Control of chronic excessive alcohol drinking by genetic manipulation of the Edinger–Westphal nucleus urocortin-1 neuropeptide system

Abstract

Midbrain neurons of the centrally projecting Edinger–Westphal nucleus (EWcp) are activated by alcohol, and enriched with stress-responsive neuropeptide modulators (including the paralog of corticotropin-releasing factor, urocortin-1). Evidence suggests that EWcp neurons promote behavioral processes for alcohol-seeking and consumption, but a definitive role for these cells remains elusive. Here we combined targeted viral manipulations and gene array profiling of EWcp neurons with mass behavioral phenotyping in C57BL/6 J mice to directly define the links between EWcp-specific urocortin-1 expression and voluntary binge alcohol intake, demonstrating a specific importance for EWcp urocortin-1 activity in escalation of alcohol intake.

The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?

“…The first is that, as mentioned earlier, CRFRs respond to multiple neuropeptides in vivo . CRFR1 for example, can also be activated by UCN1 (Henckens et al, 2016), a peptide also implicated in alcohol intake (Giardino et al., 2017). Because it is likely that endogenous CRF and UCN1 release are controlled differently, CRFR1 may be recruited by these endogenous ligands in distinct circuits for different ends.…”

Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking

“…Interestingly, the role of EWcp Ucn1 neurons in alcohol drinking seems to differ from the role of the EWcp as a whole. In a two-bottle choice continuous access paradigm, Ucn1 knockout mice do not differ from wildtype controls in levels of alcohol consumption or alcohol preference of 10% (v/v) alcohol (Giardino et al 2017). Despite being activated by moderate doses of alcohol, it does not appear that Ucn1 signaling modulates moderate alcohol consumption, and the effects of EWcp lesion on decreasing alcohol consumption in mice may be attributable to other neuropeptides and signaling pathways.…”

“…Following long-term intermittent alcohol drinking in which mice escalate alcohol intake to binge-like levels, mice exhibit increased mRNA levels of Ucn1 and CRF-BP in the EWcp (Giardino et al 2017). Furthermore, in that study, alcohol intake levels were positively correlated with fos mRNA levels in EWcp (Giardino et al 2017). Overall, these results suggest that binge alcohol increases activity of the brain Ucn1 system.…”

“…Whole brain Ucn knockout mice do not show a change in alcohol consumption in the DID procedure (Kaur et al 2012). However, in an escalating continuous-access drinking procedure, whole-brain knockout of Ucn1 decreases consumption of high alcohol concentrations (40% v/v), such that knockout mice fail to reach intoxicating binge-like intake levels and exhibit lower BACs than wildtype controls (Giardino et al 2017). This effect was alcohol-specific, as Ucn1 knockout mice did not exhibit altered sweet or bitter taste reactivity (Giardino et al 2017).…”

“…However, in an escalating continuous-access drinking procedure, whole-brain knockout of Ucn1 decreases consumption of high alcohol concentrations (40% v/v), such that knockout mice fail to reach intoxicating binge-like intake levels and exhibit lower BACs than wildtype controls (Giardino et al 2017). This effect was alcohol-specific, as Ucn1 knockout mice did not exhibit altered sweet or bitter taste reactivity (Giardino et al 2017). In contrast to the DID procedure, where mice achieve binge-like alcohol consumption in a 4-day procedure without escalating concentrations, this escalating continuous-access model increases the alcohol concentration from 10% v/v to 40% v/v over the course of 12 days (Giardino et al 2017).…”