPV treated specimens. MDPV did not cause gross morphological changes in the neural tube or in the abundance of Casp3+ cells, based on a visual impression, though quantification was not attempted. We also studied the changes in NMDA receptor (NMDAR) protein subunits NR1 and NR2B in the NAc of 7­day­old MDPV treated and control mice, using western blotting of tissue obtained by selective dissection. In MDPV treated animals, expression of NR2B was lower than in the control animals, whereas expression of NR1 did not differ significantly from controls. The findings indicate that, during early postembryonic development, downregulation of the NR2B receptor subunit (at this time predominant in the NMDAR) is accompanied by a decreased viability of neurons. Decreased viability is expressed, in this case, as enhanced susceptibility to stimulation by MDPV - essentially a robust dopaminergic agent, potently affecting the neurons of the NAc. The findings are likely relevant to dopaminergic/NMDAR interactions and a potential pro­survival role of the NR2B subunit in critical phases of neural development.

[Effects of the designer drug methylenedioxypyrovalerone on the developing brain in experimental animal model]. / A dizájner drog metiléndioxi-pirovaleron hatása a fejlodo idegrendszerre kísérletes állatmodellben.

INTRODUCTION: The designer drug methylenedioxypyrovalerone is a frequently used psychoactive drug of abuse. AIM: The aim of this study was to determine the effect of methylenedioxypyrovalerone, administrated from the 8th to the 14th day of the gestation, on the development of central nervous system and on the behaviour of offspring mice. METHOD: Pregnant mice were treated during this period either with subcutaneous injection of 1×10 mg/kg body weight methylenedioxypyrovalerone or vehicle (saline). Maternal behaviour (pup retrieval test), locomotor activity (open field test) and motor coordination (grip strength test) of dams were evaluated. Locomotor activity at the 7th and 21st postnatal day (open field test) and motor coordination at the 21st postnatal day (grip strength test) were examined. RESULTS: Reduced maternal behaviour among treated animals was observed. There was no difference in the results of the open field test between treated and control groups. Decrease of locomotor activity was observed in the pups of the methylenedioxypyrovalerone treated dams. CONCLUSIONS: The results suggest that cathinones (in particular methylenedioxypyrovalerone) may adversely affect neural integrity of the developing central nervous system.

Apoptotic effects of the 'designer drug' methylenedioxypyrovalerone (MDPV) on the neonatal mouse brain.

The designer drug of cathinone family, methylenedioxypyrovalerone (MDPV), is a cheap and frequently used psychoactive drug of abuse. However, its mechanism of action, particularly its potential detrimental effect on the developing brain, is largely unknown, despite the fact that pregnant females may occur among the users. The objective of our study was to identify the brain areas sensitive for a possible apoptotic effect of the widely abused MDPV on the developing brain. To this end, we used a mouse model which can be compared with the human fetus of third trimester, considering the developmental stage of the brain. Litters of 7-day-old C57BL/6J mice were treated either with i.p. injection of 10mg/kg b.wt.of MDPV or vehicle (saline), and sacrificed after 24h. Similar dose of MDPV enhanced locomotor activity of pups. The brains were processed for anti-caspase 3 (Casp3) immunohistochemistry and the apoptotic cells were identified and counted. We found prominent increase in the number of apoptotic cells in the piriform cortex, retrosplenial area, hippocampus CA1 and nucleus accumbens, whereas the overall density of cells did not change significantly in these regions. The neurons of the nucleus accumbens appeared to be especially sensitive to MDPV: Casp3-immunoreactive cells marked out the core and shell regions of the accumbens. Highest percentage of apoptotic cells as compared to total cell density was also found in the nucleus accumbens. However, we did not observe the same effect on the brain of adult mice. Thus, MDPV did not seem to increase apoptosis in the mature nervous system. The results are in agreement with the assumption that cathinones (in particular MDPV) may adversely affect neural integrity in the developing CNS.