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Prairie vole breeder pairs form monogamous pair bonds, which are maintained through the expression of selective aggression toward novel conspecifics. Here, we utilize behavioral and anatomical techniques to extend the current understanding of neural mechanisms that mediate pair bond maintenance. For both sexes, we show that pair bonding up-regulates mRNA expression for genes encoding D1-like dopamine (DA) receptors and dynorphin as well as enhances stimulated DA release within the nucleus accumbens (NAc). We next show that D1-like receptor regulation of selective aggression is mediated through downstream activation of kappa-opioid receptors (KORs) and that activation of these receptors mediates social avoidance. Finally, we also identified sex-specific alterations in KOR binding density within the NAc shell of paired males and demonstrate that this alteration contributes to the neuroprotective effect of pair bonding against drug reward. Together, these findings suggest motivational and valence processing systems interact to mediate the maintenance of social bonds. DOI: http://dx.doi.org/10.7554/eLife.15325.001, eLife digest The bond between parents is one of the most important social relationships that humans have. Prairie voles are one of the few other mammals whose individuals also form long-term social bonds after having offspring together, so they have frequently been used to study the brain mechanisms that underlie such bonding. However, most previous studies have focused only on how the bond between a pair of mating partners is formed: little is known about how this bond is then maintained over months and years. When a prairie vole forms a bond with a mate, it will then aggressively reject other prairie voles. This “selective aggression” only happens once a social bond between two mating prairie voles is formed, so this behavior can be used as a proxy to confirm that the social bond exists. In order to study how prairie voles maintain bonds with a mate, Resendez et al. tracked what happens in the brain of a prairie vole during selective aggression. The experiments showed that this aggressive behaviour coincides with changes in gene expression and brain chemistry that make it unpleasant for a prairie vole to be exposed to voles that are not its partner. For male prairie voles – but not females – these changes only happened if the female mating partner became pregnant during the cohabitation period. The changes that occur in the brain as a result of bonding with a partner also mean that drugs that are normally addictive are no longer pleasant and rewarding to the prairie vole. Indeed, forming a social bond between mating animals alters the brain in similar ways to the effects produced by addictive drugs. Thus, in a sense, each member of the mating pair becomes ‘addicted’ to their partner. The results presented by Resendez et al. also have implications for humans. They suggest that having a strong social support network is a powerful way of preventing casual drug use from developing into compulsive drug addiction. This may also mean that positive social relationships could help to treat people with drug addiction problems. DOI: http://dx.doi.org/10.7554/eLife.15325.002

The prairie vole is a socially monogamous species in which breeder pairs typically show strong and selective pair bonds. The establishment of a pair bond is associated with a behavioral transition from general affiliation to aggressive rejection of novel conspecifics. This “selective aggression” is indicative of mate guarding that is necessary to maintain the initial pair bond. In the laboratory, the neurobiology of this behavior is studied using resident-intruder testing. Although it is well established that social behaviors in other species are mediated by endogenous opioid systems, opiate regulation of pair bond maintenance has never been studied. Here, we used resident-intruder testing to determine whether endogenous opioids within brain motivational circuitry mediate selective aggression in prairie voles. We first show that peripheral blockade of κ-opioid receptors with the antagonist norbinaltorphimine (nor-BNI; 100 mg/kg), but not with the preferential μ-opioid receptor antagonist naloxone (1, 10, or 30 mg/kg), decreased selective aggression in males. We then provide the first comprehensive characterization of κ- and μ-opioid receptors in the prairie vole brain. Finally, we demonstrate that blockade of κ-opioid receptors (500 ng nor-BNI) within the nucleus accumbens (NAc) shell abolishes selective aggression in both sexes, but blockade of these receptors within the NAc core enhances this behavior specifically in females. Blockade of κ-opioid receptors within the ventral pallidum or μ-opioid receptors with the specific μ-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH2 (1 ng CTAP) within the NAc shell had no effect in either sex. Thus, κ-opioid receptors within the NAc shell mediate aversive social motivation that is critical for pair bond maintenance.