title: Early life stress is a risk factor for excessive alcohol drinking and impulsivity in adults and is mediated via a CRF/GABA(A) mechanism.
abstract: Childhood stress and trauma are associated with substance use disorders in adulthood, but the neurological changes that confer increased vulnerability are largely unknown. In this study, maternal separation (MS) stress, restricted to the pre-weaning period, was used as a model to study mechanisms of protracted effects of childhood stress/traumatic experiences on binge drinking and impulsivity. Using an operant self-administration model of binge drinking and a delay discounting assay to measure impulsive-like behavior, we report that early life stress due to MS facilitated acquisition of binge drinking and impulsivity during adulthood in rats. Previous studies have shown heightened levels of corticotropin releasing factor (CRF) after MS, and here, we add that MS increased expression levels of GABA(A) α2 subunit in central stress circuits. To investigate the precise role of these circuits in regulating impulsivity and binge drinking, the CRF1 receptor antagonist antalarmin and the novel GABA(A) α2 subunit ligand 3-PBC were infused into the central amygdala (CeA) and medial prefrontal cortex (mPFC). Antalarmin and 3-PBC at each site markedly reduced impulsivity and produced profound reductions on binge-motivated alcohol drinking, without altering responding for sucrose. Furthermore, whole-cell patch-clamp studies showed that low concentrations of 3-PBC directly reversed the effect of relatively high concentrations of ethanol on α2β3γ2 GABA(A) receptors, by a benzodiazepine site-independent mechanism. Together, our data provide strong evidence that maternal separation, i.e. early life stress, is a risk factor for binge drinking, and is linked to impulsivity, another key risk factor for excessive alcohol drinking. We further show that pharmacological manipulation of CRF and GABA receptor signaling is effective to reverse binge drinking and impulsive-like behavior in MS rats. These results provide novel insights into the role of the brain stress systems in the development of impulsivity and excessive alcohol consumption.
authors.affiliation: a Department of Anatomy , Howard University College of Medicine , Washington , DC , USA .|b Department of Psychiatry and Behavioral Sciences , Howard University College of Medicine , Washington , DC , USA .
authors.forename: Marjorie C
authors.initials: MC
authors.lastname: Gondré-Lewis
authors.affiliation: b Department of Psychiatry and Behavioral Sciences , Howard University College of Medicine , Washington , DC , USA .
authors.forename: Kaitlin T
authors.initials: KT
authors.lastname: Warnock
authors.affiliation: a Department of Anatomy , Howard University College of Medicine , Washington , DC , USA .
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: b Department of Psychiatry and Behavioral Sciences , Howard University College of Medicine , Washington , DC , USA .
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
authors.affiliation: b Department of Psychiatry and Behavioral Sciences , Howard University College of Medicine , Washington , DC , USA .
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bell
authors.affiliation: c Department of Psychiatry , University of Mainz , Mainz , UK .
authors.forename: Holger
authors.initials: H
authors.lastname: Rabe
authors.affiliation: d Department of Chemistry and Biochemistry , University of Wisconsin-Milwaukee , Milwaukee , WI , USA , and.
authors.forename: Veera Venkata Naga Phani Babu
authors.initials: VV
authors.lastname: Tiruveedhula
authors.affiliation: d Department of Chemistry and Biochemistry , University of Wisconsin-Milwaukee , Milwaukee , WI , USA , and.
authors.forename: James
authors.initials: J
authors.lastname: Cook
authors.affiliation: c Department of Psychiatry , University of Mainz , Mainz , UK .
authors.forename: Hartmut
authors.initials: H
authors.lastname: Lüddens
authors.affiliation: e Department of Pharmacology and Experimental Therapeutics , University of Maryland School of Medicine , Baltimore , MD , USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Aurelian
authors.affiliation: b Department of Psychiatry and Behavioral Sciences , Howard University College of Medicine , Washington , DC , USA .
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D007175:Impulsive Behavior / Q000502:physiology*; D008297:Male; D008426:Maternal Deprivation; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D012307:Risk Factors; D012646:Self Administration; D013315:Stress, Psychological / Q000378:metabolism*; D014805:Vitamin B 12 / Q000031:analogs & derivatives; D000099052:CRF Receptor, Type 1
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D011963:Receptors, GABA-A; C103016:antalarmin; C413332:factor A; D000431:Ethanol; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D014805:Vitamin B 12
keywords: 3-PBC; GABA; alpha-2 receptor; antalarmin; benzodiazepine; central amygdala; corticotropin releasing factor; limbic; medial prefrontal cortex; neuropsychiatric