Dissertations, Theses, and Capstone Projects

Date of Degree

5-2015

Document Type

Dissertation

Degree Name

Ph.D.

Program

Psychology

Advisor

Jesus A. Angulo

Subject Categories

Psychology

Keywords

Leptin; Methamphetamine; Neurodegeneration; NMDA; Striatum; Toxicity

Abstract

Methamphetamine (METH) is an addictive illicit psychostimulant that is neurotoxic and causes permanent brain injury. METH-induced neurological damage affects areas of the brain that mediates emotions, motivation, cognition and critical thinking. In the striatum METH neurotoxicity intertwines several factors such as dopamine (DA) overflow, glutamate signaling, and free radicals formation causing oxidative stress. In addition, excessive dopaminergic innervation leads to severe reduction in DA terminals, DA transporters (DAT), and vesicular monoamine transporters (VMAT)-2. METH use causes permanent damage which cannot be recovered even after three years of abstinence. Understanding the mechanism of METH-induced neurodegeneration will provide an avenue towards identifying effective therapeutic targets for treatments of METH abuse. Leptin is an important peripheral hormone produced mainly by adipose tissue in proportion to fat stores, which circulates in the plasma, and found ubiquitously in the central nervous system (CNS). Though leptin is primarily known for its regulation of energy homeostasis mediated by its receptors, ObRb, it was shown to serve other functions as ObRbs are expressed in hypothalamic and extra hypothalamic areas, specifically in the ventral tegmental area (VTA), substantia nigra (SN), and nucleus accumbens (NAc), striatum, cortex, cerebellum and hippocampus. The precise molecular pathway underlying the direct effects of leptin in these regions is mostly unknown. But studies report that leptin administration decreased the firing rate of DA neurons in the VTA. The exact cellular mechanism for this reduced excitability by leptin remains to be determined. We show evidence that leptin signaling is neuroprotective in striatal neurons upon METH-induced injury. We hypothesized leptin would attenuate METH-induced striatal neural injury. Our data suggests that leptin produced a dose dependent attenuation of apoptosis upon METH administration. METH caused about 25% of the striatal neurons to undergo apoptosis. However, leptin treatment attenuated apoptosis by 18% suggesting that it protects striatal neurons from METH toxicity. Leptin did not prevent METH-induced hyperthermia or weight loss, one reason may be that it is an anorexigenic peptide and causes animals to increase activity and energy expenditure. In support of our hypothesis leptin treatment attenuated the over activation of the astrocytes and microglia caused by METH toxicity. It also dampened oxidative stress. Furthermore, we demonstrated here that leptin mediates striatal neuroprotection by modulating glutamate transmission. N-Methyl-D-aspartate (NMDA) -mediated apoptosis was attenuated by leptin treatment. It also reduced the NMDA-induced formation of nitric oxide (NO). However, leptin failed reduce NMDA-induced striatal over activation of astrocytes and microglia. A plethora of evidence demonstrates that METH induces neural damage in the striatum and other parts of the brain. Our contribution to this area of research is the finding that peripheral hormone, leptin, can protect degeneration caused by METH in the striatum.

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