Neurotoxic effects of substituted amphetamines in rats and mice.
O'Callaghan JP; Miller DB
Handbook of Neurotoxicology. Massaro EJ, ed., Totowa, NJ: Humana Press, Chapter 11, 2001 Dec; 2:269-301
Whether you read about it in the popular press or in the scientific literature, there is no lack of coverage of the issue of amphetamine-induced neurotoxicity. Included among these articles are reports on the adverse effects in both animals and humans of methamphetamine (1-3) and methylenedioxymethamphetamine (MDMA; "Ecstasy") (4-7). Until it was withdrawn from the market for the potential to affect heart valvular function, the anorectic agent dexfenfluramine drew attention in the experimental and clinical literature for reported neurotoxic effects, even at the prescribed anorectic dosage (8). Lastly and most recently, attention has been focused on the fact that a large percentage of school-age children are maintained on stimulants, including amphetamines, for the treatment of attention deficit/hyperactivity disorder (ADHD) (9). The potential for neurotoxic effects assocated with such long-term human exposures is just now being raised (10). Clearly, the term "neurotoxicity" has been very broadly applied to describe the effects of these drugs in both humans and experimental animals. Unfortunately, emphases has been placed on documenting effects of these agents without distinguiding how and why these effects should be considered "neurotoxic." Thus, there are many descriptions of drug-induced neurotoxicity but there are very few attempts to link these purported neurotoxic effects to pathological actions on the nervous system or to functional changes meaningful to the human condition. Here, we will briefly review the current status of our understanding of the neurotoxic effects of substituted amphetamines. Empasis will be placed on defining the neurotoxic condition beyond effects attributable to the neuropharmacological actions of a specific compound. In so doing, we will challenge current dogma with regard to describing neurotoxic effects of this class of drugs. A detailed and comprehensive review of methamphetamine and amphetamine neurotoxicity recently has appeared (2) and it should be considered the authoritative source on this topic, especially with reference to effects in rats and the modulating role of body temperature. We will cover some of the issues raised by Bowyer and Holson (2), and agree with all of their points, but we will discuss effects of amphetamines in the context of the toxic actions of many known and potential chemical neurotixicants.
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