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

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.