J Pharmacol Exp Ther. 2025 Sep 12;392(10):103710. doi: 10.1016/j.jpet.2025.103710. Online ahead of print.
ABSTRACT
Early life stress (ELS) refers to maltreatment, deprivation, and other traumatic events experienced early in life. This form of uncontrollable stress is widely acknowledged to cause long-term maladaptive changes in the developing nervous system, resulting in an increased risk for affective mood disorders with lasting impacts on mnemonic and other cognitive functions. ELS is often investigated in mice and rats by presenting stressors either during the perinatal period, repeatedly separating offspring from maternal care prior to the start of adolescence, or interventions involving maternal neglect. As discussed in this article, early social and environmental variables have profound and persistent effects on brain neurochemistry, which subsequently affect the pharmacological actions of psychoactive drugs, often in a sexually dimorphic manner. We first review the behavioral and neurochemical effects of ELS in rodents within the context of the research domain criteria framework, with a specific focus on different ELS protocols. We then discuss how ELS affects the pharmacological actions of psychoactive drugs that primarily target the brain monoaminergic, glutamatergic, and endocannabinoid systems. Our analysis demonstrates that ELS is a powerful modulator of neuropsychiatric drug action with implications for therapeutic efficacy in a range of affective and cognitive disorders in humans. SIGNIFICANCE STATEMENT: This review provides a comprehensive survey of salient research findings on the behavioral and neurochemical effects of early life stress (ELS) in experimental animals. Our analysis is informed with reference to the research domain criteria framework to evaluate the broader impacts of ELS on mental health. In addition, we discuss the effects of neuropharmacological agents to prevent or reverse the effects of ELS in adulthood.
PMID:41045826 | DOI:10.1016/j.jpet.2025.103710
