Morphine-associated environmental cues elicit conditioned gene expression.

Drug-associated contextual cues can exert a powerful influence on behavior through associative pairing between the drug and the environment. However, the anatomical and molecular substrates for these effects are not well characterized. Using a drug-conditioning paradigm, we examined the expression of the immediate early gene product, Fos, within specific brain circuits using immunocytochemical detection. Rats were given either morphine (5 mg/ml/kg) or saline once a day for 10 days. The drug administration was always paired with a specific environment (activity monitors) different from the home cage. Following this treatment, the rats were returned to the cages at various times thereafter, with only a mock injection. Conditioned behavioral activation was observed in rats at 3, 5, and 7 days following treatment with morphine. In rats showing the conditioned motor response, several cortical and limbic areas showed substantial increases in the number of Fos positive cells, indicating that these regions were more active during exposure to the drug-paired environment. Areas that were most activated included prefrontal cortex, cingulate cortex, nucleus accumbens, and preoptic area. Further analysis showed that this increase in Fos expression was not directly related to the increase in motor activity, and that the drug-associated conditioning and Fos expression was lessened at 7 days and absent by 14 days post-treatment. These results are discussed in terms of their relevance to the problem of relapse in drug addiction.