Comment: Mechanisms discussed overlap with addiction mechanisms.

1) Activation of D1 receptors occurs with all addictive drugs – especially stimulants like meth and cocaine. I like my partner

2) Activation of  kappa-opioid receptors (KORs) occurs during withdrawal from drugs. These are NOT the feel good opioids. Instead activation of these receptors is associated with feeling irritable, anxious and crappy. They are activated by dynorphin – the “bad-feeling” opioid. I don’t like females who aren’t my partner.


2016;5:e15325 doi: 10.7554/eLife.15325

Shanna L ResendezPiper C KeyesJeremy J DayCaely HambroCurtis JustinFrancis K MainaLori N EidsonKirsten A Porter-StranskyNatalie NevárezJ  William McLeanMorgan A KuhnmuenchAnne Z MurphyTiffany A MathewsBrandon J Aragona


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.

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.


The ability to maintain meaningful social bonds is a critical component of human health and mental well being, yet the neural capacity to maintain such relationships is not well understood. The socially monogamous prairie vole (Michrotus ochrogaster) presents an ideal animal model to study the neural correlates of social bond maintenance because, unlike most mammals (Kleiman, 1977), prairie voles form selective and enduring attachments to their mating partner (Aragona et al., 2009). In both the field and laboratory, the maintenance of these bonds is associated with the expression of selective aggression towards novel conspecifics as well as selective affiliation with the mating partner (i.e., mate guarding) (Carter and Getz, 1993). Importantly, the expression of selective aggression provides a robust and reliable assay that can be utilized in a laboratory setting to deconstruct neural signaling pathways involved in the regulation of social bond maintenance.

To date, laboratory studies have identified that the expression of selective aggression, and therefore pair bond maintenance, requires the activation of both D1-like dopamine (DA) and kappa-opioid receptors (KORs) within the nucleus (NAc) shell as blockade of either one of the receptors attenuates aggressive rejection of novel conspecifics (Aragona et al., 2006; Resendez et al., 2012). Thus, regulation of pair bond maintenance requires neural systems that code evaluation of salient environmental stimuli as well as those that are important for the generation of motivational states (Resendez and Aragona, 2013). Interestingly, in other animal models, these receptor systems have been shown to directly interact at the molecular level (Gerfen et al., 1990; Carlezon et al., 1998) as well as in the transition between motivational states (Chartoff et al., 2016). However, it is unknown if similar interactions occur in the regulation of pair bond maintenance. This study therefore endeavored to examine pair bond induced neural plasticity within the DA and dynorphin/KOR systems as well as how these systems interact to mediate the expression of selective aggression, a well established indicator of a fully established pair bond.

Given that activation of KORs is associated with aversive states (Mucha and Herz, 1985; Pfeiffer et al., 1986; Shippenberg and Herz, 1986; Bals-Kubik et al., 1989), we first determined if activation of NAc KORs prior to pairing with a novel social stimulus is sufficient to tag a recently encountered social stimulus as aversive. Next, to assess how the establishment of a pair bond alters both motivational (DA) and aversive (dynorphin/KOR) processing systems, we conducted extensive anatomical, neurochemical, and functional comparisons within the striatum of male and female prairie voles. In total, we conducted mRNA expression analysis (RT-qPCR), protein binding measurements (receptor autoradiography), and measures of DA concentration (fast-scan cyclic-voltammetry) to identify sex-specific alterations within the DA and dynorphin/KOR systems of pair bonded voles. We next utilized site-specific behavioral pharmacology to examine interactions between NAc shell D1-like and KORs in the expression of selective aggression. Finally, in male prairie voles, we show that pair bonding, but not other social manipulations, decreases the rewarding properties of the psychostimulant amphetamine and that this attenuation requires the activation of NAc shell KORs. In total, the present study demonstrates that the development of a pair bond is underpinned by sex-specific modifications in motivational (DA/D1) and valence (dynorphin/KOR) processing systems, that these systems interact to mediate selective aggression in both sexes, and that male specific alterations in the dynorphin/KOR system buffers against the rewarding properties of amphetamine.



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