Brain Imaging and Behavior

, Volume 12, Issue 1, pp 201–216 | Cite as

Cocaine differentially affects synaptic activity in memory and midbrain areas of female and male rats: an in vivo MEMRI study

  • Pablo D. Perez
  • Gabrielle Hall
  • Jasenka Zubcevic
  • Marcelo Febo
Original Research


Manganese enhanced magnetic resonance imaging (MEMRI) has been previously used to determine the effect of acute cocaine on calcium-dependent synaptic activity in male rats. However, there have been no MEMRI studies examining sex differences in the functional neural circuits affected by repeated cocaine. In the present study, we used MEMRI to investigate the effects of repeated cocaine on brain activation in female and male rats. Adult female and male rats were scanned at 4.7 Tesla three days after final treatment with saline, a single cocaine injection (15 mg kg−1, i.p. × 1 day) or repeated cocaine injections (15 mg kg−1, i.p. × 10 days). A day before imaging rats were provided with an i.p. injection of manganese chloride (70 mg kg−1). Cocaine produced effects on MEMRI activity that were dependent on sex. In females, we observed that a single cocaine injection reduced MEMRI activity in hippocampal CA3, ventral tegmental area (VTA), and median Raphé, whereas repeated cocaine increased MEMRI activity in dentate gyrus and interpeduncular nucleus. In males, repeated cocaine reduced MEMRI activity in VTA. Overall, it appeared that female rats showed a general trend towards increase MEMRI activity with single cocaine and reduced activity with repeated exposure, while male rats showed a trend towards opposite effects. Our results provide evidence for sex differences in the in vivo neural response to cocaine, which involves primarily hippocampal, amygdala and midbrain areas.


Addiction Cocaine Manganese MEMRI Sex differences Synaptic activity 



This work was supported by NIH grant DA038009, DA019946 and the University of Florida McKnight Brain Foundation. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies. Authors acknowledge the support from the National High Magnetic Field Laboratory’s Advanced Magnetic Resonance Imaging & Spectroscopy (AMRIS) Facility (National Science Foundation Cooperative Agreement No. DMR-1157490 and the State of Florida). PDP is currently in the Department of Biomedical Engineering at Penn State University.

Compliance with ethical standards


This study was funded by NIH grants DA019946 and DA038009 to Dr. Marcelo Febo.

Conflict of interest

There are no conflict of interests.

Ethical approval of the use of animals in research

The University of Florida Institutional Animal Care and Use Committee approved the experimental protocols. All procedures adhered to the Guide for the Care and Use of Laboratory Animals (8th Edition, 2011), National Institutes of Health and the American Association for Laboratory Animal Science.

Ethical approval for human subjects

Does not apply.

Informed consent

Does not apply.


The authors have no commercial, financial, or other conflict of interests that influenced the present work.

Supplementary material

11682_2017_9691_Fig8_ESM.gif (2.2 mb)
Online Supporting Figure 1

The panel of figures on top show individual MEMRI scans of female and male rats. Images were first processed (see Materials and Methods) and are presented here in color. Color pixel values are all set at a lower threshold of −3 and upper threshold of +3. Empty squares highlight the dorsal hippocampal area. Bottom panel shows raw brain multislice multiecho scans at the level of the midbrain with the pituitary gland indicated by blue arrows. (GIF 2263 kb)

11682_2017_9691_MOESM1_ESM.tif (3.8 mb)
High Resolution Image (TIFF 3849 kb)
11682_2017_9691_Fig9_ESM.gif (43 kb)
Online Supporting Figure 2

Areas of the brain showing greater MEMRI activity female versus male rats. Data presented as Tukey box and whisker plots (median, 25-75th percentile and 1.5 interquartile range). *Significant difference between male and female. (GIF 42 kb)

11682_2017_9691_MOESM2_ESM.tiff (291 kb)
High Resolution Image (TIFF 291 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Pablo D. Perez
    • 1
  • Gabrielle Hall
    • 1
  • Jasenka Zubcevic
    • 2
  • Marcelo Febo
    • 1
    • 3
  1. 1.Department of Psychiatry, McKnight Brain Institute, College of MedicineUniversity of FloridaGainesvilleUSA
  2. 2.Department of Physiological Sciences, College of MedicineUniversity of FloridaGainesvilleUSA
  3. 3.Center for Addiction Research and Education (CARE)University of FloridaGainesvilleUSA

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