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Neurochemical neutralization of methamphetamine with high‐affinity nonselective inhibitors of biogenic amine transporters: a pharmacological strategy for treating stimulant abuse
Author(s) -
Rothman Richard B.,
Partilla John S.,
Baumann Michael H.,
Dersch Christina M.,
Carroll F. Ivy,
Rice Kenner C.
Publication year - 2000
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/(sici)1098-2396(20000301)35:3<222::aid-syn7>3.0.co;2-k
Subject(s) - meth , methamphetamine , chemistry , dopaminergic , pharmacology , serotonergic , mdma , neurochemical , monoamine neurotransmitter , dopamine , amphetamine , dopamine transporter , transporter , serotonin , biochemistry , neuroscience , receptor , biology , monomer , organic chemistry , acrylate , gene , polymer
The abuse of methamphetamine (METH) and other amphetamine‐like stimulants is a growing problem in the United States. METH is a substrate for the 12‐transmembrane proteins which function as transporters for the biogenic amines dopamine (DA), serotonin (5‐HT), and norepinephrine (NE). Increased release of CNS DA is thought to mediate the addictive effects of METH, whereas increased release of NE in both the peripheral and CNS is thought to mediate its cardiovascular effects. The neurotoxic effects of METH on both dopaminergic and serotonergic nerves requires the transport of METH into the nerve terminals. Thus, transport of METH into nerve terminals is the crucial first step in the production of METH‐associated pharmacological and toxicological effects. A single molecular entity which would block the transport of METH at all three biogenic amine transporters might function to neurochemically neutralize METH. This agent would ideally be a high‐affinity slowly dissociating agent at all three transporters, and also be amenable to formulation as a long‐acting depot medication, such as has been accomplished with an analog of GBR12909. As a first step towards developing such an agent, we established an in vitro assay which selectively detects transporter substrates and used this assay to profile the ability of a lead compound, indatraline, to block the releasing effects of METH and MDMA at the DA, 5‐HT, and NE transporters. The major finding reported here is that indatraline blocks the ability of METH and MDMA to release these neurotransmitters. Synapse 35:222–227, 2000. Published 2000 Wiley‐Liss, Inc.