Recreational drugs, 3,4-Methylenedioxymethamphetamine(MDMA), 3,4-methylenedioxyamphetamine (MDA) and diphenylprolinol, inhibit neurite outgrowth in PC12 cells

Abstract

-3,4-Methylenedioxymethamphetamine (MDMA) is widely abused as a psychoactive recreational drug. It is well known that MDMA induces neurotoxic damage of serotonergic nerve endings. Although drug abuse is increasing among youths, it is unclear whether recreational drugs affect the development of nerve growth. Thus, the present study examined the effect of recreational drugs, such as MDMA, 3,4-methylenedioxyamphetamine (MDA) and diphenylprolinol, a novel recreational drug with a similar chemical structure as that of psychoactive agent pipradrol, on nerve growth factor (NGF)-induced neurite outgrowth. These recreational drugs induced a dose-dependent cell death in PC12 cells. The IC 50 values of MDMA, MDA, R-diphenylprolinol and S-diphenylprolinol were 4.11 mM, 2.75 mM, 1.00 mM and 0.77 mM, respectively, at 24 hr. To examine the effects of these recreational drugs on NGF-induced neurite outgrowth, PC12 cells were treated with NGF together with MDMA, MDA, S-diphenylprolinol or R-diphenylprolinol at low toxic concentrations. The recreational drugs significantly suppressed neurite outgrowth of PC12 cells induced by NGF. The results suggest that these psychoactive recreational drugs may inhibit neurite growth and thus be implicated in their elicited neurotoxicity. LetterThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.35, No.3, 375-381, 2010 Vol. It has been demonstrated that acute MDMA administration induces a rapid release of serotonin (5-HT) (Gdelsky and Nash, 1996) indicating a decrease of 5-HT concentration in brain tissues (Colado et al., 1993). MDMA binds serotonin transporter with high affinity and then inhibits reuptake of 5-HT; MDMA also binds noradrenaline and dopamine transporters with lower affinities (Rothman and Baumann, 2002;Liechti et al., 2000). MDMA inhibits the enzyme tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, and produces a degeneration of serotonergic nerve terminals (Ricaurte et al., 1985;Battaglia et al., 1987;Schmidt and Taylor, 1987;O'Shea et al., 1998). In addition, MDMA is a weak inhibitor of both A and B subtypes of monoamine oxidase (Torre et al., 2004;Parrott, 2005). These observations indicate that MDMA affects brain activity by altering neurotransmission, particularly the sertonergic system. Although use of MDMA by the young generation is widely spread, the effects of the drug on pregnancy and fetal brain are not obvious. It is, therefore, important to clarify the effect of recreational drugs on nerve growth.Diphenylprolinol is a novel recreational drug with a structure similar to that of pipradrol, a drug initially developed to treat obesity (Gelvin et al., 1955). However, pipradrol was found to possess a stimulant effect on the central nervous system (CNS); it induced incoordinated motor activity and ataxia, followed by tremor and clonic convulsions (Portoghese et al., 1968). Therefore, pipradrol has been removed from the Japanese market and controlled under drug legislation since the 1970s. The psychoactive feature of racemic pipr...

Monoaminergic toxicity induced by cathinone phthalimide: An in vitro study

“…Previous reports in PC12 indicate that MDMA, cocaine, and amphetamine diminish cell viability, but at much high doses (2–2.5mM, 1mM,and 2mM respectively) [20, 29, 31, 34] than seen with CP in the present study (10µM). Additionally, much higher doses of cocaine or amphetamine (50µM and 3mM respectively) are reported to alter intracellular DA levels [19, 34], whereas CP induces a response at 10µM.…”

Maternal MDMA administration in mice leads to neonatal growth delay

“…We have previously demonstrated the effect of MDMA on nerve cells in vitro, showing that MDMA inhibits NGF-induced neurite outgrowth and suggesting that the recreational drug may cause impaired neuronal development (Kaizaki et al, 2010). The aim of the current study was to determine whether MDMA affects the ontogenetic development and growth of mouse pups.…”

Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine

“…Consistent with and bridging these findings are studies showing that psychostimulants induce alterations in neurotrophic factors which may also play a role in cognitive dysfunction (Hemmerle et al, 2012; Chen et al, 2012). For example, MDMA significantly suppresses neurite outgrowth of PC12 cells (a catecholaminergic cell line often used in neurotoxicological studies) induced by nerve growth factor (Kaizaki et al, 2010). Thus, in combination with altered brain energetics and immune function, changes in neurotrophic factor signaling may additionally contribute to the adverse CNS and neuropsychiatric effects associated with abuse of MDMA and/or methamphetamine.…”