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Updated: Jul 20, 2026
A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Sex differences in methamphetamine-evoked striatal dopamine of mice are reversed by nomifensine
Vidhya Kunnathur1, Kamal Shemisa, Bin Liu
1Department of Anatomy, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272-0095, United States.
Abstract:
Male mice show more severe striatal dopamine depletions to the psychostimulant, methamphetamine (MA). To gain some understanding for this sex difference, we examined MA-evoked dopamine (DA) responses from superfused striatal tissue fragments of male and female mice under conditions of a dopamine transporter which was either unaltered (Experiment 1) or inhibited, with use of the drug, nomifensine (Experiment 2). In Experiment 1, MA-evoked DA was significantly greater in male versus female mice. In Experiment 2, diminished, albeit statistically significant, DA responses to MA infusion in the presence of nomifensine were obtained from striatal tissue of female, but not male, mice. In Experiment 3, potassium-evoked DA responses and sex differences were abolished in the presence of nomifensine. These data demonstrate a clear sex difference in DA responses to MA. Interestingly, under conditions where dopamine transporter function is inhibited, MA retains its ability to evoke DA. However, this capacity was only observed within striatal tissue fragments of female mice and not under conditions of potassium-evoked DA. These results indicate an additional component for the bases of sex differences in nigrostriatal dopaminergic function in health and in disease. In particular, the present findings have important implications in suggesting an alternative, non-traditional, mechanism for MA effects and indicate that such a function is limited to females.
Insights
Male mice exhibit greater methamphetamine-induced dopamine depletions. A novel mechanism for methamphetamine effects, particularly in females, was identified, independent of the dopamine transporter.
Area of Science:
- Neuroscience
- Pharmacology
- Neurochemistry
Background:
- Male mice display more severe striatal dopamine depletions following methamphetamine (MA) exposure.
- Understanding the neurobiological basis of sex differences in psychostimulant response is crucial for clinical implications.
- The role of the dopamine transporter (DAT) in mediating MA effects and sex disparities requires further investigation.
Purpose of the Study:
- To investigate sex differences in methamphetamine-evoked dopamine (DA) release in mouse striatal tissue.
- To explore the involvement of the dopamine transporter in MA-induced DA responses.
- To identify potential non-traditional mechanisms underlying MA's effects on dopaminergic function.
Main Methods:
- Superfused striatal tissue fragments from male and female mice were used.
- Experiment 1: Examined MA-evoked DA release with an unaltered dopamine transporter.
- Experiment 2 & 3: Investigated MA-evoked DA release under conditions of dopamine transporter inhibition using nomifensine, and compared with potassium-evoked DA release.
Main Results:
- Experiment 1 showed significantly greater MA-evoked DA release in male versus female mice.
- Experiment 2 revealed diminished, yet significant, MA-evoked DA responses in female striatal tissue with DAT inhibition, but not in males.
- Potassium-evoked DA release and sex differences were abolished by nomifensine, suggesting a DAT-independent MA effect in females.
Conclusions:
- A clear sex difference in dopamine responses to methamphetamine exists in mouse striatum.
- Methamphetamine retains the ability to evoke dopamine release even when the dopamine transporter is inhibited, particularly in females.
- This suggests an alternative, non-traditional mechanism for MA effects, primarily observed in female mice, contributing to sex differences in dopaminergic function.
