Although psychostimulant abuse carries with it several potential health risks, the chronic use of amphetamines carries the danger of permanent brain injury. In animals, repeated administration of methamphetamine during the course of a single day produce long-lasting damage to striatal dopamine and forebrain serotonin terminals. In addition, this drug produces a degeneration of pyramidal and stellate cells in the somatosensory cortex in rats. These animal findings fit with a growing body of post-mortem neurochemical, in vivo imaging, and neuropsychological test data indicating that methamphetamine injures both monoamine terminals and cortical neurons in human abusers. The mechanisms underlying cortical cell injury are of special interest because little is known about this form of neurotoxicity. A significant advance in the ability to study this cortical cell degeneration is the use of a fluorochrome dye, Fluoro-Jade, that specifically marks dying cells. In rats, the cell loss is restricted to somatosensory cortical neurons, which may relate to the observation that somesthetic paresthesias are a hallmark of human amphetamine drug self-administration. Recent research indicates that this cortical injury results from an abnormal, sustained activation of excitatory somatosensory afferents arising as a consequence of the rats' drug-induced stereotyped whisking movements, accompanied by hyperthermia. This conclusion is supported by showing that the degeneration is seen only in the vibrissae barrels of somatosensory cortex, and is reduced in animals undergoing vibrissae clipping.
Three specific aims are proposed, including: (i) studying the roles of cortical glutamate receptors in this cell loss, (ii) determining whether the basal ganglia pathways gating cortical responsiveness to sensory inputs contribute to this degeneration, and (iii) examining a role for brain norepinephrine and serotonin systems and receptors in the cortical cell death. In addition, these studies will examine the relationship between the cortical cell injury and the damage to striatal dopaminergic processes, thereby providing a test of the hypothesis that the cortical cell excitation/degeneration contributes to the striatal dopamine terminal injury.
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