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.


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.
Department of Mental Health, Captain James A. Lovell Federal Health Care Center, North Chicago, IL 60064, USA ; Departments of Psychiatry and Behavioral Sciences, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
Sajoy Purathumuriyil
SP
Varghese
Departments of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Janitza L
JL
Montalvo-Ortiz
Departments of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
John G
JG
Csernansky
Departments of Psychiatry and Behavioral Sciences, Jesse Brown Veterans Affairs Medical Center, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
Rodney I
RI
Eiger
Departments of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA ; Department of Psychiatry and Behavioral Sciences, Center of Innovation for Complex Chronic Healthcare, Edward Hines Jr., Veteran Affairs Hospital, Hines, IL 60141, USA.
Amy A
AA
Herrold
Department of Psychiatry, Clinical Research Program, Sheppard Pratt Health System, University of Maryland School of Medicine, Baltimore, MD 21204, USA.
Maju Mathew
MM
Koola
Departments of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Hongxin
H
Dong
Corticotrophin-releasing factor; early life stress; morphine; opioid use disorder; substance use disorders