Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala crhr1 expression following a history of dependence.
BACKGROUND
A history of alcohol dependence recruits increased voluntary alcohol intake and sensitivity to stress. Corticotropin-releasing hormone (CRH) has been implicated in this transition, but underlying molecular mechanisms remain unclear.


METHODS
A postdependent state was induced using intermittent alcohol exposure. Experiments were carried out following > or =3 weeks of recovery to eliminate contributions of acute withdrawal. Voluntary alcohol consumption was assessed in a two-bottle, free choice procedure. Behavioral sensitivity to stress was examined using fear suppression of behavior in a punished drinking (Vogel) conflict test. Effects of forced swim stress on voluntary alcohol intake were examined as a function of exposure history. Expression of Crh, Crhr1, and Crhr2 transcripts was analyzed by in situ hybridization histochemistry.


RESULTS
Alcohol drinking was upregulated long-term following a history of dependence. Fear suppression of behavior was selectively potentiated in postdependent animals. This persisted 3 months after alcohol exposure and was reversed by the selective CRH-R1 antagonist 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) (10 mg/kg). Forced swim stress increased alcohol intake in postdependent animals but not in control animals. Behavioral changes were paralleled by an upregulation of Crhr1 transcript expression within basolateral (BLA) and medial (MeA) amygdala and Crh messenger RNA (mRNA) in central amygdala (CeA). In contrast, Crhr2 expression was down in the BLA.


CONCLUSIONS
Neuroadaptations encompassing amygdala CRH signaling contribute to the behavioral phenotype of postdependent animals.
Sommer
Wolfgang H
WH
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health, Bethesda, Maryland 20892-1108, USA.
Rimondini
Roberto
R
Hansson
Anita C
AC
Hipskind
Philip A
PA
Gehlert
Donald R
DR
Barr
Christina S
CS
Heilig
Markus A
MA
D000428:Alcohol Drinking / Q000503:physiopathology*; D000437:Alcoholism / Q000503:physiopathology*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D013312:Stress, Physiological / Q000473:pathology* / Q000503:physiopathology*; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D000099052:CRF Receptor, Type 1
C518650:3-(4-chloro-2-morpholin-4-ylthiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethylimidazo(1,2-b)pyridazine; D011724:Pyridazines; D018019:Receptors, Corticotropin-Releasing Hormone; D013844:Thiazoles; D000099052:CRF Receptor, Type 1