Brown Voles Two Kinds Of Social Contact With Cocaine Reward Interaction And Neural Mechanisms

International studies on reciprocal interactions between social behavior and drug abuse have been becoming a research hotspot. Investigation into the mechanisms underlying such interactions will help us to provide an insight into the understanding for the social rewards and novel thought for prevention and cure of drug addiction in human. Social bonding is a complex social behavior, including formation of attachments to offspring, mates, and peers. Since different forms of social bonding may arise from common or distinct mechanisms, more research is required to establish the nature of drug abuse and social attachment. To our knowledge, the studies examining such reciprocal interaction have mainly focused on the pair bonding or mother-offspring bonding, however, little is known about interaction between drug abuse and other forms of bonding (e.g. father-offspring bonding or peer relationship). Oxytocin (OT) and vasopressin (AVP) have been found to regulate close social attachment and enhance the reward value via activating or mediating dopaminergic reward circuits. It is therefore worth investigating the involvement of OT and AVP in such reciprocal interaction. Here, we have taken an initial step toward end this by establishing the monogamous mandarin vole (Microtus mandarinus) as a model, a highly social rodent species with high levels of paternal care, for investigating the interactions between cocaine reward and father-offspring bonding as well peer bonding, where OT and AVP have also been examined.(1) The father-offspring interaction and recognition in mandarin voles. We measured the behavioural responses between adults (including fathers and strange males) and male pups from preweaning to post-weaning to determine the father-offspring recognition and bonds. We found that levels of pup following behavior directed towards the father or towards strange male peaked on postnatal day (PND)14and PND21, and levels of social investigation peaked on PND28and PND35. Compared to encounters with strange males, PND14-35pups showed higher levels of following behavior when interacting with father. Furthermore, PND21-35pups exhibited lower levels of social investigation towards father. On the other hand, both fathers and unrelated adult males' social investigation behavior peaked during encounters with PND35and PND45pups. Amicable behavior decreased and agonistic behavior increased as the duration of pup age increased. Adults engaged in more amicable behavior (PND21-35) and less agonistic behavior (PND28-45) toward their pups than to unrelated pups of the same age. No significant difference in amicable or agonistic behavior was found for PND60encounters. The results indicate that fathers can recognize their offspring at pups' weaning and keep it up to24days post-weaning, suggesting mandarin voles are capable of forming stable and durable father-offspring bonds, as well, behavioral patterns of adult-pup interactions are associated with pup development and prior familiarity.(2) The reinforcing properties of father-offspring bonding and reciprocal interactions with cocaine in mandarin voles:Firstly, we investigated the reinforcing properties of pups on vole fathers across the postpartum period and examined the interactions between the reinforcing effects of pups and cocaine using a conditioned place preference (CPP) paradigm. We also measured levels of neuronal Fos and tyrosine hydroxylase (TH) expression underlying the preferences of fathers for pups or cocaine. Our data showed that fathers developed strong preferences for pups at various times (PND5-9, PND13-17and PND19-23) without cocaine conditioning. Fathers showed a reduced preference for pups following simultaneous conditioning with injected cocaine. Although they preferred cocaine over PND5-9pups, this preference was not detected for PND13-17pups. Fathers preferring cocaine exhibited an increase in Fos-immunoreactive neurons in the accumbens, medial nucleus of the amygdala, cingulate cortex, medial preoptic area and ventral tegmental area (VTA) and had more TH-IR neurons in the VTA compared to fathers preferring PND5-9pups. These results showed that similar to cocaine, mandarin vole pups elicit significant reward value to their fathers, but that paternal motivation is impaired by cocaine. A preference for cocaine over pups arose in part from the release of more dopamine (DA) and activation of a greater number of neurons within specific reward-associated neuronal subsets.Secondly, we assessed the reinforcing effects of fathers, mothers or cocaine on preweanling pups (including PND13-17or PND19-23). We found that preweanling pups failed to form CPP when conditioned with parents or cocaine, which may be associated with poor capacity of addictive memory and ordinary memory in preweanling pups.(3) Effects of repeated cocaine exposure on paternal behavior and central AVP and OT in mandarin vole fathers. Our data showed that no significant difference was found in levels of locomotivity and anxiety between salt-treated father and cocaine-treated father. However, repeated cocaine exposure resulted in significant attenuation of lick/grooming and contacting behavior and reduction in the expression of AVP and OT in the paraventricular nucleus (PVN). Additionally, more TH-IR neurons in the VTA were found in cocaine-treated father compared to saline control. These results indicate that cocaine elicits treatment greater rewarding effects and alters central OT or AVP levels and thereby disturbs paternal behavior.(4) Effects of peer group on cocaine-induced rewarding properties and behavioral sensitization in female mandarin voles. The results demonstrated that both group housed and single housed females (isolation on PND45) could develope conditioned place preferences for cocaine. Single housed females displayed lower levels of locomotor activity and sociability as well higher levels of anxiety and aggressive behavior than grouped females. Compared to saline control, cocaine-treated grouped females exhibited higher levels of locomotivity and less sociability. However, no cocaine-based differences were found for single housed females in locomotivity and sociability. In addition, we found that repeated cocaine exposure resulted in a reduction of OT-IR in the PVN and AVP-IR in the anterior hypothalamus (AH) in grouped voles compared to saline control. As well, more TH-IR neurons in the PVN and VTA and higher levels of serum corticosterone (CORT) were also found in cocaine-treated females. Taken together, these data illustrate the importance of the peer group on anxiety, sociability and cocaine-induced behavioral sensitization and suggest a potential role of AVP, OT, DA and CORT in the regulation of behavioral sensitization.(5) Effects of different context peer relationship and oxytocin pretreatment on cocaine CPP in female mandarin voles. The final set of studies examinedâ‘ whether the preference for cocaine is variable when conditioning with different context peer (familiar female, strange female and strange male).â‘¡whether the effects of OT pretreatment vary with different context peer reinforcing. Our data showed thatâ‘ female mandarin voles could readily develop cocaine CPP and kept it at least2week;â‘¡The preference for cocaine was shift when simultaneously conditioned with either strange females or strange males, however, this effect was not found when conditioned with familiar femalesâ‘¢OT-pretreated females inverted the cocaine preference when simultaneously conditioning with strange males, this effect was not found when conditioning with familiar or strange females. OTA pretreatment did not interrupt the expression of the preference when simultaneously conditioning with strange males and cocaine. These findings suggest that peer interaction may alter the vulnerabilities of cocaine abuse and the degree of alteration is associated with the context of peer relationship. Social context interacts with OT and contribute to attenuating cocaine's rewarding effects. The effects of the OT in modulating drug abuse may not necessarily be as a direct action but occur through indirect interactions with social bonding.Collectively, mandarin voles may form long-term father-offspring recognition and colose father-offspring bonding, furthermore, this bonding has high reward value on father. Cocaine exposure affects paternal motivation or behavior. Besides, peer group has important influence on social behavior and cocaine-induced behavioral sensitization. On the other hand, father-offspring bonds or peer interaction can attenuate the rewarding effects of cocaine. The neural mechanisms underlying this interaction are associated with the activation of specific neurons within reward-associated brain region, with a mediating of OT, AVP and DA.