Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes

Abstract

Experiencing some early life adversity can have an “inoculating” effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared to controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.

Impact of Early Life Stress on Reward Circuit Function and Regulation

“…However, LBN males administered less of a low dose of morphine than control reared males, and administered less morphine on a progressive ratio schedule, suggesting they were less motivated to take morphine at this dose. Consistent with a protective effect of LBN against this addiction-related phenotype in males, LBN reduced impulsive choice, a behavior associated with substance use disorders and mediated, in part, by the NAc ( 124 – 126 ). In contrast, no effects of LBN on motivation for morphine or impulsive choice were observed in females ( 124 ).…”

“…Males were not tested, so it is unclear whether they would also display this vulnerability. Another study including both male and female Long-Evans rats, similarly, found no effect of LBN on acquisition of morphine self-administration in females ( 124 ). However, LBN males administered less of a low dose of morphine than control reared males, and administered less morphine on a progressive ratio schedule, suggesting they were less motivated to take morphine at this dose.…”

The Paraventricular Thalamus: A Potential Sensor and Integrator of Emotionally Salient Early-Life Experiences

“…Preclinical studies indicate increased drug-seeking behavior and palatable food consumption in females (Machado et al, 2013;Levis et al, 2019) and a reduction in these behaviors in males (Bolton et al, 2018b;Ordoñes Sanchez et al, 2021). In both sexes, little is known of the contribution of the PVT in influencing reward and stress-related behaviors following earlylife emotionally salient experiences, because studies of the PVT's role in these changes were performed in adults.…”

“…ELA decreases social play, palatable food consumption, and drug-seeking in males and enhances fear expression in both sexes. These behavioral consequences may be mediated by activity in the PVT (Caldji et al, 1998;Arp et al, 2016;Molet et al, 2016;Bolton et al, 2018aBolton et al, ,b, 2019Levis et al, 2019;Ordoñes Sanchez et al, 2021).…”

Adolescent Stress Confers Resilience to Traumatic Stress Later in Life: Role of the Prefrontal Cortex

“…In general, chronic stress during development is associated with the emergence of pathology, particularly when occurring during early life (de Kloet et al, 2005;Heim et al, 2008;Oitzl et al, 2010;Riboni and Belzung, 2017;Tost et al, 2015). However, mild to moderate stress during some development periods may also promote an adaptive response to adverse situations later in life, contributing to stress resilience (Ordoñes Sanchez et al, 2021;Ricon et al, 2012;Romeo, 2015;Schmidt, 2011;Southwick and Charney, 2012). Previous work from our lab indictates that chronic variable stress (CVS) during adolescence can evoke specific effects later in life that may determine either risk or resilience (Cotella et al, 2020(Cotella et al, , 2019.…”