The effects of kappa opioid receptors (KOR) on motivated behavior are well established based on studies in male rodents, but relatively little is known about the effects of KOR in females. We examined the effects of KOR activation on conditioned place aversion and social interaction in the California mouse (Peromyscus californicus). Important differences were observed in long-term (place aversion) and short-term (social interaction) effects. Females but not males treated with a 2.5 mg/kg dose of U50,488 formed a place aversion, whereas males but not females formed a place aversion at the 10 mg/kg dose. In contrast the short term effects of different doses of U50,488 on social interaction behavior were similar in males and females. Acute injection with 10 mg/kg of U50,488 (but not lower doses) reduced social interaction behavior in both males and females. The effects of U50,488 on phosphorylated extracellular signal regulated kinase (pERK) and p38 MAP kinase were cell type and region specific. Higher doses of U50,488 increased the number of pERK neurons in the ventrolateral bed nucleus of the stria terminals in males but not females, a nucleus implicated in male aggressive behavior. In contrast, both males and females treated with U50,488 had more activated p38 cells in the nucleus accumbens shell. Unexpectedly, cells expressing activated p38 co-expressed Iba-1, a widely used microglia marker. In summary we found strong sex differences in the effects of U50,488 on place aversion whereas the acute effects on U50,488 induced similar behavioral effects in males and females
