Delayed pre‐conditioning by 3‐nitropropionic acid prevents 3,4‐methylenedioxymetamphetamine‐induced 5‐HT deficits

Abstract

J. Neurochem. (2010) 114, 843–852. Abstract The aim of the present study was to investigate whether late pre‐conditioning using 3‐nitropropionic acid (3NP) prevents the 5‐hydroxytryptamine (5‐HT) deficits caused by the amphetamine derivative 3,4‐methylenedioxymethamphetamine (MDMA) in the rat. For this purpose we administered 3NP 24 h before MDMA (3 × 5 mg/kg i.p., every 2 h) and rats were killed 7 days later. Pre‐treatment of 3NP afforded complete protection against MDMA‐induced 5‐HT deficits independent of any effect on MDMA‐induced hyperthermia or 5‐HT transporter activity. To identify the transductional mechanisms responsible for the neuroprotective effect of 3NP, we first examined the involvement of nitric oxide (NO) by using selective inhibitors of all three nitric oxide synthase isoforms. Inhibition of endothelial and neuronal nitric oxide synthase, but not inducible nitric oxide synthase, reversed 3NP‐induced pre‐conditioning. The NO donor S‐Nitroso‐N‐acetylpenicilamine mimicked 3NP effects further suggesting the involvement of NO in mediating 3NP protection. To investigate the involvement of NOS/soluble guanylate cyclase (sGC)/protein kinase G/mitochondrial ATP‐sensitive potassium channels (mitoKATP) signaling pathway we examined the effect of 5‐hydroxydecanoate (5‐HD), a selective mitoKATP blocker, and 1H‐(1,2,4)oxadiazolo[4,3‐a]quinoxaline‐1‐one, a potent inhibitor of sGC, on 3NP‐induced tolerance. 5‐hydroxydecanoate, but not 1H‐(1,2,4)oxadiazolo[4,3‐a]quinoxaline‐1‐one, suppressed 3NP‐mediated protection suggesting that mitoKATP opening, but not NO‐mediated activation of sGC, participates in the mechanism underlying tolerance to MDMA. Our data also showed that the protective effect of 3NP was abolished by cycloheximide, supporting the involvement of de novo protein synthesis. In conclusion, 3NP‐induced delayed tolerance against 5‐HT deficits caused by MDMA occurs via NO production.

Long‐lasting neuroprotective effect of sildenafil against 3,4‐methylenedioxymethamphetamine‐ induced 5‐hydroxytryptamine deficits in the rat brain

“…Not only acute but also delayed chemical preconditioning has been shown to protect the rat brain 5-HT neurotransmitter system from MDMA (Piper et al, 2006(Piper et al, , 2010Bhide et al, 2009). In this regard, 3-nitropropionic acid given 24 hr before a toxic MDMA treatment completely prevented 5-HT depletions by a mechanism involving NO production (Puerta et al, 2010c). These data were in accordance with a sizable amount of evidence indicating that increased NO production is involved in various preconditioning paradigms (Huang, 2004;Pignataro et al, 2009).…”

Adolescent MDMA Exposure Diminishes the Physiological, Behavioral, and Neurotoxic Consequences of a Subsequent Methamphetamine Binge

“…Several factors have received significant attention regarding the mechanisms underlying substituted amphetamine preconditioning. Evidence has been presented for a variety of potentially relevant cellular/biochemical/molecular changes [9,11,19,21,29,36,44,60,61,70]. But until additional research is conducted, it will remain unclear whether these changes work in concert or whether there are multiple pathways leading to the neuroprotective effects of low-dose MDMA or METH administration.…”

Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation

“…Of interest, minoxidil also afforded protection against MDMA-induced 5-HT depletion by a similar mechanism [164] including the activation of ATP-sensitive potassium (KATP) channels, an essential initiator of preconditioning in different models [165-169]. Moreover, 3-nitropropionic acid, given 24 h before a toxic MDMA treatment, completely prevented 5-HT depletions by increasing NO production [170]; which is also involved in various preconditioning paradigms [171,172]. In all these studies, the neuroprotective effect was independent of any alteration in the hyperthermia induced by MDMA.…”