Chemogenetic inhibition of corticotropin-releasing factor neurons in the central amygdala alters binge-like ethanol consumption in male mice.

Abstract

Repetitive bouts of binge drinking can lead to neuroplastic events that alter ethanol’s pharmacologic effects and perpetuate excessive consumption. The corticotropin-releasing factor (CRF) system is an example of ethanol-induced neuroadaptations that drive excessive ethanol consumption. Our laboratory has previously shown that CRF antagonist, when infused into the central amygdala (CeA), reduces binge-like ethanol consumption. The present study extends this research by assessing the effects of silencing CRF-producing neurons in CeA on binge-like ethanol drinking stemming from “Drinking in the Dark” (DID) procedures. CRF-ires-Cre mice underwent surgery to infuse Gi/o-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus or a control virus into either the CeA or basolateral amygdala (BLA). Gi/o-DREADD-induced CRF-neuronal inhibition in the CeA resulted in a 33% decrease in binge-like ethanol consumption. However, no effect on ethanol consumption was seen after DREADD manipulation in the BLA. Moreover, CeA CRF-neuronal inhibition had no effect on sucrose consumption. The effects of silencing CRF neurons in the CeA on ethanol consumption are not secondary to changes in motor function or anxiety-like behaviors as assessed in the open-field test (OFT). Finally, the DREADD construct’s functional ability to inhibit CRF-neuronal activity was demonstrated by reduced ethanol-induced c-Fos following DREADD activation. Together, these data suggest that the CRF neurons in the CeA play an important role in binge ethanol consumption and that inhibition of the CRF-signaling pathway remains a viable target for manipulating binge-like ethanol consumption.

Inhibiting CRF Projections from the Central Amygdala to Lateral Hypothalamus and Amygdala Deletion of CRF Alters Binge-Like Ethanol Drinking in a Sex-Dependent Manner

“…The injection needle remained in place for 10-15 additional minutes before being withdrawn. This Designer Receptor Exclusive Activated by Designer Drugs (DREADD) has been validated and used to manipulate CRF activity in the central amygdala previously 31–33 . Additionally, bilateral guide cannulas (Plastics One; Roanoke, VA) were implanted into the LH (AP −1.10, ML +/-1.10, DV −5.10; injector: 5MM with 0.5MM projection).…”

“…The injection needle remained in place for 10-15 additional minutes before being withdrawn. This Designer Receptor Exclusive Activated by Designer Drugs (DREADD) has been validated and used to manipulate CRF activity in the central amygdala previously [31][32][33] .…”

Mouse parasubthalamicCrhneurons drive alcohol drinking escalation and behavioral disinhibition

“…In rodent models of AUD combining alcohol self-administration with chronic intermittent exposure (CIE) to alcohol vapor inhalation (9,10), CeA Crh neurons drive alcohol intake escalation in rats (11), but not in mice (12), even though mouse CeA Crh neurons are activated by and promote alcohol binge drinking (13)(14)(15). In the present study, we investigated the role of the parasubthalamic nucleus (PSTN) as a potential source of CRF that may be relevant to the behavioral adaptations induced by CIE in mice.…”