Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: A pharmacological strategyfor treating stimulant abuse

The abuse of methamphetamine (METH) and other amphetamine-like stimulants i s a growing problem in the United States. METH is a substrate for the 12-tr ansmembrane proteins which function as transporters for the biogenic amines dopamine (DA), serotonin (5-HT), and norepinephrine (NE). Increased releas e of CNS DA is thought to mediate the addictive effects of METH, whereas in creased release of NE in both the peripheral and CNS is thought to mediate its cardiovascular effects. The neurotoxic effects of METH on both dopamine rgic and serotonergic nerves requires the transport of METH into the nerve terminals. Thus, transport of METH into nerve terminals is the crucial firs t step in the production of METH-associated pharmacological and toxicologic al effects. A single molecular entity which would block the transport of ME TH at all three biogenic amine transporters might function to neurochemical ly neutralize METH. This agent would ideally be a high-affinity slowly diss ociating agent at all three transporters, and also be amenable to formulati on 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 e stablished an in vitro assay which selectively detects transporter substrat es and used this assay to profile the ability of a lead compound, indatrali ne, 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 t he ability of METH and MDMA to release these neurotransmitters. (C) Publish ed 2000 Wiley-Liss, Inc.