Drug exposure during adolescence, when the "reward" circuitry of the brain is developing, can permanently impact reward-related behavior. Epidemiological studies show that opioid treatment during adolescence, such as pain management for a dental procedure or surgery, increases the incidence of psychiatric illness including substance use disorders. Moreover, the opioid epidemic currently in the United States is affecting younger individuals raising the impetus to understand the pathogenesis of the negative effects of opioids. One reward-related behavior that develops during adolescence is social behavior. We previously demonstrated that social development occurs in rats during sex-specific adolescent periods: early to mid-adolescence in males (postnatal day (P)30-40) and pre-early adolescence in females (P20-30). We thus hypothesized that morphine exposure during the female critical period would result in adult sociability deficits in females, but not males, and morphine administered during the male critical period would result in adult sociability deficits in males, but not females. We found that morphine exposure during the female critical period primarily resulted in deficits in sociability in females, while morphine exposure during the male critical period primarily resulted in deficits in sociability primarily in males. However, depending on the test performed and the social parameter measured, social alterations could be found in both sexes that received morphine exposure at either adolescent stage. These data indicate that when drug exposure occurs during adolescence, and how the endpoint data are measured, will play a large role in determining the effects of drug exposures on social development.
Social networks and support are integral to health and wellness across the lifespan, and social engagement may be particularly important during aging. However, social behavior and social cognition decline naturally during aging across species. Social behaviors are in part supported by the reward circuitry, a network of brain regions that develops during adolescence. We published that male and female rats undergo adolescent social development during sex-specific periods, pre-early adolescence in females and early-mid adolescence males. Although males and females have highly dimorphic development, expression, and valuation of social behaviors, there is relatively little data indicating whether social aging is the same or different between the sexes. Thus, we sought to test two hypotheses: (1) natural social aging will be sex-speciifc, and (2) social isolation stress restricted to sex-specific adolescent critical periods for social development would impact social aging in sex-specific ways. To do this, we bred male and female rats in-house, and divided them randomly to receive either social isolation for one week during each respective critical period, or no manipulation. We followed their social aging trajectory with a battery of five tests at 3, 7, and 11 months of age. We observed clear social aging signatures in all tests administered, but sex differences in natural social aging were most robustly observed when a familiar social stimulus was included in the test. We also observed that adolescent isolation did impact social behavior, in both age-independent and age-dependent ways, that were entirely sex-specific.
Opioids have long been used for clinical pain management, but also have addictive properties that have contributed to the ongoing opioid epidemic. While opioid activation of opioid receptors is well known to contribute to reward and reinforcement, data now also suggest that opioid activation of immune signaling via toll-like receptor 4 (TLR4) may also play a role in addiction-like processes. TLR4 expression is enriched in immune cells in peripheral organs and blood and in the nervous system is primarily expressed in microglia, the resident immune cells of the central nervous system. In peripheral immune cells, morphine is repeatedly shown to decreases immune activation and phagocytosis in vivo and in vitro. Phagocytosis is an important immune effector that serves to clear damage, debris, and infection. Unlike peripheral immune cells, the effect of morphine on microglia is less well studied. Morphine is reported to both increase and decrease microglial phagocytosis. Several different factors contribute to microglial phagocytic activity, including sex, region, and local microglial density. We hypothesized that morphine increases phagocytic activity in microglia, but in a density-, dose-, region-, and sex-dependent manner ex vivo. To test this, we isolated microglia from adult male and female rat cortex and striatum and plated them ex vivo at a relatively low or high density. Microglia were incubated with neutral fluorescent microbeads to stimulate phagocytosis in the presence of one of four morphine doses. We found that brain region of origination and plating density, but not sex, impacted microglial phagocytosis at baseline. These heterogenous properties further diverge when morphine is applied causing emergence of effects not observed at baseline, maintenance of some baseline effects, and disappearance of effects observed at baseline. Further work is necessary to identify the precise interactions and signaling that is dominant in different sex, region, and density contexts to better understand the complex effects of opioids on microglial immunoregulation.
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