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Psychopharmacology

, Volume 197, Issue 2, pp 203–216 | Cite as

NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking

  • Herbert E. CovingtonIII
  • Thomas F. Tropea
  • Anjali M. Rajadhyaksha
  • Barry E. Kosofsky
  • Klaus A. MiczekEmail author
Original Investigation

Abstract

Rationale

Cocaine strengthens behaviors associated with its administration. The stress response by individuals that are defeated in a brief aggressive confrontation can also promote enduring behavioral consequences similar to those of stimulants.

Objectives

The study intends to find whether intermittent episodes of defeat promote cocaine’s reinforcing effects by triggering N-methyl-d-aspartic acid (NMDA)-receptor-mediated plasticity in the ventral tegmental area (VTA).

Materials and methods

Long–Evans rats were investigated after four social defeats in three experiments. Two experiments examined systemic or intra-VTA antagonism of NMDA receptors during stress on the later expression of behavioral sensitization and cocaine self-administration during fixed and progressive ratio (PR) schedules of reinforcement (0.3 mg/kg/infusion), including a novel 24-h variable-dose continuous access binge (0.2, 0.4, and 0.8 mg/kg/infusion, delivered in an irregular sequence). Third, the expression of receptor proteins NR1 (NMDA) and GluR1 [alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)] were examined in VTA and nucleus accumbens.

Results

Intermittent defeats augment locomotor responses to cocaine and increase cocaine taking. Rates of responding during binges are increased after defeat stress. These effects are prevented when NMDA or AMPA receptor antagonists are administered before defeats. VTA infusions of the NMDA antagonist AP-5 (5 nmol/side) before stress prevents locomotor sensitization to cocaine and intensified responding for cocaine during a PR schedule or binge. Episodic defeats increase GluR1 AMPA subunit protein expression in the VTA.

Conclusions

Social stress stimulates NMDA receptors in the VTA, and this neural action of defeat may be essential for prompting a later increase in cocaine intake during binges.

Keywords

Cocaine Self-administration Ventral tegmental area Glutamate NMDA–AMPA Progressive ratio schedule Binge 

Notes

Acknowledgements

This research was supported by USPHS research grants DA02632 (KAM), KO1DA14057 (AMR), and KO2DA00354 (BEK).

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Herbert E. CovingtonIII
    • 1
    • 7
  • Thomas F. Tropea
    • 1
    • 5
  • Anjali M. Rajadhyaksha
    • 5
    • 6
  • Barry E. Kosofsky
    • 5
    • 6
  • Klaus A. Miczek
    • 1
    • 2
    • 3
    • 4
    • 8
    Email author
  1. 1.Department of PsychologyTufts UniversityMedford and BostonUSA
  2. 2.Department of PsychiatryTufts UniversityMedford and BostonUSA
  3. 3.Department of PharmacologyTufts UniversityMedford and BostonUSA
  4. 4.Department of NeuroscienceTufts UniversityMedford and BostonUSA
  5. 5.Division of Pediatric Neurology, Department of PediatricsWeill Medical College of Cornell UniversityNew YorkUSA
  6. 6.Department of Neurology and NeuroscienceWeill Medical College of Cornell UniversityNew YorkUSA
  7. 7.Department of Psychiatry and Center for Basic NeuroscienceUniversity of Texas Southwestern Medical CenterDallasUSA
  8. 8.Tufts UniversityMedfordUSA

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