"Involvement of nicotinic receptors in methamphetamine- and MDMA-induced neurotoxicity: pharmacological implications.
During the last years, we have focused on the study of the neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) on the central nervous system (CNS) and their pharmacological prevention methods. In the process of this research, we have used a semipurified synaptosomal preparation from striatum of mice or rats as a reliable in vitro model to study reactive oxygen species (ROS) production by these amphetamine derivatives, which is well-correlated with their dopaminergic injury in in vivo models. Using this preparation, we have demonstrated that blockade of alpha7 nicotinic receptors with methyllycaconitine (MLA) prevents ROS production induced by MDMA and METH. Consequently, in vivo, MLA significantly prevents MDMA- and METH-induced neurotoxicity at dopaminergic level (mouse striatum), without affecting hyperthermia induced by these amphetamines. Additionally, when neuroprotection was assayed with memantine (MEM), a dual antagonist of NMDA and alpha7 receptors, an effective neuroprotection was obtained also ahead of serotonergic injury induced by MDMA in rats. MEM also prevents MDMA effect on serotonin transporter functionality and METH effect on dopamine transporter (DAT), suggesting that behavioral effects of these psychostimulants can also be modulated by MEM. Finally, we have demonstrated that MEM prevents the impaired memory function induced by MDMA, and also, using binding studies with radioligands, we have characterized the interaction of these substances with nicotinic receptors. Studies at molecular level showed that both MDMA and METH displaced competitively the binding of radioligands with homomeric alpha7 and heteromeric nicotinic acetylcholine receptors (nAChRs), indicating that they can directly interact with them. In all the cases, MDMA displayed higher affinity than METH and it was higher for heteromeric than for alpha7 subtype. Pre-incubation of differentiated PC12 cells with MDMA or METH induces nAChR upregulation in a concentration- and time-dependent manner, as many nicotinic ligands do, supporting their functional interaction with nAChRs. Such interaction expands the pharmacological profile of amphetamines and can account for some of their effects."
http://lib.bioinfo.pl/pmid:19897077
SIMPLIFIED
MLA: nACh anatagonist
MEM: NMDA antagonist and a nACh anatagonist (alpha7 subunit)
ROS: Reactive Oxygen Species
Meth: Methamphetamine
SERT: Serotonin Transporter
DAT: Dopamine Transporter
AChR: Nicotinic Acetylcholine Recepter
They used two antagonists to see how they effected MDMA/Meth neurotoxicity. ROS is associated with dopaminergic injury. MLA prevents ROS induced by Meth or MDMA. MEM prevented serotonergic injury but also prevented the reversal of DAT by Meth and SERT by MDMA basically inhibiting the main function of these drugs. MEM therefore inhibits neurotoxicity including memory damage from MDMA. MDMA and Meth are ligands at nAChRs and MDMA has a higher affinity for the non-alpha7 subtype of nAChR then Meth did.
During the last years, we have focused on the study of the neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) on the central nervous system (CNS) and their pharmacological prevention methods. In the process of this research, we have used a semipurified synaptosomal preparation from striatum of mice or rats as a reliable in vitro model to study reactive oxygen species (ROS) production by these amphetamine derivatives, which is well-correlated with their dopaminergic injury in in vivo models. Using this preparation, we have demonstrated that blockade of alpha7 nicotinic receptors with methyllycaconitine (MLA) prevents ROS production induced by MDMA and METH. Consequently, in vivo, MLA significantly prevents MDMA- and METH-induced neurotoxicity at dopaminergic level (mouse striatum), without affecting hyperthermia induced by these amphetamines. Additionally, when neuroprotection was assayed with memantine (MEM), a dual antagonist of NMDA and alpha7 receptors, an effective neuroprotection was obtained also ahead of serotonergic injury induced by MDMA in rats. MEM also prevents MDMA effect on serotonin transporter functionality and METH effect on dopamine transporter (DAT), suggesting that behavioral effects of these psychostimulants can also be modulated by MEM. Finally, we have demonstrated that MEM prevents the impaired memory function induced by MDMA, and also, using binding studies with radioligands, we have characterized the interaction of these substances with nicotinic receptors. Studies at molecular level showed that both MDMA and METH displaced competitively the binding of radioligands with homomeric alpha7 and heteromeric nicotinic acetylcholine receptors (nAChRs), indicating that they can directly interact with them. In all the cases, MDMA displayed higher affinity than METH and it was higher for heteromeric than for alpha7 subtype. Pre-incubation of differentiated PC12 cells with MDMA or METH induces nAChR upregulation in a concentration- and time-dependent manner, as many nicotinic ligands do, supporting their functional interaction with nAChRs. Such interaction expands the pharmacological profile of amphetamines and can account for some of their effects."
http://lib.bioinfo.pl/pmid:19897077
SIMPLIFIED
MLA: nACh anatagonist
MEM: NMDA antagonist and a nACh anatagonist (alpha7 subunit)
ROS: Reactive Oxygen Species
Meth: Methamphetamine
SERT: Serotonin Transporter
DAT: Dopamine Transporter
AChR: Nicotinic Acetylcholine Recepter
They used two antagonists to see how they effected MDMA/Meth neurotoxicity. ROS is associated with dopaminergic injury. MLA prevents ROS induced by Meth or MDMA. MEM prevented serotonergic injury but also prevented the reversal of DAT by Meth and SERT by MDMA basically inhibiting the main function of these drugs. MEM therefore inhibits neurotoxicity including memory damage from MDMA. MDMA and Meth are ligands at nAChRs and MDMA has a higher affinity for the non-alpha7 subtype of nAChR then Meth did.
