Maternal separation in two periods of early development: effect on adolescent rats social behavior and drug reward

Social environment is critical for the development of drug-related problems, with social features playing an important role in the initial drug use, maintenance and recovery from addiction. This is particularly important in the period of adolescence, where social peer influences are strong predictors of risk-taking behaviors. As such, it is crucial to understand which factors across ontogeny will affect the modulation of personality traits and be determinant for relationships in adolescence. This is a period of emergence of personal beliefs and values, which associates with increasing independence and shifts in relationships with parents and peers. Like in human adolescents, rats undergoing this developmental transition also show a marked increase in the amount of time spent in social investigation and interaction with peers, along with elevation in risk-taking behaviors. Developmental individual differences emerge, revealing behavioral vulnerabilities that can become decisive for a positive or negative course of development. However, this important topic did not yet receive enough attention in pre-clinical studies. As early mother–infant attachment seems to establish the basic parameters for later social interactions, in the present study, a maternal separation (MS) paradigm was used as an animal model of physical mother absence, a relevant issue in modern societies. Since development is an ongoing process, the imprinting consequences of early adversity are highly dependent on the “time window” in which they occur. In this context, we explored this issue using two different periods of MS in Wistar rats, which correspond approximately to 5 month or 3 years of age in humans, to mimic the periods where most children initiate their stay at a nursery. The study aimed at investigating if short periods of early MS could disrupt the way adolescent rats would interact with peers and consequently increase their susceptibility to drug abuse.

MS was imposed for 2 hours/daily from postnatal day (PND)2-6, or from PND10-14, evaluations were conducted on the adolescent period using, different social behavior paradigms. Collected data were correlated with the expression profile of the oxytocin receptor (OXTR) gene. Sensitivity to the conditioned reward effect of cocaine was also evaluated. Results showed that MS from PND2-6 highly reduced social affiliation/motivation and social novelty preference in adolescent rats, indicating inability to establish strong bonds. These animals also presented decreased reward value in the Conditioned Place Preference test. These data suggest that MS from PND2-6 diminished susceptibility to reward. These results highlight that MS shortly after birth may induce anhedonia, which may be an important mechanism of vulnerability to affective disorders, linked to non-negligent maternal separation.After MS from PND10-14, dams increased affiliative behaviors and the adolescent offspring become also more affiliative in interaction with peers. Moreover these adolescent rats also displayed higher OXTR expression in prefrontal cortex. This study reveals that early short periods of MS are able to shape the adolescent rat social behavior and affect the reward circuit. These results also indicate that PND10-14 may be a key period for parental care investment and a critical window for the quality of mother- infant bonding, which suggested that this later period of MS reduces social risk factors.