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Sex differences in behavioral and PKA cascade responses to repeated cocaine administration

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Abstract

Previous studies have shown sex different patterns in behavioral responses to cocaine. Here, we used between-subject experiment design to study whether sex differences exist in the development of behavioral sensitization and tolerance to repeated cocaine, as well as the role of protein kinase A (PKA) signaling cascade in this process. Ambulatory and rearing responses were recorded in male and female rats after 1 to 14 days of administration of saline or cocaine (15 mg/kg; ip). Correspondent PKA-associated signaling in the nucleus accumbens (NAc) and caudate-putamen (CPu) was measured at each time point. Our results showed that females exhibited higher cocaine-induced behavioral responses and developed behavioral sensitization and tolerance faster than males. Whereas females developed behavioral sensitization to cocaine after 2 days and tolerance after 14 days, male rats developed sensitization after 5 days. In addition, cocaine induced a sexual dimorphic pattern in the progression of neuronal adaptations on the PKA cascade signaling in region (NAc vs. CPu) and time (days of cocaine administration)-dependent manners. In general, more PKA signaling cascade changes were found in the NAc of males on day 5 and in the CPu of females with repeated cocaine injection. In addition, in females, behavioral activities positively correlated with FosB levels in the NAc and CPu and negatively correlated with Cdk5 and p35 in the CPu, while no correlation was observed in males. Our studies suggest that repeated cocaine administration induced different patterns of behavioral and molecular responses in the PKA cascade in male and female rats.

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Acknowledgments

We are grateful to Dr. Patricia Stephens for her editorial comments. This work was supported by SCORE 5506-GM60654, MIDARP DA12136, and MD007599RCMI RR-03037. We declare that all the experiments comply with the current laws of the USA.

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Author notes

  1. Luyi Zhou & Wei-Lun Sun

    Present address: Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA

Authors and Affiliations

  1. Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, 10065, USA

    Luyi Zhou

  2. Department of Biology PhD Program, Graduate School and University Center of the City University of New York, New York, NY, 10016, USA

    Luyi Zhou & Vanya Quinones-Jenab

  3. Department of Psychology, Hunter College of the City University of New York, New York, NY, 10065, USA

    Wei-Lun Sun, Karen Weierstall, Ana Christina Minerly, Jan Weiner, Shirzad Jenab & Vanya Quinones-Jenab

  4. Department of Biopsychology and Behavioral Neuroscience PhD Subprogram, Graduate School and University Center of the City University of New York, New York, NY, 10016, USA

    Wei-Lun Sun, Karen Weierstall, Ana Christina Minerly, Jan Weiner, Shirzad Jenab & Vanya Quinones-Jenab

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  1. Luyi Zhou
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Corresponding author

Correspondence to Vanya Quinones-Jenab.

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Animal care and use were in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication 85-23, Bethesda, MD) and approved by the Institutional Animal Care Use Committee of Hunter College of CUNY.

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The authors declare that they have no conflict of interest.

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Luyi Zhou and Wei-Lun Sun are equal contributors.

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Zhou, L., Sun, WL., Weierstall, K. et al. Sex differences in behavioral and PKA cascade responses to repeated cocaine administration. Psychopharmacology 233, 3527–3536 (2016). https://doi.org/10.1007/s00213-016-4387-6

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  • DOI: https://doi.org/10.1007/s00213-016-4387-6

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