Effects of Early Life Stress on Addiction Vulnerability are Sex Specific and Driven by Immune Signals

• In Event: 1-015 - Translational Perspectives on the Role of Inflammation in Brain Development and Function

Integrative Statement

Childhood adversity in humans can increase later vulnerability to substance abuse disorders (Young et al., 1997). However, neurobiological processes underlying drug reward and addiction involve multiple contributing factors, including individual differences. Indeed, studies reveal sex-specific effects of childhood adversity on psychopathology, with males more prone to externalizing, (e.g., drug addiction) and females more prone to internalizing (e.g., depression), symptomatology (Grasso et al., 2013). Additionally, several stress-attributable disorders involve neuroimmune signaling, and inflammatory molecules play a significant role in how drugs of abuse affect the brain (Cui et al., 2014). Early life stress disrupts normative development of the immune system and impacts neuronal circuits - particularly during adolescence (Crews et al., 2011; Ganguly and Brenhouse, 2015). While converging evidence suggests a link between early life stress, neuroimmune changes, and increased addiction-like behavior in adolescence, the mechanistic underpinnings of this relationship are not well-understood. The conditioned place preference (CPP) paradigm is used in rodent models to study the associative rewarding effects of abused drugs, an important component of drug addiction vulnerability (Prus et al., 2009). The glutamatergic system - and AMPA receptors (AMPARs) in particular - is involved in cocaine CPP memory retrieval (Cervo and Samanin, 1995). In rodents, early stressors such as repeated maternal separation (MS) impact AMPA activity in the prefrontal cortex (PFC) and nucleus accumbens (NAc) (Chocyk et al., 2013; Vrettou et al., 2017), regions involved in drug-cue association after cocaine conditioning. Notably, previous reports suggest that the pro-inflammatory cytokine tumor necrosis factor (TNF) regulates AMPAR subunit composition; increased TNF levels are reported to reduce GluA2-positive AMPARs (Stellwagen et al., 2005). Since MS can reportedly elevate adolescent TNF levels (doPrado et al., 2015), the stressor may therefore alter AMPAR subunit composition via neuroimmune signaling, thereby affecting cocaine-induced CPP. We tested the specific role of soluble TNF in MS-induced GluA2 loss and cocaine-induced CPP with pharmacological disruption of TNF signaling. TNF gene expression was elevated in both PFC and NAc of MS males, but not females. GluA2 expression was reduced in both regions in MS male rats, and systemic treatment with either ibudilast - a phosphodiesterase inhibitor, or XPro1595 - a blood-brain barrier-permeable blocker of soluble TNF - reversed such loss. MS males also formed greater preference for a cocaine-paired environment, the expression of which returned to control levels after XPro1595 administration. These data suggest a sex-specific mechanistic link between TNF signaling and changes in GluA2 expression and drug-cue conditioning, thereby providing further evidence for a role of MS and neuro-immune activity in cortical and striatal AMPAR changes. Moreover, manipulation of the TNF signaling pathway represents a novel approach for influencing response to rewarding effects of drug use.

Authors

• Prabarna Ganguly, Northeastern University
  Non-Presenting Author

• June Rowe, Northeastern University
  Non-Presenting Author

• Camila Demaestri, Northeastern University
  Non-Presenting Author

• Jennifer Honeycutt, Northeastern University
  Non-Presenting Author

• Heather Brenhouse, Northeastern University
  Presenting Author