Release of serotonin induced by 3,4-methylenedioxymethamphetamine (MDMA) and other substituted amphetamines in cultured fetal raphe neurons: further evidence for calcium-independent mechanisms of release

The substituted amphetamines 3,4-methylenedioxyamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), p-chloroamphetamine (PCA) and fenfluramine (FEN) all exert their effects by releasing serotonin (5-HT) from presynaptic nerve terminals. In the current study, we examined the ability of these agents to induce the release of 5-HT in cultured fetal raphe neurons. The data indicate that the rank order of release potencies for these agents was (±)PCA > (+)MDMA = (+)MDA = (±)FEN. Studies examining the role of calcium in 5-HT release demonstrate that preventing calcium influx with L- and N-type calcium channel blockers inhibits potassium-stimulated release of [³H]5-HT but has no effect on release induced by the substituted amphetamines. Furthermore, omitting calcium from the extracellular media or depleting the vesicular pool of neurotransmitter with continual potassium stimulation did not affect the release of [³H]5-HT induced by these compounds. Administration of fluoxetine prior to the substituted amphetamines significantly attenuated the releasing effects of these agents, while producing no effect on potassium-stimulated release. These results are consistent with the notion that the amphetamines induce release of cytoplasmic 5-HT via the plasma membrane transporter.     

Exposure to 3,4-methylenedioxymethamphetamine (MDMA) on postnatal days 11-20 induces reference but not working memory deficits in the Morris water maze in rats: implications of prior learning.

3,4-methylenedioxymethamphetamine (MDMA) in previous experiments has been shown to induce long-term spatial and sequential learning and memory deficits in adult offspring after exposure to the drug on postnatal (P) days 11-20, but not after exposure on P1-10. Herein we further tested for the effects of MDMA (0, 5, 10 or 20 mg/kg x 2/day) after exposure on P11-20 on reference and working memory in the Morris water maze (MWM), on reference memory in the Barnes maze, and on cued learning in the visible platform version of the MWM. The MWM and Barnes mazes were counterbalanced such that half the litters received the MWM-first and the other half received the Barnes maze first. Effects on MWM performance as a function of test order were observed. For animals that received the Barnes maze first, spatial MWM learning and memory trends were seen but they were not significantly different between MDMA groups and saline controls. For those receiving the MWM-first, there are consistent impairments on all measures in the MDMA groups compared to controls on MWM performance (latency, path length, and cumulative distance from the goal). On probe trials, MDMA animals receiving the MWM-first showed increased distance from the target site compared to controls. There were no MDMA effects seen on cued trials in the MWM or on straight channel swimming trials regardless of test order, indicating that MDMA had no effects on swimming ability or on the skills needed to learn the MWM. Similarly, there were no effects of MDMA on MWM working memory regardless of test order. No MDMA effects on the Barnes maze were found regardless of test order, however, the interpretation of this finding was compromised by the poor performance of the animals on this task.     

Genetic and non-genetic factors responsible for antiplatelet effects of clopidogrel in Japanese patients undergoing coronary stent implantation: An algorithm to predict on-clopidogrel platelet reactivity

Introduction

Antiplatelet effects of clopidogrel appear to be affected by various factors including genetic polymorphism. So far, there has been little information about the response of clopidogrel in Asians, whose prevalence of a CYP2C19 loss-of-function (LOF) allele is high.

Methods and Results

We investigated background and clinical factors affecting on-clopidogrel platelet reactivity in Japanese patients undergoing coronary stent implantation (n = 114). In univariate analysis, antiplatelet effects of clopidogrel in a steady state were associated with not only CYP2C19 genotypes but also several factors including dyslipidemia. In addition, we developed an algorithm that can estimate P2Y12 Reaction Units (PRU) in a steady state by multiple regression analysis and evaluated the adequacy of the algorithm by the Akaike Information Criterion.

Conclusions

We revealed several factors influencing on-clopidogrel platelet reactivity in Japanese patients. We also succeeded in developing an algorithm that estimates PRU in a steady state, although it is uncertain whether the algorithm can be applied to other populations.