κ-Opioid Receptors within the Nucleus Accumbens Shell Mediate Pair Bond Maintenance

“, 2006; Aragona and Wang, 2007) and unconditioned incentives, including those of an aversive nature (Kalivas and Duffy, 1995; Ikemoto and Panksepp, 1999; Kelley and Berridge, 2002; Everitt and Robbins, 2005; Becker, 2009).”

“Moreover, activation of D1-like receptors increases dynorphin levels (Gerfen et al., 1990), indicating a direct interaction between these systems.”

“While recent data have demonstrated that different subsets of DA containing neurons within the VTA are activated by rewarding versus aversive stimuli (Brischoux et al., 2009; Matsumoto and Hikosaka, 2009; Bromberg-Martin et al., 2010; Lammel et al., 2011), it has yet to be determined how this may be associated with so…”

“The socially monogamous prairie vole (Microtus ochrogaster) is an excellent model system to study the neurobiology of social attachment (Young and Wang, 2004; Young et al., 2005; Aragona and Wang, 2009).”

“For example, both unconditioned rewarding and aversive stimuli increase DA in the NAc shell (Kalivas and Duffy, 1995; Ikemoto, 2007), and this increase is associated with aspects of both approach and avoidance behaviors (Ikemoto and Panksepp, 1999; Di Chiara and Bassareo, 2007; Oleson et al.”

“Thus, site-specific behavioral pharmacology identified -opioid receptors within the NAc shell—a key brain region in mediating unconditioned motivational responses (Ikemoto and Panksepp, 1999; Kelley and Berridge, 2002)—as important for aversive social motivation in pair-bonded prairie voles.”

“While the NAc shell is well known to play a critical role in the processing of unconditioned rewarding and aversive stimuli (Ikemoto and Panksepp, 1999; Ito et al., 2000; Di Chiara et al., 2004; Everitt and Robbins, 2005; Aragona et al., 2008, 2009), the neural mechanisms within this brain region…”

“…that different subsets of DA containing neurons within the VTA are activated by rewarding versus aversive stimuli (Brischoux et al., 2009; Matsumoto and Hikosaka, 2009; Bromberg-Martin et al., 2010; Lammel et al., 2011), it has yet to be determined how this may be associated with social…”

“Conversely, D1-expressing neurons contain dynorphin, the endogenous ligand for -opioid receptors that mediates aversion and negative affect (Chavkin et al., 1982; Mucha and Herz, 1985; Pfeiffer et al., 1986).”

“Given that selective aggression is a form of aversive motivation and that -opioid receptors mediate aversion (van Ree et al., 1999; Le Merrer et al., 2009), we hypothesized that these receptors would be important for selective aggression, whereas -opioid receptors (i.e., receptors that mediate…”

“This is studied in the lab using tests of selective aggression toward unfamiliar conspecifics (Gavish et al., 1983; Winslow et al., 1993; Young et al., 1997), and it is known that this behavior is regulated by D1-like receptors within the NAc shell (Aragona et al., 2006).”

“…known to play a critical role in the processing of unconditioned rewarding and aversive stimuli (Ikemoto and Panksepp, 1999; Ito et al., 2000; Di Chiara et al., 2004; Everitt and Robbins, 2005; Aragona et al., 2008, 2009), the neural mechanisms within this brain region that promote approach…”

“Here, we demonstrate that blockade of -opioid receptors (known to mediate aversion) (Mucha and Herz, 1985; Pfeiffer et al., 1986), but not -opioid receptors (known to mediate reward and positive hedonics) (Weeks, 1962; Bozarth and Wise, 1981), prevents selective aggression.”

“…recent data have demonstrated that different subsets of DA containing neurons within the VTA are activated by rewarding versus aversive stimuli (Brischoux et al., 2009; Matsumoto and Hikosaka, 2009; Bromberg-Martin et al., 2010; Lammel et al., 2011), it has yet to be determined how this may be…”

“…such as depression (Shirayama et al., 2004; Carlezon et al., 2006; Chartoff et al., 2011), anxiety (Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute activation of this…”

“D2-like receptors are expressed on neurons that contain enkephalin, an endogenous ligand for -opioid receptors that mediate motivation and positive hedonics (Bozarth and Wise, 1981; Gerfen and Young, 1988; Pecina and Berridge, 2005).”

“D2-like receptors are expressed on neurons that contain enkephalin, an endogenous ligand for -opioid receptors that mediate motivation and positive hedonics (Bozarth and Wise, 1981; Gerfen and Young, 1988; Pecina and Berridge, 2005).”

“, 1986), but not -opioid receptors (known to mediate reward and positive hedonics) (Weeks, 1962; Bozarth and Wise, 1981), prevents selective aggression.”

“…such as depression (Shirayama et al., 2004; Carlezon et al., 2006; Chartoff et al., 2011), anxiety (Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute activation of this…”

“Consistent with the methods established by previous studies (Liu and Wang, 2003; Aragona et al., 2006), subjects were implanted with 26-guage bilateral guide cannulae (Plastics One) anchored to the skull with stainless-steel screws and dental cement and aimed at the NAc shell ( 1.6 mm AP; 1 mm ML;…”

“Differential regulation over pair bonding by D1- and D2-like receptors is significant because these receptors are primarily expressed on distinct neuron populations (Le Moine and Bloch, 1995; Perreault et al., 2011).”

“…Carlezon et al., 2006; Chartoff et al., 2011), anxiety (Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute activation of this system evolved to signal avoidance of potentially…”

“For example, both unconditioned rewarding and aversive stimuli increase DA in the NAc shell (Kalivas and Duffy, 1995; Ikemoto, 2007), and this increase is associated with aspects of both approach and avoidance behaviors (Ikemoto and Panksepp, 1999; Di Chiara and Bassareo, 2007; Oleson et al., 2012).”

“…whether global blockade of - or -opioid receptors alter selective aggression, either the -opioid receptor antagonist [norbinaltorphimine (nor-BNI] (Portoghese et al., 1987) or the preferential -opioid receptor antagonist (naloxone) (Magnan et al., 1982) was administered intraperitoneally 1 h…”

“…affective states induced by -opioid-receptor blockade, activation of these receptors is associated with positive hedonics and mediates the rewarding properties of positive social incentives such as play and contact comfort (Panksepp et al., 1980; Vanderschuren et al., 1995; Trezza et al., 2011).”

“” Here, we demonstrate that blockade of -opioid receptors (known to mediate aversion) (Mucha and Herz, 1985; Pfeiffer et al., 1986), but not -opioid receptors (known to mediate reward and positive hedonics) (Weeks, 1962; Bozarth and Wise, 1981), prevents selective aggression.”

“…or -opioid receptors alter selective aggression, either the -opioid receptor antagonist [norbinaltorphimine (nor-BNI] (Portoghese et al., 1987) or the preferential -opioid receptor antagonist (naloxone) (Magnan et al., 1982) was administered intraperitoneally 1 h before the resident-intruder test.”

“Together, data from the current study and previously published work suggest that novel conspecific exposure to pair-bonded voles increases DA transmission within the NAc shell, which then activates D1-like receptors that may promote dynorphin release (Gerfen et al., 1991).”

“The doses of U50,488 used in the present study were chosen because they have been demonstrated previously to decrease motor activity (Ukai and Kameyama, 1985; Schnur and Walker, 1990; Leyton and Stewart, 1992; Brent, 1993; Kuzmin et al., 2000; Mague et al., 2003) and enhance analgesia (Kuzmin et al.”

“This length of cohabitation, as well as the occurrence of mating during this period, has been used to infer pair bonding as characterized by selective affiliation toward the familiar partner and selective aggression toward novel conspecifics (Aragona et al., 2006; Gobrogge et al., 2009).”

“Importantly, as in other rodent species (Pert et al., 1976; Herkenham and Pert, 1981; Gerfen and Young, 1988; Mansour et al., 1994; Brown et al., 2002; Crittenden and Graybiel, 2011), a clear patch-matrix pattern of -opioid receptor distribution can be seen throughout the striatum (Fig.”

“Effect of peripheral blockade of opioid receptor on selective aggression Although there are quantitative differences in selective aggression between male and female prairie voles, both sexes show this behavior (Getz et al., 1981).”

“While the NAc shell is well known to play a critical role in the processing of unconditioned rewarding and aversive stimuli (Ikemoto and Panksepp, 1999; Ito et al., 2000; Di Chiara et al., 2004; Everitt and Robbins, 2005; Aragona et al., 2008, 2009), the neural mechanisms within this brain region that promote approach…”

“Thus, higher doses of nor-BNI are needed to alter motor activity compared to other rodent species (Lindholm et al., 2001; McLaughlin et al., 2003; McCurdy et al., 2006; Zhang et al., 2007).”

“Unlike -opioid receptors, -opioid receptors antagonize reward (Shippenberg et al., 1996; Carlezon and Miczek, 2010; Wee and Koob, 2010) and are thus a candidate to mediate aversive motivational social interactions, such as aggressive interactions.”

“For example, both unconditioned rewarding and aversive stimuli increase DA in the NAc shell (Kalivas and Duffy, 1995; Ikemoto, 2007), and this increase is associated with aspects of both approach and avoidance behaviors (Ikemoto and Panksepp, 1999; Di Chiara and Bassareo, 2007; Oleson et al.”

“Additionally, because testosterone has been implicated in general aggression in other species (Beeman, 1947; Edwards, 1968; Bronson and Desjardins, 1969; Schuurman, 1980), the relationship between selective aggression and plasma testosterone was also assessed.”

“This behavior is regulated by the processing of social reward within motivational circuitry (Aragona et al., 2003; Liu and Wang, 2003; Lim and Young, 2004; Curtis and Wang, 2005).”

“Results Fecundity and pair bonding While prairie voles are socially monogamous, males of this species display important individual variation in reproductive strategy (Getz et al., 1993; Solomon et al., 2009).”

“Thus, while aversive chemical stimuli have been shown to decrease DA transmission in the NAc shell (Roitman et al., 2008; Wheeler et al., 2011), there are many conditions in which DA release in the NAc shell is critical for the attribution of motivational salience to unconditioned salient stimuli…”

“This is especially interesting given the relationship between -opioid receptors and D2-like receptors, which also facilitate pair bond formation (Gingrich et al., 2000; Aragona et al., 2006).”

“D2-like receptors are expressed on neurons that contain enkephalin, an endogenous ligand for -opioid receptors that mediate motivation and positive hedonics (Bozarth and Wise, 1981; Gerfen and Young, 1988; Pecina and Berridge, 2005).”

“This behavior is regulated by the processing of social reward within motivational circuitry (Aragona et al., 2003; Liu and Wang, 2003; Lim and Young, 2004; Curtis and Wang, 2005).”

“Thus, there is a behavioral transition in selective affiliation and aggression, with non-pair-bonded voles being generally affiliative and then becoming more aggressive once pair bonded (Getz, 1978; Carter and Getz, 1993; Young et al., 1998; Aragona et al., 2006; Aragona and Wang, 2009).”

“Although negative affective states induced by -opioid receptor activation are usually associated with maladaptive conditions such as depression (Shirayama et al., 2004; Carlezon et al., 2006; Chartoff et al., 2011), anxiety (Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or…”

“Given that selective aggression is a form of aversive motivation and that -opioid receptors mediate aversion (van Ree et al., 1999; Le Merrer et al., 2009), we hypothesized that these receptors would be important for selective aggression, whereas -opioid receptors (i.e., receptors that mediate…”

“However, it is difficult to interpret data resulting from peripheral injections of antagonists because this manipulation blocks receptors globally in both the peripheral nervous system and the CNS (Wittert et al., 1996).”

“…usually associated with maladaptive conditions such as depression (Shirayama et al., 2004; Carlezon et al., 2006; Chartoff et al., 2011), anxiety (Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker…”

“6B,C) (Liu et al., 2001).”

“It is not surprising that peripheral blockade of -opioid receptors failed to inhibit selective aggression since previous studies have demonstrated that blockade of these receptors is aversive (van Ree et al., 1999; Kenny et al., 2006; Le Merrer et al., 2009).”

“…Carlezon et al., 2006; Chartoff et al., 2011), anxiety (Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute activation of this system evolved to signal avoidance of potentially…”

“Thus, there is a behavioral transition in selective affiliation and aggression, with non-pair-bonded voles being generally affiliative and then becoming more aggressive once pair bonded (Getz, 1978; Carter and Getz, 1993; Young et al., 1998; Aragona et al., 2006; Aragona and Wang, 2009).”

“Thus, D1- and D2-like receptors within the NAc shell—a region important for processing social incentives (Li and Fleming, 2003; Champagne et al., 2004; Trezza et al., 2011)— exert differential regulation over the formation and maintenance of monogamous pair bonds (Aragona et al., 2006).”

“Voles have higher baseline analgesia compared to mice (Table 2), and higher doses of the -opioid receptor agonist were needed to enhance antinociception (Tables 2, 3) (McLaughlin et al., 2006b).”

“This is studied in the lab using tests of selective aggression toward unfamiliar conspecifics (Gavish et al., 1983; Winslow et al., 1993; Young et al., 1997), and it is known that this behavior is regulated by D1-like receptors within the NAc shell (Aragona et al., 2006).”

“…maladaptive conditions such as depression (Shirayama et al., 2004; Carlezon et al., 2006; Chartoff et al., 2011), anxiety (Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute…”

“Voles have higher baseline analgesia compared to mice (Table 2), and higher doses of the -opioid receptor agonist were needed to enhance antinociception (Tables 2, 3) (McLaughlin et al., 2006b).”

“…of unconditioned rewarding and aversive stimuli (Ikemoto and Panksepp, 1999; Ito et al., 2000; Di Chiara et al., 2004; Everitt and Robbins, 2005; Aragona et al., 2008, 2009), the neural mechanisms within this brain region that promote approach versus avoidance behavior are not well understood.”

“Finally, since our data indicate that -opioid receptors within the NAc shell mediate selective aggression through modulation of aversive social motivation, and aversive stimuli are known to increase corticosterone signaling, we determined whether blockade of -opioid receptors alters selective aggression indirectly tho…”

“Finally, since our data indicate that -opioid receptors within the NAc shell mediate selective aggression through modulation of aversive social motivation, and aversive stimuli are known to increase corticosterone signaling, we determined whether blockade of -opioid receptors alters selective aggression indirectly tho…”

“Studies using rats have indeed implicated the NAc core in sex differences in other motivated behavior (van Haaren and Meyer, 1991; Li et al., 2004; Wissman et al., 2011).”

“…(Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute activation of this system evolved to signal avoidance of potentially harmful stimuli (Amit and Galina, 1988; Teskey and…”

“In other species, testosterone is known to regulate aggressive behavior (Edwards, 1968; Bronson and Desjardins, 1969; Schuurman, 1980).”

“Additionally, since multiple doses were used, a series of planned contrast was used to determine whether peripheral opioid receptor blockade decreased aggression in a dose-dependent manner (Zhang and Kelley, 1997).”

“On the test day, a 33-guage injector was used to infuse either artificial CSF (ACSF; male, n 8, NAc shell; n 6, NAc core; female, n 6, NAc core; n 7, NAc shell), ACSF containing 500 ng of nor-BNI (male, n 7, NAc core; n 8, NAc shell; n 8, NAc VP; female, n 7, shell; n 6, core; n 6, VP), or ACSF containing 1 ng of the…”

“Studies using rats have indeed implicated the NAc core in sex differences in other motivated behavior (van Haaren and Meyer, 1991; Li et al., 2004; Wissman et al., 2011).”

“Adult males and intact, nonestrogen primed females were paired for a 2 week cohabitation period (Aragona et al., 2006; Gobrogge et al., 2009).”

“Same-sex intruders were chosen because previous research has shown that pair-bonded animals show consistently high levels of aggression toward same-sex intruders, whereas this behavior is more modest and variable with opposite-sex intruders (Firestone et al., 1991a; Wang et al., 1997; Aragona et al., 2006).”

“For example, both unconditioned rewarding and aversive stimuli increase DA in the NAc shell (Kalivas and Duffy, 1995; Ikemoto, 2007), and this increase is associated with aspects of both approach and avoidance behaviors (Ikemoto and Panksepp, 1999; Di Chiara and Bassareo, 2007; Oleson et al., 2012).”

“The socially monogamous prairie vole (Microtus ochrogaster) is an excellent model system to study the neurobiology of social attachment (Young and Wang, 2004; Young et al., 2005; Aragona and Wang, 2009).”

“In other species, testosterone is known to regulate aggressive behavior (Edwards, 1968; Bronson and Desjardins, 1969; Schuurman, 1980).”

“…then directly facilitate the perception of the stimulus as aversive, and continued -opioid receptor activation will then decrease DA transmission (Heijna et al., 1990; Spanagel et al., 1992), and this may be involved in the termination of the aggressive interaction via DA regulation over general…”

“Unlike -opioid receptors, -opioid receptors antagonize reward (Shippenberg et al., 1996; Carlezon and Miczek, 2010; Wee and Koob, 2010) and are thus a candidate to mediate aversive motivational social interactions, such as aggressive interactions.”

“Initial pair bond formation involves prosocial behaviors that are reliably assayed with the partner preference test (Williams et al., 1992).”

“…by -opioid receptor activation are usually associated with maladaptive conditions such as depression (Shirayama et al., 2004; Carlezon et al., 2006; Chartoff et al., 2011), anxiety (Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011;…”

“The doses of nor-BNI tested were as follows: 10 mg/kg (n 10 male; n 10 female), 32 mg/kg (n 10 male; n 11 female), 50 mg/kg (n 10 male; n 9 female), or 100 mg/kg (n 7 male; n 10 female) (Broadbear et al., 1994).”

“Thus, higher doses of nor-BNI are needed to alter motor activity compared to other rodent species (Lindholm et al., 2001; McLaughlin et al., 2003; McCurdy et al., 2006; Zhang et al., 2007).”

“…2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute activation of this system evolved to signal avoidance of potentially harmful stimuli (Amit and Galina, 1988; Teskey and Kavaliers, 1988; Yamada and Nabeshima, 1995).”

“, 1993; Solomon and Jacquot, 2002), and the biological basis of this variation continues to be studied (Fink et al., 2006; Young and Hammock, 2007; Ophir et al., 2008; Mabry et al., 2011).”

“Moreover, activation of -opioid receptors is important for the early stages of pair bond formation, as blockade of these receptors within the striatum inhibits the formation of a partner preference (Burkett et al., 2011).”

“, 1993; Solomon and Jacquot, 2002), and the biological basis of this variation continues to be studied (Fink et al., 2006; Young and Hammock, 2007; Ophir et al., 2008; Mabry et al., 2011).”

“Differential regulation over pair bonding by D1- and D2-like receptors is significant because these receptors are primarily expressed on distinct neuron populations (Le Moine and Bloch, 1995; Perreault et al., 2011).”

“Thus, while aversive chemical stimuli have been shown to decrease DA transmission in the NAc shell (Roitman et al., 2008; Wheeler et al., 2011), there are many conditions in which DA release in the NAc shell is critical for the attribution of motivational salience to unconditioned salient stimuli…”

“Given the Levene test of homogeneity of variances failed for site-specific data, a one-way ANOVA could not be used, and thus a Mann–Whitney U test (Stribley and Carter, 1999) was conducted to test whether site-directed blockade of opioid receptors decreased aggression levels compared to controls.”

“Thus, these systems may interact to mediate social reward necessary for pair bond formation (Aragona et al., 2009), while those that mediate negative affect and stress are important for aversive social encounters that are important for maintaining the bond.”

“…females were not studied in these previous experiments (Aragona et al. 2006), and since the NAc core receives direct input from the NAc shell (van Dongen et al., 2005), it is possible that increased DA transmission in the NAc shell drives core-mediated behavior important for pair bonding in…”

“For this reason, the present study characterized the relationships between mating onset and pregnancy as well as the relationship between pregnancy status of the female and selective aggression (i.e., the behavioral index of pair bond maintenance) (Carter and Getz, 1993; Aragona and Wang, 2009).”

“…affective states induced by -opioid-receptor blockade, activation of these receptors is associated with positive hedonics and mediates the rewarding properties of positive social incentives such as play and contact comfort (Panksepp et al., 1980; Vanderschuren et al., 1995; Trezza et al., 2011).”

“Thus, higher doses of nor-BNI are needed to alter motor activity compared to other rodent species (Lindholm et al., 2001; McLaughlin et al., 2003; McCurdy et al., 2006; Zhang et al., 2007).”

“, 2006; Aragona and Wang, 2007) and unconditioned incentives, including those of an aversive nature (Kalivas and Duffy, 1995; Ikemoto and Panksepp, 1999; Kelley and Berridge, 2002; Everitt and Robbins, 2005; Becker, 2009).”

“As determined previously, plasma corticosterone levels of male and female prairie voles were high compared to those in other rodent species (DeVries et al., 1997; Taymans et al., 1997; Campbell et al., 2009) (Table 5).”

“The selective -opioid receptor agonist C19H26Cl2N2O HCl H2O U50,488 (Von Voigtlander and Lewis, 1982) was dissolved in sterile saline and administered by intraperitoneal injection at a dose of 0 mg/kg (male, n 7; female, n 7), 5 mg/kg (male, n 7; female, n 7), 10 mg/kg (male, n 8; female, n 6), or…”

“Additionally, the presence of acute aversive stimuli, including those of a social nature, increase plasma corticosterone levels (Schuurman, 1980; Buwalda et al., 2011).”

“This distribution pattern is similar to that of other rodents (guinea pig, rabbit, mouse, and rat) that also show dense binding within the striatum (Robson et al., 1985; Wang et al., 2011).”

“Because baseline analgesia measures of male and female prairie voles were higher than those reported for other species (Butelman et al., 1993; McLaughlin et al., 2006b), C57BL/6 mice were also tested under control conditions (i.”

“Studies using rats have indeed implicated the NAc core in sex differences in other motivated behavior (van Haaren and Meyer, 1991; Li et al., 2004; Wissman et al., 2011).”

“There is only light binding within the periaqueductal gray and substantia nigra, which is consistent with other rodent species (Mansour et al., 1988; Laprairie and Murphy, 2009) (Fig.”

“These effects are specific to the NAc shell, a component of brain motivational circuitry that is critical for neural processing of both social bonding (Li and Fleming, 2003; Champagne et al., 2004; Aragona et al., 2006; Aragona and Wang, 2007) and unconditioned incentives, including those of an aversive nature (Kaliva…”

“…n 7, NAc core; n 8, NAc shell; n 8, NAc VP; female, n 7, shell; n 6, core; n 6, VP), or ACSF containing 1 ng of the highly selective -opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 CTAP (Pelton et al., 1986) into the NAc shell (male, n 5; female, n 5) (Simmons and Self, 2009).”

“…et al., 2011), anxiety (Bruchas et al., 2007; Knoll et al., 2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute activation of this system evolved to signal avoidance of potentially harmful stimuli (Amit and…”

“Thus, higher doses of nor-BNI are needed to alter motor activity compared to other rodent species (Lindholm et al., 2001; McLaughlin et al., 2003; McCurdy et al., 2006; Zhang et al., 2007).”

“…populations, approximately one-half of males “wander” across multiple female territories attempting to mate with multiple females (Getz et al., 1993; Solomon and Jacquot, 2002), and the biological basis of this variation continues to be studied (Fink et al., 2006; Young and Hammock, 2007; Ophir…”

“Indeed, in addition to enhancing DA release within the NAc shell, exposure to stress is known to increase prodynorphin signaling (Chartoff et al., 2009) and activation of -opioid receptors within this region (Land et al.”

“This behavior is regulated by the processing of social reward within motivational circuitry (Aragona et al., 2003; Liu and Wang, 2003; Lim and Young, 2004; Curtis and Wang, 2005).”

“This is similar to previous laboratory studies showing that long-term cohabitation, but not mating, was correlated with aggression in females (Bowler et al., 2002) as well as data from the field that show no correlation between stage of pregnancy and wounding (a proxy for aggressive encounters)…”

“While prairie voles are socially monogamous, males of this species display important individual variation in reproductive strategy (Getz et al., 1993; Solomon et al., 2009).”

“Importantly, as in other rodent species (Pert et al., 1976; Herkenham and Pert, 1981; Gerfen and Young, 1988; Mansour et al., 1994; Brown et al., 2002; Crittenden and Graybiel, 2011), a clear patch-matrix pattern of -opioid receptor distribution can be seen throughout the striatum (Fig.”

“Consistent with previous studies that have shown that males are more aggressive than females (Gavish et al., 1981; Firestone et al., 1991b; Carter et al., 1997), we found a significant sex difference in the magnitude of selective aggression with control males showing significantly greater attack…”

“, 1993; Solomon and Jacquot, 2002), and the biological basis of this variation continues to be studied (Fink et al., 2006; Young and Hammock, 2007; Ophir et al., 2008; Mabry et al., 2011).”

“, 1993; Solomon and Jacquot, 2002), and the biological basis of this variation continues to be studied (Fink et al., 2006; Young and Hammock, 2007; Ophir et al., 2008; Mabry et al., 2011).”

“We therefore used two higher doses, 10 mg/kg (Grimm et al., 2007) and 30 mg/kg, and these doses ensured that the lack of effect on selective aggression by naloxone treatment was not due to using a behaviorally ineffective dose because these higher doses significantly decreased general locomotor activity in females (Ta…”

“This distribution pattern is similar to that of other rodents (guinea pig, rabbit, mouse, and rat) that also show dense binding within the striatum (Robson et al., 1985; Wang et al., 2011).”

“…2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute activation of this system evolved to signal avoidance of potentially harmful stimuli (Amit and Galina, 1988; Teskey and Kavaliers, 1988; Yamada and Nabeshima, 1995).”

“This is studied in the lab using tests of selective aggression toward unfamiliar conspecifics (Gavish et al., 1983; Winslow et al., 1993; Young et al., 1997), and it is known that this behavior is regulated by D1-like receptors within the NAc shell (Aragona et al., 2006).”

“Mate guarding is adaptive for males because it helps to ensure paternity (Stehn and Jannett, 1981; Heske and Nelson, 1984; Wolff and Dunlap, 2002).”

“As determined previously, plasma corticosterone levels of male and female prairie voles were high compared to those in other rodent species (DeVries et al., 1997; Taymans et al., 1997; Campbell et al., 2009) (Table 5).”

“Consistent with previous studies, males were more aggressive than females (Gavish et al., 1981), and mate guarding helps ensure the male that his partner will not mate with novel males (Wolff et al., 2002).”

“Mate guarding is adaptive for males because it helps to ensure paternity (Stehn and Jannett, 1981; Heske and Nelson, 1984; Wolff and Dunlap, 2002).”

“In other species, testosterone is known to regulate aggressive behavior (Edwards, 1968; Bronson and Desjardins, 1969; Schuurman, 1980).”

“As determined previously, plasma corticosterone levels of male and female prairie voles were high compared to those in other rodent species (DeVries et al., 1997; Taymans et al., 1997; Campbell et al., 2009) (Table 5).”

“…the reduction of selective aggression by nor-BNI was due to blockade of -opioid receptors, a separate experiment was conducted in which the highly selective -opioid receptor antagonist, CTAP (Crain and Shen, 1992; Nestler, 1993), was infused into the NAc shell before resident-intruder testing.”

“While this dose (1 mg/kg) has also been shown to decrease locomotor behavior in rats (Sisti and Lewis, 2001), it had no effect on either locomotor activity or selective aggression in prairie voles (see below).”

“The doses of U50,488 used in the present study were chosen because they have been demonstrated previously to decrease motor activity (Ukai and Kameyama, 1985; Schnur and Walker, 1990; Leyton and Stewart, 1992; Brent, 1993; Kuzmin et al., 2000; Mague et al., 2003) and enhance analgesia (Kuzmin et…”

“Consistent with previous studies that have shown that males are more aggressive than females (Gavish et al., 1981; Firestone et al., 1991b; Carter et al., 1997), we found a significant sex difference in the magnitude of selective aggression with control males showing significantly greater attack…”

“These effects are specific to the NAc shell, a component of brain motivational circuitry that is critical for neural processing of both social bonding (Li and Fleming, 2003; Champagne et al., 2004; Aragona et al., 2006; Aragona and Wang, 2007) and unconditioned incentives, including those of an aversive nature (Kaliva…”

“Mate guarding is adaptive for males because it helps to ensure paternity (Stehn and Jannett, 1981; Heske and Nelson, 1984; Wolff and Dunlap, 2002).”

“However, consistent with other species, including humans (Mansour et al., 1987, 1988; Quirion et al., 1987), there is dense -opioid receptor binding throughout the striatum.”

“Consistent with previous studies, males were more aggressive than females (Gavish et al., 1981), and mate guarding helps ensure the male that his partner will not mate with novel males (Wolff et al., 2002).”

“…laboratory studies showing that long-term cohabitation, but not mating, was correlated with aggression in females (Bowler et al., 2002) as well as data from the field that show no correlation between stage of pregnancy and wounding (a proxy for aggressive encounters) (Rose and Gaines, 1976).”

“…2007; Land et al., 2008), or drug-related behaviors (Bruchas et al., 2010, 2011; Schindler et al., 2010; Walker et al., 2011), acute activation of this system evolved to signal avoidance of potentially harmful stimuli (Amit and Galina, 1988; Teskey and Kavaliers, 1988; Yamada and Nabeshima, 1995).”

“This study demonstrates that for a pair bond to be consistently established, the pair must achieve estrous, mating, ovulation, and impregnation within an optimal time frame (Curtis, 2010).”

“…of U50,488 used in the present study were chosen because they have been demonstrated previously to decrease motor activity (Ukai and Kameyama, 1985; Schnur and Walker, 1990; Leyton and Stewart, 1992; Brent, 1993; Kuzmin et al., 2000; Mague et al., 2003) and enhance analgesia (Kuzmin et al., 2000;…”

“Unlike -opioid receptors, -opioid receptors antagonize reward (Shippenberg et al., 1996; Carlezon and Miczek, 2010; Wee and Koob, 2010) and are thus a candidate to mediate aversive motivational social interactions, such as aggressive interactions.”

“These doses were chosen because 1 mg/kg (but not lower doses) of naloxone has been shown to decrease aggression in mice (Haug et al., 1986).”

“Many studies have also investigated the role of the mesolimbic dopamine system and opioid regulation of rewarding social behaviors such as pair-bonds between mates (Aragona, 2009; Resendez et al., 2012); we describe these and additional research avenues throughout.”

“A second recent study investigated the role of KOR in the maintenance of pair bonds in prairie voles (Resendez et al. 2012).”

“…and acetylcholine, opioid signaling also appears to be an important mediator of aversive processing within the NAc, most notably through the kappa opioid receptor (KOR) (McCutcheon et al., 2012; Resendez et al., 2012), and interactions between nicotinic and KOR signaling have been established.”

“…www.frontiersin.org July 2014 | Volume 8 | Article 241 | 4 assays of pair bonding in prairie voles to reveal the importance of oxytocin, vasopressin, dopamine, and opioids in selective social attachment (Insel and Hulihan, 1995; Cho et al., 1999; Aragona et al., 2003, 2006; Resendez et al., 2012).”

“Accordingly, KOR activation in the NAc decreased social play in adolescent rats [19], and mediated selective aggression towards novel conspecifics in prairie voles, thereby supporting pair bond maintenance [26].”

“…prairie voles (Getz et al., 1981), the choice of a mate that will result in successful reproduction is of critical importance (Curtis, 2010; Resendez et al., 2012), and the present study demonstrates that appropriate MOR activation within distinct regions of the striatum has evolved to…”

“Pregnancy was confirmed by extracting embryos from pregnant females and subsequently categorizing pregnancy status by average neonatal weight of the embryos (Curtis, 2010; Resendez et al., 2012)”

“It is also worth noting that Resendez et al demonstrated an increase in NAc MOR mRNA during bond formation, a time associated with increased NAc OXT release, although whether this increase is OXT-dependent has not been directly tested (42, 55, 56).”

“…formation and maintenance of pair bonds relies on both MOR and KOR signaling (Resendez and Aragona 2013; Resendez et al. 2013; Resendez et al. 2016; Resendez et al. 2012), in the nucleus accumbens where these receptors are thought to mediate reinforcing interactions with the preferred partner…”

“Furthermore, treatment with KOR antagonists decrease male resident-intruder aggression in prairie voles (Resendez et al., 2012).”

“…and opioid systems in mediating pair bond formation inmonogamous prairie voles [Burkett et al., 2011; Cho et al., 1999; Gingrich et al., 2000; Resendez et al., 2012; Williams et al., 1994; Young et al., 2001], and it has also been used to study social preferences in non-monogamous rodents…”

“Infusion of the KOR antagonist norbinaltorphimine (nor-BNI) into the NAc shell of pair-bonded prairie voles reduces aggressive behavior (Resendez et al., 2012).”

“suggesting that kappa antagonism reduces aversive social motivation (Resendez & Aragona, 2013; Resendez et al., 2012) in addition to exerting more general anxiolytic effects (Falcon, Maier, Robinson,”

“…receptors (Ragen et al., 2015a). κ opioid receptors are associated with negative affect and the dysphoria of social separation in vole and titi monkeys (Resendez et al., 2012; Resendez and Aragona, 2013; Ragen et al., 2015b). κ opioid receptors are also present in titi monkey LS (Ragen et al.,…”

“, 2013), while the dysphoric effects of separation are mediated by kappa opioid receptors (Ragen et al., 2015a,b; Resendez and Aragona, 2013; Resendez et al., 2012).”

“The current study replicates findings in prairie voles that did not find an effect of opioid blockade on affiliative behaviors (Shapiro et al., 1989; Burkett et al., 2011; Resendez et al., 2012).”

“These drugs have been used in rodents and nonhuman primates with little to no side effects [124,132,133].”

“However, prairie voles display normal social behavior toward, and form partner preferences with, a gonadectomized partner (DeVries and Carter 1999) and will form and maintain pair bonds in the absence of mating (Cho et al. 1999; Resendez et al. 2012; Winslow et al. 1993).”

“Our findings and those of Resendez et al. (2012) now suggest some interesting locations where MOR and KOR intersect, which may provide clues as to a mechanism of cross-talk between these behavioral systems.”

“Recently the contribution of dynorphin signalling in pair bonding maintenance was also suggested: Pharmacological manipulation of its receptor, the kappa opioid receptor (KOR), altered aversive social motivation in prairie vole (Resendez et al., 2012).”

“Steroid and opioid signaling have been extensively implicated in pair bonding ( Resendez et al., 2016 ; Resendez et al., 2012 ; Loth and Donaldson, 2021 ; Inoue et al., 2013 ; Stetzik et al., 2018 ; Carter and Perkeybile, 2018 ; Lei et al., 2010 ; Cushing et al., 2008 ).”

“, OXT, vasopressin, serotonin, noradrenaline), cytokines (14), opioids (15, 16), and dopamine (17), as well as epigenetic (18) and environmental factors (19).”

“Also likely involved are µ and ĸ opioid receptors, which are involved in pair bond regulation in both prairie voles (Resendez et al., 2012, Resendez et al., 2013) and titi monkeys (Ragen et al., 2013, Ragen et al., 2015b).”

“Opioid signaling is also necessary for partnership maintenance, and interacts with dopamine signaling within the nucleus accumbens.(11,12) Behaviorally, prairie voles show a conditioned preference for cues associated with mates in socially conditioned place preference tests,(13,14) although unfamiliar opposite-sex con…”

“Laboratory simulations of territorial encounters have been used frequently in the study of socially monogamous rodents (primarily prairie voles, Microtus ochrogaster) in order to examine both the neurobiological basis of mate-guarding (although often not in the presence of the mate), and to pharmacologically manipulat…”

“In pair-bonded male and female prairie voles, KOR activation in the nucleus accumbens facilitates aggression towards same-sex intruders (Resendez et al., 2012).”

“…2009; Williams et al., 1994), vasopressin (Lim et al., 2004; Lim and Young, 2004; Pitkow et al., 2001), dopamine (Aragona and Wang, 2009; Hostetler et al., 2011; Resendez et al., 2016), and opioid systems (Burkett et al., 2011; Resendez et al., 2013; Resendez et al., 2016; Resendez et al., 2012).”

“Specifically, women are generally considered more susceptible to drug cravings and relapse (Fox et al, 2014; Hitschfeld et al, 2015; Kennedy et al, 2013; Kippin et al, 2005; Robbins et al, 1999; Rubonis et al, 1994).”

“These affiliative behaviors start to become directed specifically toward their partner once they formed a pair bond (18, 38, 42).”

“…GABA, glutamate, and opioids have also been implicated in pair-bonding behavior (Williams et al. 1992, 1994; Winslow et al. 1993; Carter et al. 1995; Wang et al. 1998; Liu et al. 2001; Aragona et al. 2003; Liu and Wang 2003; Lim and Young 2004; Curtis and Wang 2005b; Resendez et al. 2012).”

“…kappa opioid receptors are more intimately involved in reinforcement systems in the prairie vole relatively to other typical laboratory rodent species, as has been suggested by the involvement of kappa opioid receptors in male-male aggression following pair bond formation (Resendez et al., 2012).”

“While activation of KOR has been linked to increased aggression, this effect was observed in the nucleus accumbens and in a specific context of pair bonding [72].”

“…food and drugs [Mcbride et al., 1999; Alderson et al., 2001; Pecina, 2005; Van Der Plasse et al., 2012] and social reward related to pair bonding [Resendez et al., 2012, 2013], while the ACC plays a significant role in the approach to motivational stimuli and learning [Parkinson et al., 1999;…”

“Similarly, Resendez et al. (2012) found that males from pairs with smaller pups in utero after two weeks of pairing did not display the stranger-directed aggression typical of pair-bonded males.”

“neural mechanisms that function to maintain long-term, affiliative bonds.(9-11) Furthermore, most of the studies on pair bond mainte-”

“The answer is found in the study by Resendez et al. (2012) which showed that the effects of pregnancy status on pair-bond expression are sexually dimorphic in prairie voles.”

“In addition, selective aggression toward a stranger was stopped by blocking D1R in the NAc ( Resendez et al., 2012 ).”

“For example, in monogamous prairie voles, the activation of κ-opioid receptors stimulates the formation of aversive motivations aimed at unknown intruders (Resendez et al., 2012).”