Early Life Stress as a Risk Factor for Substance use Disorders: Clinical and Neurobiological Substrates

Abstract

Background:Early Life Stress (ELS) can profoundly influence an individual's genotype and phenotype. Effects of ELS can manifest in the short-term, late life and even in subsequent generations. ELS activate corticotrophin releasing factor (CRF); CRF influences drug seeking and addiction. The aim of this study was to examine the effects of endogenous elevated levels of CRF on addiction.Materials and Methods:Inducible forebrain over-expression of CRF mice (tetop-CRH x CaMKII-tTA) was used for this study. Morphine (10 mg/kg) was administered every other day for 10 days or with increasing doses of morphine: 20, 40, 60, 80, 100, and 100 mg/kg. The behavioral trials including morphine sensitization, Somatic Opiate Withdrawal Symptoms (SOWS) were conducted in a single, open field, activity. After behavioral trial, animals were perfused for immunohistochemistry analysis.Results:CRF-over expressed (CRF-OE) mice showed increase in morphine sensitization and withdrawal symptoms after morphine administration compared to wild type (WT) mice. The two-way ANOVA in the morphine sensitization study showed a significant effect of treatment (P<0.05) and genotype for distance traveled (P<0.01). In the SOWS study, opiate withdrawal symptoms such as rearings, circling behavior, grooming, and jump in CRF-OE were amplified in parallel to WT mice. In the immunohistochemistry study, pro-dynorphine (PDYN) expression was increased after morphine administration in both amygdala and nucleus accumbens (NAcc).Conclusions:CRF-OE in the forebrain increases the sensitization and withdrawal symptoms in morphine treated mice. On exposure to morphine, in CRF-OE mice the PDYN protein expression was increased as compared to WT mice in the amygdala and NAcc.

An Overview of Mindfulness-Oriented Addiction and Pain Recovery

“…A review of RCT data shows that mindfulness interventions for SUDs are at least as effective as other evidence-based interventions and perhaps particularly helpful in patients with comorbid anxiety or depression (Korecki et al, 2020). These findings align with our prior studies highlighting the link among chronic stress, CNS dysregulation, and SUDs (Varghese et al, 2015; Varghese et al, 2019). Likewise, we have previously published on the benefit of mindfulness-based treatments in patients with SUDs and other psychiatric illnesses (Varghese et al, 2014; Varghese et al, 2021).…”

Early Life Stress and Substance Use Disorders: Underlying Neurobiology and Pathways to Adverse Outcomes

“…Fahlke et al, (2000) found that non-human primates stressed in early life (i.e., maternal deprivation) exhibited elevated cortisol levels in response to stressors, which was associated with increased alcohol self-administration (Fahlke et al, 2000). A hyperactive stress response is also linked to increased drug sensitivity and greater withdrawal symptoms in preclinical models (Varghese, Montalvo-Ortiz, Csernansky, Eiger, Herrold, Koola, et al, 2015). These studies converge to suggest that dysregulation of the HPA axis (both blunting and hyperactivity), in general, may serve as a biomarker for risky substance use behaviors, as well as a pre-morbid risk factor for developing SUDs.…”

Association between RMTg Neuropeptide Genes and Negative Effect during Alcohol Withdrawal in Mice

“…For example, CRF overexpression leads to increased PDYN protein in mice after morphine administration [ 86 ]. Moreover, while certain neuropeptides are linked to “pro-stress” responses and alcohol addiction, their variation during alcohol withdrawal is not uniform.…”