Date of Degree
Jesus A. Angulo
Biochemistry | Neuroscience and Neurobiology
apoptosis, DARPP32, hyperthermia, Methamphetamine, Neurodegeneration, Neurotensin receptor 1
Methamphetamine (METH) is a widely abused psychostimulant that induces neurotoxicity to several brain regions, including the striatum. Similar to dopamine (DA) in chemical structure, METH can be transported into DA pre-synaptic terminals, evoking the neurodegeneration in DA terminals and post-synaptic striatal neurons. Despite the critical role of DA in METH-induced neurodegeneration, no pharmaceutical therapeutics has been approved for these conditions. It is therefore essential to investigate the endogenous factors regulating the dopaminergic system. The neuropeptide neurotensin has emerged as a potential modulator of METH-induced striatal neurodegeneration mainly due to its intimate interactions with dopamine in the striatum.
In this study, we investigated the role of the neuropeptide neurotensin on METH-induced striatal neurodegeneration in mice. We observed that a single injection of METH (30 mg/kg, ip) induced the loss of approximately 15% of striatal neurons. An agonist of the neurotensin receptor 1 (PD149163, ip) attenuated the METH-induced striatal neuron apoptosis in a dose-dependent manner, while exerted no effect on METH-induced dopamine terminal degeneration. Utilizing quantitative Real Time PCR, we showed that METH also up-regulated neurotensin gene expression by 96% in stratal neurotensin mRNA. These data demonstrate that neurotensin modulates METH-induced striatal apoptosis through neurotensin receptor 1 (NTR1) in the striatum. In addition, NTR1 agonist attenuated METH-induced hyperthermia and can also attenuated the striatal apoptosis independent of body temperature regulation. To further investigate the corresponding mechanisms, we assessed its effect on glial cell activation, nitric oxide accumulation and DARPP32 phosphorylation in the striatum, which are all believed to aggravate METH-induced neurodegeneration. We observed that the NTR1 agonist attenuated the effects of METH on each of these three bio-markers. Our results also show that the NTR1 agonist alone caused decrease in phosphorylation of DARPP32 at Thr34, while NTR1 antagonist (SR48692) per se increased the phosphorylation of DARPP32 at Thr34. Since the DARPP32 phosphorylation pathway is responsible for interpreting signals to striatal projection neurons, neurotensin possibly modulates DARPP32 phosphorylation through regulation of DA and glutamate neurotransmission. Finally, the agonist of neurotensin, PD149163, may be considered as a potential therapeutic for treatment of METH-induced neurotoxicity. (Supported by R01 DA020142 from NIH)
Liu, Qingkun, "The Role of the Striatal Neuropeptide Neurotensin in the Methamphetamine-induced Neural Injury in Mice" (2014). CUNY Academic Works.