Cocaine differentially affects synaptic activity in memory and midbrain areas of female and male rats: an in vivo MEMRI study
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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.
KeywordsAddiction 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.
Does not apply.
The authors have no commercial, financial, or other conflict of interests that influenced the present work.
- Aoki, I., Tanaka, C., Takegami, T., Ebisu, T., Umeda, M., Fukunaga, M., Fukuda, K., Silva, A. C., Koretsky, A. P., & Naruse, S. (2002). Dynamic activity-induced manganese-dependent contrast magnetic resonance imaging (DAIM MRI). Magnetic Resonance in Medicine, 48, 927–933.CrossRefPubMedGoogle Scholar
- Chiu, C. H., Siow, T. Y., Weng, S. J., Hsu, Y. H., Huang, Y. S., Chang, K. W., Cheng, C. Y., & Ma, K. H. (2015). Effect of MDMA-induced Axotomy on the dorsal raphe forebrain tract in rats: an in vivo manganese-enhanced magnetic resonance imaging study. PloS One, 10, e0138431.CrossRefPubMedPubMedCentralGoogle Scholar
- Dong, Y., Saal, D., Thomas, M., Faust, R., Bonci, A., Robinson, T., & Malenka, R. C. (2004). Cocaine-induced potentiation of synaptic strength in dopamine neurons: behavioral correlates in GluRA(−/−) mice. Proceedings of the National Academy of Sciences of the United States of America, 101, 14282–14287.CrossRefPubMedPubMedCentralGoogle Scholar
- Kamii, H., Kurosawa, R., Taoka, N., Shinohara, F., Minami, M., & Kaneda, K. (2015). Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior. The European Journal of Neuroscience, 41, 1126–1138.CrossRefPubMedGoogle Scholar
- Kaufman, M. J., Levin, J. M., Maas, L. C., Kukes, T. J., Villafuerte, R. A., Dostal, K., Lukas, S. E., Mendelson, J. H., Cohen, B. M., & Renshaw, P. F. (2001). Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle phase. Biological Psychiatry, 49, 774–781.CrossRefPubMedGoogle Scholar
- Kimura, T., Yamashita, S., Fukuda, T., Park, J. M., Murayama, M., Mizoroki, T., Yoshiike, Y., Sahara, N., & Takashima, A. (2007). Hyperphosphorylated tau in parahippocampal cortex impairs place learning in aged mice expressing wild-type human tau. The EMBO Journal, 26, 5143–5152.CrossRefPubMedPubMedCentralGoogle Scholar
- Lu, H., Xi, Z. X., Gitajn, L., Rea, W., Yang, Y., & Stein, E. A. (2007). Cocaine-induced brain activation detected by dynamic manganese-enhanced magnetic resonance imaging (MEMRI). Proceedings of the National Academy of Sciences of the United States of America, 104, 2489–2494.CrossRefPubMedPubMedCentralGoogle Scholar
- Lu, H., Zou, Q., Chefer, S., Ross, T. J., Vaupel, D. B., Guillem, K., Rea, W. P., Yang, Y., Peoples, L. L., & Stein, E. A. (2014). Abstinence from cocaine and sucrose self-administration reveals altered mesocorticolimbic circuit connectivity by resting state MRI. Brain Connectivity, 4, 499–510.CrossRefPubMedPubMedCentralGoogle Scholar
- Perez, P. D., Hall, G., Kimura, T., Ren, Y., Bailey, R. M., Lewis, J., Febo, M., & Sahara, N. (2013). In vivo functional brain mapping in a conditional mouse model of human tauopathy (tauP301L) reveals reduced neural activity in memory formation structures. Molecular Neurodegeneration, 8, 9.CrossRefPubMedPubMedCentralGoogle Scholar
- Perrine, S. A., Ghoddoussi, F., Desai, K., Kohler, R. J., Eapen, A. T., Lisieski, M. J., Angoa-Perez, M., Kuhn, D. M., Bosse, K. E., Conti, A. C., Bissig, D., & Berkowitz, B. A. (2015). Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI. NMR in Biomedicine, 28, 1480–1488.CrossRefPubMedPubMedCentralGoogle Scholar
- SAMHSA (2014). Substance Use and Mental Health Estimates from the 2013 National Survey on Drug Use and Health: Overview of Findings. In Substance Abuse and Mental Health Services Administration (pp. 1–8).Google Scholar
- Saunders, N. R., Dreifuss, J. J., Dziegielewska, K. M., Johansson, P. A., Habgood, M. D., Mollgard, K., et al. (2014). The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Frontiers in Neuroscience, 8, 404. doi: 10.3389/fnins.2014.00404.
- Sinha, R., Fox, H., Hong, K. I., Sofuoglu, M., Morgan, P. T., & Bergquist, K. T. (2007). Sex steroid hormones, stress response, and drug craving in cocaine-dependent women: implications for relapse susceptibility. Experimental and Clinical Psychopharmacology, 15, 445–452.CrossRefPubMedGoogle Scholar
- Zhao-Shea, R., DeGroot, S. R., Liu, L., Vallaster, M., Pang, X., Su, Q., Gao, G., Rando, O. J., Martin, G. E., George, O., Gardner, P. D., & Tapper, A. R. (2015). Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal. Nature Communications, 6, 6770.CrossRefPubMedPubMedCentralGoogle Scholar