Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the AMPA glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment of the NAc. Wistar rats pre-exposed to acute stress showed increased basal levels of glutamate in the core but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, since blocking AMPAR by CNQX microinjection into the core prevented both the behavioral cross-sensitization and the augmented increase in cocaine-induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre-stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long-term expression of restraint stress-induced behavioral cross-sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long-term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross-sensitization to cocaine.

Systemic administration of dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC) antagonists blocked both acquisition and expression of fructose-conditioned flavor preferences (CFP). It is unclear what brain circuits are involved in mediating these effects. The present study investigated DA signaling within the nucleus accumbens shell (NAcS), amygdala (AMY) and medial prefrontal cortex (mPFC) in the acquisition and expression of fructose-CFP. In Experiment 1, separate groups of rats were injected daily in the NAcS or AMY with saline, SCH (24 nmol) or RAC (24 nmol) prior to training sessions with a flavor (CS+) mixed with 8% fructose and 0.2% saccharin (CS+/F) and a different flavor (CS−) mixed with only 0.2% saccharin. In the two-bottle choice tests with 0.2% saccharin, only rats injected with RAC in the AMY failed to acquire a CS+ preference (45–54%). In Experiment 2, new rats were identically trained, but saline, SCH and RAC were injected in the mPFC. In subsequent two-bottle choice tests, SCH- and RAC-treated rats failed to exhibit a CS+ preference (50–56%). In Experiment 3, new rats were trained with CS+/F and CS− without injections. Subsequent two-bottle choice tests were then conducted following bilateral injections of SCH or RAC in the mPFC at total doses of 0, 12, 24 and 48 nmol. Expression of the CS+ preference failed to be affected by either antagonist, indicating that the mPFC is not involved in the maintenance of this preference. These data indicate that the acquisition of fructose-CFP is dependent on DA signaling in the mPFC and AMY.