Corticotropin Releasing Factor Type 1 and 2 Receptor Signaling in the Medial Prefrontal Cortex Modulates Binge-Like Ethanol Consumption in C57BL/6J Mice

Abstract

Corticotropin releasing factor (CRF) signaling via limbic CRF1 and 2 receptors (CRF1R and CRF2R, respectively) is known to modulate binge-like ethanol consumption in rodents. Though CRF signaling in the medial prefrontal cortex (mPFC) has been shown to modulate anxiety-like behavior and ethanol seeking, its role in binge ethanol intake is unknown. Here, we used “drinking-in-the-dark” (DID) procedures in male and female C57BL/6J mice to address this gap in the literature. First, the role of CRF1R and CRF2R signaling in the mPFC on ethanol consumption was evaluated through site-directed pharmacology. Next, we evaluated if CRF1R antagonist reduction of binge-intake was modulated in part through CRF2R activation by co-administration of a CRF1R and CRF2R antagonist. Intra-mPFC inhibition of CRF1R and activation of CRF2R resulted in decreased binge-like ethanol intake. Further, the inhibitory effect of the CRF1R antagonist was attenuated by co-administration of a CRF2R antagonist. We provide novel evidence that (1) inhibition of CRF1R or activation of CRF2R in the mPFC reduces binge-like ethanol intake; and (2) the effect of CRF1R antagonism may be mediated via enhanced CRF2R activation. These observations provide the first direct behavioral pharmacological evidence that CRF receptor activity in the mPFC modulates binge-like ethanol consumption.

Bi-directional control of a prelimbic somatostatin microcircuit decreases binge alcohol consumption

“…Additionally, the current study have yet to address the involvement of neuropeptide signaling, especially that of somatostatin, in modulating alcohol consumption. Previous reports have demonstrated that DID reduces NPY expression in the PL, and conversely intra-PL administration of NPY1 agonist and CRF1 antagonist could reduce alcohol binge drinking (17,16). Here we did not assess whether the effects of hM3Dq-induced excitation of PL SST neurons on alcohol binge drinking could be partially attributed to SST peptide release and SST signaling in the PL.…”

“…Intragastric administration of high ethanol doses in rats (5 g/kg) diminished GABAA receptor-mediated inhibitory currents in PFC layer 5/6 pyramidal neurons accompanied by a reduction in expression of the α1 GABAA receptor subunit (50). As pyramidal neurons are the main group of projection neurons from the PL, providing strong glutamatergic input to associated cortical regions (6,7), nucleus accumbens (10), ventral tegmental area (51) and amygdala (52), which are critically involved in emotional and intra-PL administration of NPY1 agonist and CRF1 antagonist could reduce alcohol binge drinking (17,16). Here we did not assess whether the effects of hM3Dq-induced excitation of PL SST neurons on alcohol binge drinking could be partially attributed to SST peptide release and SST signaling in the PL.…”

“…The prelimbic (PL) cortex is a key brain region in addiction and substance abuse (6,7), with projections to many limbic areas (7) including the bed nucleus of the stria terminalis (8,9) and the nucleus accumbens (10) to provide top-down regulation of affective and motivational behaviors. It receives excitatory glutamate afferents from the basolateral amygdala (11,12), and the hippocampus (13), and inhibitory control from a variety of subpopulations of gamma aminobutyric acide (GABA) neurons that express peptidergic markers and receptors such as dynorphin (DYN; 14), corticotropin-releasing factor (CRF; (15,16)), neuropeptide-y (NPY;(17)) and somatostatin (SST; (18,19)). Neurotransmission within the PL is known to be altered in multiple animal models of alcohol exposures, including binge drinking (20) and vapor ethanol exposure (21,22).…”

Turning the ′Tides on Neuropsychiatric Diseases: The Role of Peptides in the Prefrontal Cortex

“…Orozco-Cabal and colleagues demonstrated that chronic cocaine results in increased functionality of presynaptic CRF-R2 and loss of postsynaptic function of CRF-R1 in the PFC of male rats. Moreover, an interesting, recent study found that inhibition of CRF-R2 and separate activation of CRF-R1 in the PFC both resulted in decreased binge-like ethanol consumption in male and female C57BL/6J mice, confirming that much like in the CEA, these two receptors may play opposite roles in substance use (Robinson et al, 2019b). In this work, Robinson et al (2019b) demonstrated that co-administration of CRF-R1 and CRF-R2 antagonists attenuated the behavioral effect of CRF-R1 antagonist.…”

“…Moreover, an interesting, recent study found that inhibition of CRF-R2 and separate activation of CRF-R1 in the PFC both resulted in decreased binge-like ethanol consumption in male and female C57BL/6J mice, confirming that much like in the CEA, these two receptors may play opposite roles in substance use (Robinson et al, 2019b). In this work, Robinson et al (2019b) demonstrated that co-administration of CRF-R1 and CRF-R2 antagonists attenuated the behavioral effect of CRF-R1 antagonist. This suggests that decreased binge-like ethanol drinking resulting from inhibition of CRF-R1 may result from increased activation of the CRF-R2, providing strong evidence in support of an important role of both CRF-R1 and CRF-R2 in the PFC in regulating substance abuse.…”