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.
Highlights
Alcoholism can emerge as a maladaptive coping strategy in stressexperienced individuals, highlighting the importance of biological stress systems in maintaining addiction.[1]
EWcp neurons are activated by stressors[31] and highly enriched in genes encoding neuropeptide transmitters: cocaine- and amphetamine-related transcript (Cart);, cholecystokinin (Cck); nesfatin-1 (Nucb2); pituitary adenylyl cyclase-activating polypeptide (PACAP, Adcyap1); and urocortin-1 (Ucn[1], Ucn).[32]
We documented alcohol-induced fluctuations in neuropeptide gene expression within these stress-responsive midbrain neurons, and provided converging lines of evidence that EWcp-Ucn[1] activity is essential for chronic escalated alcohol drinking. These studies point to contrasting contributions of corticotropin-releasing factor (CRF) system ligands to the development of excessive alcohol use
Summary
Alcoholism can emerge as a maladaptive coping strategy in stressexperienced individuals, highlighting the importance of biological stress systems in maintaining addiction.[1] Stress-responsive neuronal populations release peptide modulators to facilitate appropriate responding to environmental challenges, but dysregulation of these circuits can have profound consequences on behavior.[2,3] Following repeated cycles of alcohol intoxication and withdrawal, stress-sensitive neural systems can perpetuate the addiction cycle via persistent adaptations known as allostatic shifts.[4,5] In particular, recent investigations of stress-related neuropeptide contributions to binge alcohol drinking focused on the bed nuclei of stria terminalis,[6] lateral hypothalamus,[7] central nucleus of the amygdala,[8,9,10,11] ventral tegmental area,[12,13,14] and dorsal raphe nucleus.[15,16] These are well-established regions in the addiction neural network, and likely interact at the circuit level with other uncharacterized neuronal populations to coordinate complex motivated behaviors. Our findings establish the EWcp as a fundamental component of the alcohol addiction neurocircuitry
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