Region-specific alterations of AVP and D2 gene expression were found in the rats after heroin self-administration, and expression of these genes correlated with individual differences in stress-induced reinstatement of heroin-seeking. In contrast, a decrease in POMC gene expression was found in parallel with an increase in orexin gene expression in the hypothalamus of all rats after heroin self-administration. Our present data suggest that (1) the consequence of a new set point of AVP and D2 gene expressions in response to stress may play an important role in individual vulnerability to acute stress-induced relapse during opiate abstinence; and (2) the alterations of hypothalamic orexin and POMC expression may be involved in drug-seeking behavior induced by a drug prime.