Abstract
Methamphetamine (METH) is an addictive and neurotoxic psychostimulant widely abused in the USA and throughout the world. When administered in large doses, METH can cause depletion of striatal dopamine terminals, with preservation of midbrain dopaminergic neurons. Because alterations in the expression of transcription factors that regulate the development of dopaminergic neurons might be involved in protecting these neurons after toxic insults, we tested the possibility that their expression might be affected by toxic doses of METH in the adult brain. Male Sprague-Dawley rats pretreated with saline or increasing doses of METH were challenged with toxic doses of the drug and euthanized two weeks later. Animals that received toxic METH challenges showed decreases in dopamine levels and reductions in tyrosine hydroxylase protein concentration in the striatum. METH pretreatment protected against loss of striatal dopamine and tyrosine hydroxylase. In contrast, METH challenges caused decreases in dopamine transporters in both saline- and METH-pretreated animals. Interestingly, METH challenges elicited increases in dopamine transporter mRNA levels in the midbrain in the presence but not in the absence of METH pretreatment. Moreover, toxic METH doses caused decreases in the expression of the dopamine developmental factors, Shh, Lmx1b, and Nurr1, but not in the levels of Otx2 and Pitx3, in saline-pretreated rats. METH pretreatment followed by METH challenges also decreased Nurr1 but increased Otx2 and Pitx3 expression in the midbrain. These findings suggest that, in adult animals, toxic doses of METH can differentially influence the expression of transcription factors involved in the developmental regulation of dopamine neurons. The combined increases in Otx2 and Pitx3 expression after METH preconditioning might represent, in part, some of the mechanisms that served to protect against METH-induced striatal dopamine depletion observed after METH preconditioning.
Highlights
Methamphetamine (METH) is a psychostimulant that is abused throughout the world
The lack of further reductions after the second METH challenge is probably related to the fact that decreases in dopamine transporters (DAT) binding are measurable within 24 hours after injections of toxic doses of METH [8] and to the findings that DAT is an important determinant of METH toxicity [53]
This pattern of METH pretreatment allowed only partial protection against reductions in striatal DAT protein levels even though Dat mRNA expression was robustly increased in the midbrain
Summary
Methamphetamine (METH) is a psychostimulant that is abused throughout the world. Acute administration of the drug causes behavioral changes that are secondary to activation of dopaminergic systems located in various brain regions [1]. Of significant concern are the findings from imaging and postmortem studies describing decreases in the density of striatal dopamine transporters (DAT), reductions in tyrosine hydroxylase (TH) levels as well as decreases in the concentrations of dopamine (DA) in the brains of chronic METH abusers [5,6]. These abnormalities might reflect damage to DA neurons and the possibility that dysfunctional DA neurons could lead to the appearance of neurological syndromes over time [7,8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
