Methamphetamine and 3,4-methylenedioxymethamphetamine interact with central nicotinic receptors and induce their up-regulation.
Sara Garcia-Ratés, Jordi Camarasa, Elena Escubedo, David Pubill
Toxicology and Applied Pharmacology September 15, 2007 DOI: 10.1016/j.taap.2007.05.015 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro and ex vivo receptor binding study Peer reviewed |
|---|---|
| Population | NGF-differentiated PC12 cells and mouse brain membranes |
| Interventions | Methamphetamine MDMA |
| Duration | Pretreatment up to 48 h |
| Measures | [3H]methyllycaconitine binding, [3H]epibatidine binding |
| Topics | MDMA |
| Key points | Methamphetamine and MDMA bind nicotinic acetylcholine receptors with micromolar affinity and up-regulate them in a time- and concentration-dependent manner, with MDMA showing greater affinity and larger increases than methamphetamine. The up-regulation involves newly synthesized proteins and may relate to neurotoxicity, cholinergic neurotransmission, and addiction. |
Abstract
Previous work from our group indicated that alpha7 nicotinic acetylcholine receptors (alpha7 nAChR) potentially play a role in methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) neurotoxicity. The aims of the present study were two-fold: (1) to demonstrate the interaction of METH and MDMA with homomeric alpha7 nAChR ([(3)H]methyllycaconitine binding) and other heteromeric subtypes ([(3)H]epibatidine binding); and (2) to show the effects of amphetamine derivative pretreatment on the density of binding sites. METH and MDMA displaced [(3)H]methyllycaconitine and [(3)H]epibatidine binding in membranes from NGF-differentiated PC 12 cells and mouse brain, with K(i) values in the micromolar range, MDMA revealing a greater affinity than METH. In addition, METH and MDMA induced a time- and concentration-dependent increase in [(3)H]methyllycaconitine and [(3)H]epibatidine binding; which had already been apparent after 6 h of pretreatment, and which peaked in differentiated PC 12 cells after 48 h. The highest increases were found in [(3)H]epibatidine binding, with MDMA inducing higher increases than METH. Treatment with METH and MDMA increased B(max) of high-affinity sites for both radioligands without affecting K(d). The heightened binding was inhibited by pretreatment with cycloheximide, suggesting the participation of newly synthesised proteins while inhibition of protein trafficking to plasma membrane did not block up-regulation. The effects of protein kinase and cyclophilin inhibitors on such up-regulation were explored, revealing a rapid, differential and complex regulation, similar to that described for nicotinic ligands. All of these results demonstrate that METH and MDMA have affinity for, and can interact with, nAChR, inducing their up-regulation, specially when higher doses are used. Such effects may have a role in METH- and MDMA-induced neurotoxicity, cholinergic neurotransmission, and in processes related to addiction and dependence.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 11
- Neurochemical binding profiles of novel indole and benzofuran MDMA analogues. Naunyn-Schmiedeberg's Archives of Pharmacology September 20, 2016
- Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity Pharmaceuticals June 15, 2011
- Of mice and men on MDMA: a translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy'). Brain Research November 14, 2019
- 3,4-Methylenedioxymethamphetamine (MDMA) Alters Synaptic Dopamine Release in the Dorsal Striatum Through Nicotinic Receptors and DAT Inhibition. Neuroscience May 1, 2018
- Hippocampal nicotinic receptors have a modulatory role for ethanol and MDMA interaction in memory retrieval. Brain Research May 23, 2017
and 6 more in the library
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