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

Rationale: Psychomotor stimulant drugs engender intense euphoria as well as anxiogenic effects, both potentially involving the mesolimbic dopamine sys tem. Objectives: (1) Do animals that discriminate a psychomotor stimulant d rug from saline generalize to a non-pharmacological stressful event such as social defeat? (2) How does the generalization from d-amphetamine to socia l defeat stress relate to dopamine overflow in the mesocorticolimbic system in response to this stress? Methods: Adult male Long-Evans rats were train ed 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, a dditional discrimination tests involved exposure to several stress conditio ns; (1) brief confrontations with an aggressive resident rat that resulted in the intruder's defeat. Rats were administered saline, then exposed to ag gressive threats behind a protective screen for 15 min, and subsequently pe rformed the two-lever discrimination task; (2) exposure for 15 min to aggre ssive 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 gene ralized 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. Soc ial defeat stress increased dopamine in nucleus accumbens, with a closely s imilar dopamine response in amphetamine-discriminating rats that were behav iorally sensitized versus those that were not sensitized by amphetamine. Co nclusions: Generalization from social stress to the stimulant "cue" differs among individuals, which may be relevant to the anxiety-like effects of st imulants. By contrast, mesolimbic DA activity and motor activity was increa sed in response to social defeat stress or a d-amphetamine challenge, regar dless of the qualitatively different stimulant-stress generalization. Mesol imbic DA in response to stress or amphetamine appears significant in behavi oral activation, but not in the qualitatively divergent internal stimulus p roperties.