Social stressors such as depressed maternal care and family conflict are robust challenges which can have long-term physiological and behavioral effects on offspring and future generations. The current study investigates the transgenerational effects of an ethologically relevant chronic social stress on the behavior and endocrinology of juvenile and adult rats. Exposure to chronic social stress during lactation impairs maternal care in F0 lactating dams and the maternal care of the F1 offspring of those stressed F0 dams. The overall hypothesis was that the male and female F2 offspring of stressed F1 dams would display decreased social behavior as both juveniles and adults and that these behavioral effects would be accompanied by changes in plasma corticosterone, prolactin, and oxytocin. Both the female and male F2 offspring of dams exposed to chronic social stress displayed decreased social behavior as juveniles and adults, and these behavioral effects were accompanied by decreases in basal concentrations of corticosterone in both sexes, as well as elevated juvenile oxytocin and decreased adult prolactin in the female offspring. The data support the conclusion that social stress has transgenerational effects on the social behavior of the female and male offspring which are mediated by changes in the hypothalamic–pituitary–adrenal axis and hypothalamic–pituitary–gonadal axis. Social stress models are valuable resources in the study of the transgenerational effects of stress on the behavioral endocrinology of disorders such as depression, anxiety, autism, and other disorders involving disrupted social behavior.

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Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a chemogenetic tool commonly-used to manipulate rodent brain circuit activity. The most widely-used synthetic ligand for DREADDs is Clozapine-N-oxide (CNO). However, CNO is back-metabolized to clozapine, which itself activates numerous endogenous receptors and therefore may influence rodent behavior. To eliminate potential off-target effects of CNO, a new DREADD agonist, Compound 21 (C21), has been proposed as an alternative as it lacks active metabolites. The literature is mixed on whether acute administration of CNO or C21 changes mouse behavior. In contrast, there is no substantial literature on whether chronic administration of CNO or C21 changes mouse behavior. Here we tested whether chronic injections of these two distinct DREADD agonists change key behaviors in non-designer receptor-expressing mice relative to Vehicle (Veh)-injected control mice. Mice (CamKIIα-icre males) were injected i.p. with Veh (0.5% dimethyl sulfoxide in 0.9% saline, 5ml/kg), CNO (0.2mg/ml, 1mg/kg), or C21 (0.2mg/ml, 1mg/kg) 5 days a week for 16 weeks. All three groups had similar weight gain over the 16 week-experiment, and showed similar measures in behaviors assessed during week 3 (beam breaks in a 30-min locomotion task, time in center of open field or open arms of elevated plus maze) and week 14-16 (ambulatory distance during 240-min activity monitoring, percent marbles buried, grooming time during the sucrose splash test). These data show chronic injections of CNO or C21 do not affect key behaviors as compared to chronic injections of Veh, and may be helpful for behavioral neuroscientists when study design requires repeated injection of these DREADD agonists. Highlights Acute injection of CNO changes behavior of non-DREADD-expressing mice It’s not known if chronic CNO or alternative agonist C21 also changes mouse behavior DREADD agonists or Veh were given chronically to non-DREADD-expressing mice Mice given Veh, CNO, or C21 were similar in regard to locomotion and other behaviors Thus CNO and C21 can be injected repeatedly without non-specific behavior effects

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