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CRF type 1 receptor antagonism in ventral tegmental area of adolescent rats during social defeat: prevention of escalated cocaine self-administration in adulthood and behavioral adaptations during adolescence

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Abstract

Background

Activation of corticotropin-releasing factor type 1 receptors (CRF-R1) in the ventral tegmental area (VTA) represents a critical mechanism for social defeat to escalate cocaine self-administration in adult rats.

Objective

We determined the acute effect of a CRF-R1 antagonist (CP376395) microinfusion into the VTA prior to each episode of social defeat in adolescent rats and determined whether this drug treatment could prevent later escalation of cocaine taking in early adulthood.

Methods

Rats were implanted with bilateral cannulae aimed at the VTA 5 days before the first social defeat. Bilateral microinfusion of CP376395 (500 ng/side) or vehicle occurred 20 min before each episode of social defeat on postnatal days (P) 35, 38, 41, and 44. Behavior was quantified on P35 and P44. On P57, rats were implanted with intra-jugular catheters, and subsequent cocaine self-administration was analyzed.

Results

CP376395-treated adolescent rats walked less and were attacked more slowly but were socially investigated more than vehicle-treated adolescents. Vehicle-treated rats showed increased social and decreased non-social exploration from P35 to P44, while CP376395-treated rats did not. Socially defeated, vehicle-treated adolescents took more cocaine during a 24-h unlimited access binge during adulthood. The latency to supine posture on P44 was inversely correlated with later cocaine self-administration during fixed and progressive ratio schedules of reinforcement and during the binge.

Conclusions

CP376395 treatment in adolescence blocked escalation of cocaine taking in adulthood. Episodes of social defeat stress engender neuroadaptation in CRF-R1s in the VTA that alter coping with social stress and that persist into adulthood.

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Acknowledgments

The authors acknowledge the support from the National Institutes of Health R01DA031734 (KAM), F32DA032226 (ARB), Tufts University Office of the Vice Provost for Research, and Tufts University Graduate School of Arts and Sciences and thank the Tufts University undergraduate assistants Shreya Bhatia and Rebecca Nardulli.

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Author notes

  1. Andrew R. Burke

    Present address: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

Authors and Affiliations

  1. Department of Psychology, Tufts University, 530 Boston Avenue (Bacon Hall), Medford, MA, 02155, USA

    Andrew R. Burke, Joseph F. DeBold & Klaus A. Miczek

  2. Department of Neuroscience, Tufts University, Boston, MA, 02111, USA

    Klaus A. Miczek

  3. Department of Pharmacology, Tufts University, Boston, MA, 02111, USA

    Klaus A. Miczek

  4. Department of Psychiatry, Tufts University, Boston, MA, 02111, USA

    Klaus A. Miczek

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  1. Andrew R. Burke
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Correspondence to Klaus A. Miczek.

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Facilities and procedures were approved by the Tufts Institutional Animal Care and Use Committee in adherence with the guidelines established by the National Institutes of Health (National Research Council 2011).

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The authors declare that they have no conflicts of interest.

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Burke, A.R., DeBold, J.F. & Miczek, K.A. CRF type 1 receptor antagonism in ventral tegmental area of adolescent rats during social defeat: prevention of escalated cocaine self-administration in adulthood and behavioral adaptations during adolescence. Psychopharmacology 233, 2727–2736 (2016). https://doi.org/10.1007/s00213-016-4336-4

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  • DOI: https://doi.org/10.1007/s00213-016-4336-4

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