Methamphetamine (METH) abuse has reached alarming proportions, leading numerous federal agencies including NIDA, ONDCP, and the DEA to liken it to an epidemic. The medical, legal, and societal problems associated with any drug of abuse are compounded in the case of METH because it causes persistent damage to the dopamine (DA) neuronal system. Nowhere is this more evident than in individuals with AIDS, who show heightened neurotoxicity when they also abuse METH. The only cells in brain that are productively infected with HIV are microglia. The long-term objective of this proposal is to achieve a better understanding of the mechanisms by which METH exerts neurotoxicity. We hypothesize that METH intoxication leads to microglial activation. The ensuing cross-talk between distressed DA nerve endings and activated microglia, which secrete numerous species capable of damaging neurons, creates and perpetuates a vicious cycle that culminates in DA neurotoxicity. We propose 5 specific aims to test our hypotheses: 1) determine the pharmacological characteristics of methamphetamine-induced activation of microglia; 2) determine the role of COX-2, PGE2, and DA quinones in METH toxicity; 3) determine the influence of microglial status (activated by the neurotoxic HIV TAT protein or inhibited by non-competitive NMDA antagonists) on METH toxicity; 4) determine if nicotine and ?9 -tetrahydrocannabinol (THC) protect against METH toxicity through interaction with their cognate receptors on microglia; and 5) determine how microglial activation influences DAT function by culturing mammalian cells stably expressing the DA transporter with media from activated microglia. The experimental approach to these studies will combine neurochemistry, neuropharmacology, laser scanning microscopy, use of knock-out mice, and parallel studies with cultured mouse microglia cells to evaluate microglial involvement in METH toxicity. A better understanding of the mechanisms by which METH causes persistent damage to the DA neuronal system could lead to more targeted therapies and would open newer lines of investigation into this and other neurotoxic drugs of abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017327-03
Application #
7198113
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Frankenheim, Jerry
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$301,181
Indirect Cost
Name
Wayne State University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I et al. (2012) Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity. J Neurochem 121:974-84
Kane, Michael J; Angoa-Perez, Mariana; Francescutti, Dina M et al. (2012) Altered gene expression in cultured microglia in response to simulated blast overpressure: possible role of pulse duration. Neurosci Lett 522:47-51
Angoa-Pérez, Mariana; Kane, Michael J; Francescutti, Dina M et al. (2012) Mephedrone, an abused psychoactive component of 'bath salts' and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum. J Neurochem 120:1097-107
Kane, Michael J; Angoa-Pérez, Mariana; Briggs, Denise I et al. (2012) A mouse model of human repetitive mild traumatic brain injury. J Neurosci Methods 203:41-9
Kuhn, Donald M; Angoa-Pérez, Mariana; Thomas, David M (2011) Nucleus accumbens invulnerability to methamphetamine neurotoxicity. ILAR J 52:352-65
Kuhn, Donald M; Sykes, Catherine E; Geddes, Timothy J et al. (2011) Tryptophan hydroxylase 2 aggregates through disulfide cross-linking upon oxidation: possible link to serotonin deficits and non-motor symptoms in Parkinson's disease. J Neurochem 116:426-37
Thomas, David M; Angoa Perez, Mariana; Francescutti-Verbeem, Dina M et al. (2010) The role of endogenous serotonin in methamphetamine-induced neurotoxicity to dopamine nerve endings of the striatum. J Neurochem 115:595-605
Angoa-Perez, Mariana; Kreipke, Christian W; Thomas, David M et al. (2010) Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage. Neurotoxicology 31:738-46
Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M (2009) Increases in cytoplasmic dopamine compromise the normal resistance of the nucleus accumbens to methamphetamine neurotoxicity. J Neurochem 109:1745-55
Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M (2008) Methamphetamine-induced neurotoxicity and microglial activation are not mediated by fractalkine receptor signaling. J Neurochem 106:696-705

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