Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity

Autor: Tamara J. Phillips, Nicholas B. Miner, Josh S. Elmore, Michael H. Baumann, Aaron Janowsky
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
medicine.medical_specialty
Time Factors
Tyrosine 3-Monooxygenase
Toxicology
Neuroprotection
Article
Methamphetamine
Receptors
G-Protein-Coupled
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
Glial Fibrillary Acidic Protein
medicine
Animals
Biogenic Monoamines
Mice
Knockout
Glial fibrillary acidic protein
biology
Tyrosine hydroxylase
Chemistry
General Neuroscience
Dopaminergic
Homovanillic acid
Neurotoxicity
Brain
Homovanillic Acid
Hypothermia
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Endocrinology
Gene Expression Regulation
biology.protein
3
4-Dihydroxyphenylacetic Acid
Central Nervous System Stimulants
Female
Neurotoxicity Syndromes
medicine.symptom
030217 neurology & neurosurgery
Body Temperature Regulation
medicine.drug
Zdroj: NeuroToxicology. 63:57-69
ISSN: 0161-813X
DOI: 10.1016/j.neuro.2017.09.006
Popis: Trace amine-associated receptor 1 (TAAR1) is activated by methamphetamine (MA) and modulates dopaminergic (DA) function. Although DA dysregulation is the hallmark of MA-induced neurotoxicity leading to behavioral and cognitive deficits, the intermediary role of TAAR1 has yet to be characterized. To investigate TAAR1 regulation of MA-induced neurotoxicity, Taar1 transgenic knock-out (KO) and wildtype (WT) mice were administered saline or a neurotoxic regimen of 4 i.p. injections, 2 hr apart, of MA (2.5, 5, or 10 mg/kg). Temperature data were recorded during the treatment day. Additionally, striatal tissue was collected 2 or 7 days following MA administration for analysis of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. MA elicited an acute hypothermic drop in body temperature in Taar1-WT mice, but not in Taar1-KO mice. Two days following treatment, DA and TH levels were lower in Taar1-KO mice compared to Taar1-WT mice, regardless of treatment, and were dose-dependently decreased by MA. GFAP expression was significantly increased by all doses of MA at both time points and greater in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5 mg/kg. Seven days later, DA levels were decreased in a similar pattern: DA was significantly lower in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5 mg/kg. TH levels were uniformly decreased by MA, regardless of genotype. These results indicate that activation of TAAR1 potentiates MA-induced hypothermia and TAAR1 confers sustained neuroprotection dependent on its thermoregulatory effects.
Databáze: OpenAIRE
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