Multiple high-dose administrations of methamphetamine (METH) both rapidly (within hours) decrease plasmalemmal dopamine (DA) uptake and cause long-term deficits in DA transporter (DAT) levels and other dopaminergic parameters persisting weeks to months in rat striatum. In contrast, either a single administration of METH or multiple administrations of methylenedioxymethamphetamine (MDMA) cause less of an acute reduction in DA uptake and little or no persistent dopaminergic deficits. The long-term dopaminergic deficits caused by METH have been suggested, in part, to involve the DAT. Hence, this study assessed the impact of METH and MDMA administration on the DAT protein per se. Results revealed that multiple administrations of METH promoted formation of higher molecular weight (Ͼ170 kDa) DAT-associated protein complexes 24 -48 hr after treatment. This increase was attenuated by either preventing hyperthermia or pretreatment with the tyrosine hydroxylase inhibitor ␣-methyl-p-tyrosine; notably, each of these manipulations has also been demonstrated previously to prevent the persistent deficits in dopaminergic function caused by METH treatment. In contrast, either a single injection of METH or multiple injections of MDMA caused little or no formation of these DAT complexes. The addition of the reducing agent ␤-mercaptoethanol to samples prepared from METH-treated rats diminished the intensity of these complexes. Taken together, these data are the first to demonstrate higher molecular weight DAT complex formation in vivo and that such formation can be altered by both pharmacological and physiological manipulations. The implications of this phenomenon with regard to the neurotoxic potential of these stimulants are discussed.

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Repeated high-dose injections of methamphetamine (METH) rapidly decrease dopamine uptake by the vesicular monoamine transporter-2 (VMAT-2) associated with dopaminergic nerve terminals, as assessed in nonmembrane-associated vesicles purified from striata of treated rats. The purpose of this study was to determine whether METH similarly affects vesicular uptake in the hippocampus; a region innervated by both serotonergic and noradrenergic neurons and profoundly affected by METH treatment. Results revealed that repeated high-dose METH administrations rapidly (within 1 h) reduced hippocampal vesicular dopamine uptake, as assessed in vesicles purified from treated rats. This reduction was likely associated with serotonergic nerve terminals because METH did not further reduce vesicular monoamine uptake in para-chloroamphetamine-lesioned animals. Pretreatment with the serotonin transporter inhibitor fluoxetine blocked both this acute effect on VMAT-2 and the decrease in serotonin content observed 7 days after METH treatment. In contrast, there was no conclusive evidence that METH affected vesicular dopamine uptake in noradrenergic neurons or caused persistent noradrenergic deficits. These findings suggest a link between METH-induced alterations in serotonergic hippocampal vesicular uptake and the persistent hippocampal serotonergic deficits induced by the stimulant.

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This article provides the position of the American Council on Science and Health regarding how breast cancer is defined and classified; the magnitude of the public health problem of breast cancer among women; the implications of variation in incidence of breast cancer internationally and with migration; access to health care as a factor in slight differences in incidence and mortality rates among African‐American and white women; and the evidence concerning various proposed human‐breast‐cancer risk factors. The article classifies risk factors as either established, speculated, or unsupported on the basis of available evidence. Specific genes have been identified that may explain as much as 5–10% of new breast cancer cases. Inherited predispositions may be characterized by family history of breast or ovarian cancer, young age at diagnosis, breast cancer diagnosed in both breasts, and male breast cancer. Benign breast disease (BBD), particularly the subtypes of BBD involving atypical hyperplasia, and exposure early in life to ionizing radiation is an established risk factor for breast cancer. Several reproductive characteristics are established as risk factors for breast cancer: early age at menarche, first full‐term pregnancy after age 35 years of late age, and late age of menopause. Obesity and low physical activity are established as risk factors for breast cancer and are modifiable. Speculated risk factors for breast cancer that are gaining scientific support include nulliparity, oral contraceptive use, and postmenopausal estrogen replacement therapy. Speculated risk factors for which there is conflicting or preliminary support include not breast feeding, postmenopausal estrogen/progestogen replacement therapy, prescribed diethylstilbestrol, low consumption of phytoestrogens, specific dietary practices, alcohol consumption, not using nonsteroidal antinflammatory drugs, abortion, and breast augmentation. Unsupported risk factors include higher than average consumption of phytoestrogens, premenopausal obesity, electromagnetic fields, and low‐dose ionizing radiation after 40 years of age. There is only limited support for xenoestrogens and large breast size as risk factors for breast cancer.