Abstract

Methamphetamine (METH) use is increasing in the United States. Striatal deficits in humans induced by METH persist after detoxification and protracted abstinence and have been associated with impairment of motor tasks and learning. Our lab discovered that pharmacological .blockade of the striatal neurokinin-1 receptor (NK-1R) confers protection from METH to both dopamine (DA) terminals and striatal neurons. This interesting and novel finding needs further investigation because it provides a therapeutic target for the treatment 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 latter neurons, nNOS is up-regulated and excessive NO produced. We suggest that the excessive NO is what is causing the loss of DA-terminals and neuronal cell death in the striatum. This hypothesis will be tested by the following specific aims:
Aim 1 : The purpose of this aim is to test the hypothesis that SP induces striatal injury in the presence of METH. To this end, the selective SP agonist GR73632 will be utilized to exacerbate METH-induced striatal neural damage.
Aim 2 : The purpose of this aim is to test the hypothesis that the striatal NK-1 Rs signal neural damage in the presence of METH. To this end, the striatal NK-1R-expressing cells will be destroyed with the selective toxin SSP-saporin.
Aim 3 : The purpose of this aim is to test the hypothesis that SP modulates striatal NO production. To this end, neurochemical and histological methods will be utilized to establish a connection between the striatal NK-1Rs 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 injury induced by METH. This information may prove valuable for the treatment of METH abuse and may also describe a new role for this receptor in the striatum.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA020142-05
Application #
7797580
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Frankenheim, Jerry
Project Start
2006-04-15
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$215,507
Indirect Cost

  Institution

Name
Hunter College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
620127915
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Liu, Qingkun; Hazan, Ariela; Grinman, Eddie et al. (2017) Pharmacological activation of the neurotensin receptor 1 abrogates the methamphetamine-induced striatal apoptosis in the mouse brain. Brain Res 1659:148-155
Tulloch, I K; Afanador, L; Baker, L et al. (2014) Methamphetamine induces low levels of neurogenesis in striatal neuron subpopulations and differential motor performance. Neurotox Res 26:115-29
Afanador, Lauriaselle; Mexhitaj, Ina; Diaz, Carolyn et al. (2013) The role of the neuropeptide somatostatin on methamphetamine and glutamate-induced neurotoxicity in the striatum of mice. Brain Res 1510:38-47
Yarosh, Haley L; Angulo, Jesus A (2012) Modulation of methamphetamine-induced nitric oxide production by neuropeptide Y in the murine striatum. Brain Res 1483:31-8
Afanador, Lauriaselle; Yarosh, Haley; Wang, Jing et al. (2012) Contrasting Effects of the Neuropeptides Substance P, Somatostatin, and Neuropeptide Y on the Methamphetamine-Induced Production of Striatal Nitric Oxide in Mice. J Drug Alcohol Res 1:
Tulloch, I K; Afanador, L; Zhu, J et al. (2011) Methamphetamine induces striatal cell death followed by the generation of new cells and a second round of cell death in mice. Curr Neuropharmacol 9:79-83
Tulloch, I; Afanador, L; Mexhitaj, I et al. (2011) A single high dose of methamphetamine induces apoptotic and necrotic striatal cell loss lasting up to 3 months in mice. Neuroscience 193:162-9
Wang, Jing; Angulo, Jesus A (2011) Synergism between methamphetamine and the neuropeptide substance P on the production of nitric oxide in the striatum of mice. Brain Res 1369:131-9
Tulloch, Ingrid; Ghazaryan, Nane; Mexhitaj, Ina et al. (2011) Role of neurokinin-1 and dopamine receptors on the striatal methamphetamine-induced proliferation of new cells in mice. Brain Res 1399:33-9
Wang, Jing; Angulo, Jesus A (2011) Methamphetamine induces striatal neurokinin-1 receptor endocytosis primarily in somatostatin/NPY/NOS interneurons and the role of dopamine receptors in mice. Synapse 65:300-8

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