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Social defeat stress-induced sensitization and escalated cocaine self-administration: the role of ERK signaling in the rat ventral tegmental area

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Abstract

Rationale

Intermittent social defeat stress can induce neuroadaptations that promote compulsive drug taking. Within the mesocorticolimbic circuit, repeated cocaine administration activates extracellular signal-regulated kinase (ERK).

Objective

The present experiments examine whether changes in ERK phosphorylation are necessary for the behavioral and neural adaptations that occur as a consequence of intermittent defeat stress.

Materials and methods

Rats were exposed to four brief intermittent defeats over the course of 10 days. Ten days after the last defeat, rats were challenged with cocaine (10 mg/kg, i.p.) or saline, and ERK activity was examined in mesocorticolimbic regions. To determine the role of ERK in defeat stress-induced behavioral sensitization, we bilaterally microinjected the MAPK/ERK kinase inhibitor U0126 (1 μg/side) or vehicle (20 % DMSO) into the ventral tegmental area (VTA) prior to each of four defeats. Ten days following the last defeat, locomotor activity was assessed for the expression of behavioral cross-sensitization to cocaine (10 mg/kg, i.p.). Thereafter, rats self-administered cocaine under fixed and progressive ratio schedules of reinforcement, including a 24-h continuous access “binge” (0.3 mg/kg/infusion).

Results

We found that repeated defeat stress increased ERK phosphorylation in the VTA. Inhibition of VTA ERK prior to each social defeat attenuated the development of stress-induced sensitization and prevented stress-induced enhancement of cocaine self-administration during a continuous access binge.

Conclusions

These results suggest that enhanced activation of ERK in the VTA due to brief defeats is critical in the induction of sensitization and escalated cocaine taking.

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Acknowledgments

We thank Tom Sopko for excellent technical assistance. This research was supported by grants from the National Institute on Drug Abuse (DA02632, DA18478) and the National Institute of Mental Health (MH063266). Jasmine Yap is currently affiliated with the University of Colorado Denver School of Education and Human Development.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Psychology, Tufts University, Medford, MA, 02155, USA

    Jasmine J. Yap, Elizabeth N. Holly & Klaus A. Miczek

  2. Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA

    Elena H. Chartoff, David N. Potter & William A. Carlezon Jr.

  3. Departments of Psychiatry, Pharmacology, and Neuroscience, Tufts University School of Medicine, Boston, MA, 02110, USA

    Klaus A. Miczek

  4. School of Education and Human Development, University of Colorado Denver, Campus Box 106, PO Box 173364, Denver, CO, 80217–3364, USA

    Jasmine J. Yap

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  1. Jasmine J. Yap
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  2. Elena H. Chartoff
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Correspondence to Jasmine J. Yap.

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Yap, J.J., Chartoff, E.H., Holly, E.N. et al. Social defeat stress-induced sensitization and escalated cocaine self-administration: the role of ERK signaling in the rat ventral tegmental area. Psychopharmacology 232, 1555–1569 (2015). https://doi.org/10.1007/s00213-014-3796-7

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