Methamphetamine (METH) use is increasing in the United States. Striatal deficits in humans induced byMETH persist after detoxification and protracted abstinence and have been associated with impairment ofmotor tasks and learning. Our lab discovered that pharmacological blockade of the striatal neurokinin-1receptor (NK-1R) confers protection from METH to both dopamine (DA) terminals and striatal neurons. Thisinteresting and novel finding needs further investigation because it provides a therapeutic target for thetreatment of METH abuse. Our working hypothesis is that the excessive DA released in response to METH,interacts with substance P-containing striatal neurons. This in turn causes excessive release of substance P(SP), which then acts through NK-1Rs on cholinergic and somatostatin/NOS interneurons. In the latterneurons, nNOS is up-regulated and excessive NO produced. We suggest that the excessive NO is what iscausing the loss of DA-terminals and neuronal cell death in the striatum. This hypothesis will be tested by thefollowing specific aims:
Aim 1 : The purpose of this aim is to test the hypothesis that SP induces striatal injury in the presence ofMETH. To this end, the selective SP agonist GR73632 will be utilized to exacerbate METH-induced striatalneural damage.
Aim 2 : The purpose of this aim is to test the hypothesis that the striatal NK-1 Rs signal neural damage inthe presence of METH. To this end, the striatal NK-1 R-expressing cells will be destroyed with.the selectivetoxin SSP-saporin.
Aim 3 : The purpose of this aim is to test the hypothesis that SP modulates striatal NO production. To thisend, neurochemical and histological methods will be utilized to establish a connection between the striatalNK-1 Rs and the glutamate/NO neurotoxic cascade.The overall, long-term goal of these studies is to define the role of the NK-1Rs in the striatal injuryinduced by METH. The information gathered may prove valuable for the treatment of METH abuse and mayalso describe a role for this receptor in the striatum.
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