The experiments proposed represent a series of interwined specific aims that tachykinin peptides, namely substance P and neurokinin A, protect neostriatal dopamine terminals from methamphetamine-induced damage. Furthermore, the experiments proposed will determine if neuroprotection by tachykinin peptides is mediated through the neurokinin receptors. The first specific aim will unambiguously demonstrate the extend of methamphetamine-induced damage on selective neostriatal parameters. We will assess dopamine content by HPLC, dopamine transporter sites, dopamine terminal morphology by immunocytochemistry for tyrosine hydroxylase, astrocytic reaction by immunocytochemical staining of glial fibrillary acidic protein, terminal and nerve fiber degeneration by the Fink-Heimer silver stain, and post-synaptic neuropeptide mRNA expression by in situ hybridization histochemistry. This aim will also determine the optimal dose of methamphetamine to be used in aims II & III, because the manipulations in aims II & III will render the neostriatum methamphetamine to be use din aims II & III, because the manipulations in aims III & III will render the neostriatum more vulnerable to methamphetamine-induced by administering the highly selective non- peptide neurokinin 1 and 3 (NK1 & NK receptor) antagonist CP-99,994 and PD-161,182. We hypothesize that treatment with the neurokinin receptor antagonists will exacerbate methamphetamine-induced toxicity and damage in the neostriatum. Reciprocally, neurokinin receptor agonists will be infused into the neostriatum in order to protect the neurons from methamphetamine-induced toxicity and damage in the neostriatum. Reciprocally, receptor will be infused into the neostriatum in order to protect neurons from methamphetamine. The third specific aim will further characterize the protective role played by tachykinin peptides by exposing to methamphetamine a gene knockout mouse lacking the pre- pro-tachykinin-A gene, which encodes the neuropeptides substance P and neurokinin A. We hypothesize that the mutant mice will be much more vulnerable to the damaging effects of methamphetamine than the wildtype mice. These studies will provide strong mechanistic evidence in support of the observation that the tachykinin peptide substance P protects dopaminergic neurons from the damaging effects of excessive extracellular concentrations of dopamine. An understanding of mechanisms of neuroprotection in the central nervous will benefit humanity.