d-amphetamine "cue" generalizes to social defeat stress: behavioral sensitization and attenuated accumbens dopamine

Psychopharmacology (Berl). 1999 Nov;147(2):190-9. doi: 10.1007/s002130051160.


Rationale: Psychomotor stimulant drugs engender intense euphoria as well as anxiogenic effects, both potentially involving the mesolimbic dopamine system.

Objectives: (1) Do animals that discriminate a psychomotor stimulant drug from saline generalize to a non-pharmacological stressful event such as social defeat? (2) How does the generalization from d-amphetamine to social defeat stress relate to dopamine overflow in the mesocorticolimbic system in response to this stress?

Methods: Adult male Long-Evans rats were trained to discriminate either 1.0 mg/kg d-amphetamine or 10 mg/kg cocaine from saline in a two-lever drug discrimination task; each injection-appropriate tenth lever press was reinforced by milk presentation (fixed ratio, FR10). After confirming systematic cocaine and d-amphetamine dose-effect curves, additional discrimination tests involved exposure to several stress conditions; (1) brief confrontations with an aggressive resident rat that resulted in the intruder's defeat. Rats were administered saline, then exposed to aggressive threats behind a protective screen for 15 min, and subsequently performed the two-lever discrimination task; (2) exposure for 15 min to aggressive threats without prior defeat; (3) exposure to a novel cage for 15 min. A subgroup of rats was prepared for in vivo microdialysis after they generalized the social stress response to the d-amphetamine cue.

Results: Nine of 35 d-amphetamine-trained and six of 18 cocaine-trained animals responded at least 80% at the drug-appropriate lever after social defeat stress. Social defeat stress increased dopamine in nucleus accumbens, with a closely similar dopamine response in amphetamine-discriminating rats that were behaviorally sensitized versus those that were not sensitized by amphetamine.

Conclusions: Generalization from social stress to the stimulant "cue" differs among individuals, which may be relevant to the anxiety-like effects of stimulants. By contrast, mesolimbic DA activity and motor activity was increased in response to social defeat stress or a d-amphetamine challenge, regardless of the qualitatively different stimulant-stress generalization. Mesolimbic DA in response to stress or amphetamine appears significant in behavioral activation, but not in the qualitatively divergent internal stimulus properties.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamine / pharmacology*
  • Animals
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / pharmacology*
  • Cues
  • Discrimination, Psychological / drug effects*
  • Dominance-Subordination
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Long-Evans
  • Stress, Physiological / metabolism*


  • Central Nervous System Stimulants
  • Amphetamine
  • Cocaine
  • Dopamine