Age-dependent and strain-dependent influences of morphine on mouse social investigation behavior

Abstract

Opioid-coded neural circuits play a substantial role in how individuals respond to drugs of abuse, and most individuals begin using such drugs during adolescence and within a social context. Several studies indicate that adolescent mice exhibit a heightened sensitivity to the effects of morphine, the prototypical opiate drug, when compared with adults, but it is unclear whether these developmental differences are related to aspects of motivated behavior. Moreover, exposure to opioids within the rodent brain can alter the expression of social behavior, yet little is known about whether this relationship changes as a function of development or genetic variation. In this study, we conducted a series of experiments to characterize the relationship between genetic background, adolescent development and morphine-induced changes in mouse social investigation (SI). At two time-points during adolescent development (postnatal day [PD] 25 and 45), social interactions of test mice of the gregarious C57BL/6J (B6) strain were more tolerant to the suppressive effects of morphine (ED50 = 0.97 and 2.17 mg/kg morphine, respectively) than test mice from the less social BALB/cJ (BALB) strain (ED50 = 0.61 and 0.91 mg/kg morphine, respectively). By contrast, this strain-dependent difference was not evident among adult mice on PD 90 (ED50 = 1.07 and 1.41 mg/kg morphine for BALB and B6 mice, respectively). An additional experiment demonstrated that the ability of morphine to alter social responsiveness was not directly related to drug-induced changes in locomotor behavior. Finally, administration of morphine to stimulus mice on PD 25 reduced social interaction of test mice only when individuals were from the B6 genetic background. Overall, these results indicate that alterations in endogenous opioid systems are related to changes in SI that occur during adolescence and that morphine administration may mimic the rewarding nature of SI.

Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure

“…A number of the behavioral effects were less robust in the F2 generation compared to the F1 generation, which may implicate a role for direct exposure. In addition, exposure to opioids during the adolescent window may impact the development of both endocrine and neural circuits, which could contribute to the F1 effects to a greater extent than the F2 effect (Cicero et al, 1991; Hofford et al, 2012; Kennedy et al, 2011). Moreover, it is not uncommon nor unexpected to see effects in only one generation, effects that skip a generation, or effects that weaken with subsequent generations (Daxinger and Whitelaw, 2012; Dunn and Bale, 2011; Dunn et al, 2011; van Otterdijk and Michels, 2016; Vassoler et al, 2014a; Yohn et al, 2015).…”

Social Reward and Empathy as Proximal Contributions to Altruism: The Camaraderie Effect

“…Social recognition tests (Ferguson et al 2001) and social preference tests (Moy et al 2004) are variants of these social approach measures. Social approach tests have been used to compare the responses of rodent sociability to genetic background (Moy et al 2009; Panksepp et al 2007; Sankoorikal et al 2006), variations in brain anatomy (Fairless et al 2008), targeted alleles including knockout mice (Spencer et al 2008), brain lesions (Yang et al 2009), exposures to modulators of opiate and dopamine pathways (Benton et al 1984; Gariepy et al 1998; Kennedy et al 2011), toxic chemicals (Belloni et al 2011), and candidates for pharmacological treatments (Calamandrei et al 2000; and for reviews, see Halladay et al 2009; Moy et al 2009; Silverman et al 2010). Measures of social approach often tally how often the subject rodent brings itself into close proximity or physical contact with the object rodent.…”

Social influences on morphine-conditioned place preference in adolescent BALB/cJ and C57BL/6J mice

“…Specifically, morphine exposure can suppress social investigation by adolescent mice (Kennedy et al 2011), which might diminish the quality of social interaction and thus reduce social reward. Consistent with this explanation, treatment of adolescent rats with another psychoactive drug, methylphenidate, both depresses play behavior (Vanderschuren et al 2008) and diminishes expression of social CPP, irrespective of whether the drug was administered to the subject rat, its social partner, or both individuals (Trezza et al 2009).…”

“…Morphine has substantial effects on the social behaviors of juvenile rodents, including both suppression of social behavior (Kennedy et al 2011) as well as facilitation (Vanderschuren et al 1995a; Panksepp et al 1985) depending on the dose administered as well as the age and species of test animals. However, with the exception of the sensitization experiments described above (Hodgson et al 2010; Hofford et al 2010), we know little about how social context influences the responses of adolescents to this drug.…”

“…This difference in social motivation may explain the different responses of BALB and B6 mice to conspecifics that have been exposed to morphine. Adolescent B6 mice express diminished social investigation towards a social partner that has been administered with morphine, whereas BALB social behavior is not affected by the drug state of social partners (Kennedy et al 2011). Taken together, these findings suggest that genetically based differences in sociability could play a substantial role in determining whether the social environment influences morphine sensitivity during adolescence.…”