Table 2.
Small-molecule and genetic manipulations of the CRF system in alcohol use disorder.
| Target | Manipulation | Result | Reference |
|---|---|---|---|
| CRF | Genetic KO | KO mice consumed more alcohol than WT | (Olive et al., 2002) |
| CRF1 receptor | Genetic KO | KO mice did not exhibit increase in alcohol self-administration during withdrawal | (Chu et al., 2007) |
| KO mice exhibited decrease in HPA recruitment, measured by corticosterone | (Pastor et al., 2008) | ||
| KO mice exhibited increase in alcohol intake and increase in withdrawal-included alcohol self-administration | (Molander et al., 2012) | ||
| CRF2 receptor | Genetic KO | Alcohol intake was slightly reduced | (Sharpe et al., 2005) |
| When stressed, KO animals consumed more alcohol than WT | (Sillaber et al., 2002) | ||
| Alcohol intake was slightly reduced, but reduction was not maintained throughout the study | (Kaur et al., 2012) | ||
| CRF1/CRF2 receptor | Genetic KO | KO mice did not exhibit alcohol-induced locomotor sensitization but exhibited decrease in HPA axis recruitment, measured by corticosterone in response to alcohol intake | (Pastor et al., 2008) |
| Repeated forced swim increased alcohol intake | (Pastor et al., 2011) | ||
| CRF-BP | Genetic KO | No change in alcohol intake in mouse DID paradigm | (Ketchesin and Seasholtz, 2015) |
| CRF | Genetic overexpression | KO mice consumed less alcohol than WT | (Palmer et al., 2004) |
| CRF1/CRF2 receptor | Agonist | Decrease in alcohol intake during two-bottle choice (i.c.v.) | (Bell et al., 1998) |
| Decrease in alcohol intake in dependent vapor-exposed rats (i.c.v.) | (Thorsell et al., 2005) | ||
| Increase in withdrawal-induced stress, measured by social interaction (i.c.v., intra-CeA, intra-BNST) | (Huang et al., 2010) | ||
| Alcohol-withdrawn animals spent less time on the open arms of the elevated plus maze, indicating increase in the stress response (i.c.v.) | (Zhao et al., 2013) | ||
| Decrease in social interaction as a measure of withdrawal-induced anxiety (i.c.v.) | (Overstreet et al., 2004b) | ||
| Induction of alcohol reinstatement (i.c.v., intra-MRN) | (Le et al., 2002) | ||
| CRF1/CRF2 receptor | Antagonist (D-Phe CRF12/41) | Decrease in anxiety-like behavior (i.c.v.) | (Valdez et al., 2003) |
| Decrease in footshock-induced reinstatement (i.c.v.) | (Liu and Weiss, 2003) | ||
| Decrease in alcohol-seeking behavior in dependent rats (intra-CeA) | (Funk et al., 2006) | ||
| Decrease in alcohol withdrawal-induced alcohol self-administration (intra-CeA) | (Finn et al., 2007) | ||
| Lower elevation of brain reward thresholds during alcohol withdrawal (i.c.v.) | (Bruijnzeel et al., 2010) | ||
| CRF1 receptor | Antagonist (MTIP) | Decrease in anxiety-like behavior in elevated plus maze during acute alcohol withdrawal (i.p.) | (Gehlert et al., 2007) |
| CRF2 receptor | Agonist (Ucn3) | Decrease in alcohol intake after escalation (i.c.v.) | (Sharpe and Phillips, 2009) (Valdez et al., 2004) |
| Increase in drinking in control animals (intra-CeA) | (Funk et al., 2007) | ||
| CRF2 receptor | Antagonist (astressin-2B) | Decrease in alcohol intake (intra-VTA) No effect (intra-CeA) | (Albrechet-Souza et al., 2015) |
| CRF-BP | Antagonist (CRF[6–33]) | ||
| CRF1/CRF2 receptor | Antagonist (α-helical CRF) | Decrease in anxiety-like behavior in elevated plus maze during acute alcohol withdrawal (i.c.v.) | (Baldwin et al., 1991) |
| No change in anxiogenic-like effect of acute alcohol withdrawal (i.c.v.) | (Rassnick et al., 1993) | ||
| Increase in alcohol preference in low-alcohol-preferring mice but not high-alcohol-preferring mice (i.c.v.) | (O'Callaghan et al., 2005) | ||
| Decrease in alcohol intake in DID paradigm (i.c.v.) | (Lowery and Thiele, 2010) | ||
| Decrease in anxiety-like behavior in elevated plus maze during acute alcohol withdrawal (intra-CeA) | (Rassnick et al., 1993) | ||
| CRF1 receptor | Antagonist (LWH-63) | Decrease in withdrawal-induced alcohol self-administration | (Sabino et al., 2006) |
| Decreases in alcohol intake and blood alcohol levels (s.c.) | (Lowery-Gionta et al., 2012) | ||
| CRF1 receptor | Antagonist (antalarmin) | Decrease in acquisition of alcohol drinking and alcohol consumption (i.p.) | (Lodge and Lawrence, 2003) |
| Decrease in alcohol self-administration and blockade of footshock-induced reinstatement in Marchigian Sardinian alcohol-preferring rats (i.p.) | (Hansson et al., 2006) | ||
| Decrease in withdrawal-induced alcohol self-administration (i.p.) | (Chu et al., 2007) | ||
| Decrease in withdrawal-induced alcohol self-administration in dependent but not nondependent rats (i.p.) | (Funk et al., 2007) | ||
| Decrease in stress (yohimbine)-induced alcohol self-administration (i.p.) | (Marinelli et al., 2007) (Yang et al., 2008) (Ayanwuyi et al., 2013) |
||
| CRF1 receptor | Antagonist (CP-154,526) | Decrease in alcohol withdrawal-induced stress, measured by social interaction (i.p.) | (Overstreet et al., 2004b) (Overstreet et al., 2004a) (Breese et al., 2005) (Wills et al., 2009) |
| Decrease in swim stress-induced alcohol intake in mice (i.p.) | (Lowery et al., 2008) | ||
| CRF1 receptor | Antagonist (CP-37,395) | Decrease in alcohol intake (i.p.) | (Giardino and Ryabinin, 2013) (Simms et al., 2014) |
| CRF1 receptor | Antagonist (CRA-1000) | Decrease in alcohol withdrawal-induced stress, measured by social interaction (i.p.) | (Knapp et al., 2004) |
| CRF1 receptor | Antagonist (MJL-1–109-2) | Decrease in withdrawal-induced alcohol self-administration in dependent but not nondependent rats (i.p.) | (Funk et al., 2007) |
| CRF1 receptor | Antagonist (MPZP) | Decrease in withdrawal-induced alcohol self-administration in dependent but not nondependent rats (i.p.) | (Gilpin et al., 2008) |
| Decrease in withdrawal-induced alcohol self-administration in dependent but not nondependent rats (s.c.) | (Richardson et al., 2008) | ||
| CRF-BP | Antagonist (CRF[6–33]) | Decrease in alcohol intake (intra-VTA but not intra-CeA) | (Albrechet-Souza et al., 2015) |
BP, binding protein; KO, knockout; WT, wildtype; CeA, central nucleus of the amygdala; BNST, bed nucleus of the stria terminalis; VTA, ventral tegmental area; DID, drinking-in-the-dark; HPA, hypothalamic-pituitary-adrenal; MRN, median raphe nucleus.