Department of Biochemistry and Molecular Biology (R-629), University of Miami School of Medicine, P.O. Box 016129, 1600 NW 10th Avenue, Miami, Florida 33101, USANeurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079, USA.
3 papers in the library · 111 citations · publishing 1998-2004
Methamphetamine and MDMA are widely abused drugs that may damage dopamine- and serotonin-producing neurons. Evidence from rodent and primate studies strongly indicates these drugs cause neurotoxicity, though human data remain limited. Recent work with genetically modified mice has identified several molecular players in this damage, including dopamine transporters, nitric oxide, apoptotic proteins, and inflammatory cytokines. Understanding the mechanisms behind this neurotoxicity and its behavioral effects could clarify how human methamphetamine and MDMA abuse affects cognition, drug-seeking behavior, extinction, and relapse.
Mice lacking the neuronal nitric oxide synthase (nNOS) gene are resistant to methamphetamine-induced psychomotor sensitization and dopaminergic neurotoxicity, but not to serotonin-mediated effects of MDMA (Ecstasy). Repeated MDMA administration caused psychomotor sensitization in both normal and nNOS knockout mice, while methamphetamine caused sensitization only in normal mice. Sensitization to both drugs persisted for 40 days in normal mice but not in knockouts. High-dose MDMA depleted serotonin in several brain regions of both types, indicating nNOS absence does not protect against serotonin loss. Striatal dopamine neurotoxicity from high-dose MDMA and methamphetamine was partially prevented in knockouts given MDMA and fully prevented in knockouts given methamphetamine. The nNOS gene is required for dopamine-mediated effects of both drugs but not for serotonin-mediated effects of MDMA.
Ibogaine, a hallucinogenic alkaloid, may help treat opioid and cocaine addiction. Its neurochemical mechanisms are unclear. In rat cortex and cerebellum membrane preparations, ibogaine bound to high- and low-affinity phencyclidine (PCP) sites in the cortex (Ki(H) = 0.01-0.05 μM; Ki(L) = 2-4 μM) and only low-affinity sites in the cerebellum (Ki = 2-4 μM). It showed no affinity for NMDA receptor binding sites at concentrations >100 μM. Affinity for sigma-1 and sigma-2 sites ranged from 1.5-3 μM. Binding to PCP sites may contribute to ibogaine's potential anti-addiction properties, while sigma site interactions may cause adverse effects.