Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 24, Pages 9981-9986Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1107592108
Keywords
basal ganglia; drug addiction; Eph-ephrin signaling; gene regulation; transmission blocking
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [KAKENHI 22220005, 22659069, 23110522]
- Ministry of Health and Labour and Welfare
- Japan Science and Technology Agency
- Takeda Science Foundation
- Daiichi-Sankyo Foundation of Life Science
- Grants-in-Aid for Scientific Research [22659069, 22220005, 23680034] Funding Source: KAKEN
Ask authors/readers for more resources
The nucleus accumbens (NAc) serves as a key neural substrate that controls acute and adaptive behavioral responses to cocaine administration. In this circuit, inputs from the NAc are transmitted through two parallel pathways, named the direct and indirect pathways, and converge at the substantia nigra pars reticulata (SNr). Our previous study using reversible neurotransmission blocking (RNB) of each pathway revealed that the dual stimulation of the SNr by both pathways is necessary for the acute response, but that the direct pathway predominantly controls the adaptive response to repeated cocaine administration. This study aimed at exploring the pathway-specific mechanism of cocaine actions at the convergent SNr. We examined a genome-wide expression profile of the SNr of three types of experimental mice: the direct pathway-blocked D-RNB mice, the indirect pathway-blocked I-RNB mice, and wild-type mice. We identified the up-regulation of ephrinA5, EphA4, and EphA5 specific to D-RNB mice during both acute and adaptive responses to cocaine administration. The activation by EphA4 and EphA5 in the SNr of wild-type mice by use of the immunoadhesin technique suppressed the adaptive response to repeated cocaine administration. Furthermore, cocaine exposure stimulated the phosphorylation of Erk1/2 in ephrinA5-expressing SNr cells in a direct pathway-dependent manner. The results have demonstrated that the ephrinA5-EphA4/EphA5 system plays an important role in the direct pathway-dependent regulation of the SNr in both acute and adaptive cocaine responses and would provide valuable therapeutic targets of cocaine addiction.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available