Recent evidence suggests an important role for hypothalamic orexins/hypocretins in modulation of drug reward and addiction-like behaviors in rodents. Our recent study has shown that the aversive state of arousal during acute morphine withdrawal is associated with increased orexin gene expression in lateral hypothalamus (LH) of Fischer 344 (F344) inbred rats, with no change in the expression of preprodynorphin (ppDyn), a gene co-expressed with LH orexin. Therefore, we determined whether orexin and ppDyn mRNA levels in LH or medial hypothalamus (including perifornical and dorsomedial areas) of F344 or Sprague-Dawley (SD) outbred rats, are altered following: 1) cocaine (10 mg/kg, i.p.) conditioned place preference (CPP); 2) chronic (14 days) cocaine exposure using both "binge" pattern administration in steady-dose (45 mg/kg/day) and escalating-dose (45-90 mg/kg/day) regimens; and 3) acute (1 day) and chronic (14 days) withdrawal from cocaine with opioid receptor antagonist naloxone treatment (1 mg/kg). We found that orexin mRNA levels were decreased after cocaine place conditioning in the LH of SD rats. A decreased LH orexin mRNA level was also observed after chronic escalating-dose cocaine (but not CPP pattern regimen without conditioning, or steady-dose regimen) in both strains. In F344 rats only, acute withdrawal from chronic escalating-dose cocaine administration resulted in increases in both LH orexin and ppDyn mRNA levels, which were unaltered by naloxone or after chronic withdrawal. Our results suggest that (1) alteration of LH orexin gene expression is region-specific after cocaine place conditioning in SD rats and dose-dependent after chronic exposure in both strains; and (2) increased LH orexin and ppDyn gene expressions in F344 rats may contribute to negative affective states in cocaine withdrawal.