PT  - JOURNAL ARTICLE
AU  - Giordano de Guglielmo
AU  - Marsida Kallupi
AU  - Matthew B. Pomrenze
AU  - Elena Crawford
AU  - Sierra Simpson
AU  - Paul Schweitzer
AU  - George F. Koob
AU  - Robert O. Messing
AU  - Olivier George
TI  - Central amygdala CRF pathways in alcohol dependence
AID  - 10.1101/134759
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 134759
4099  - http://biorxiv.org/content/early/2017/05/21/134759.short
4100  - http://biorxiv.org/content/early/2017/05/21/134759.full
AB  - Alcohol withdrawal activates a neuronal ensemble in the central nucleus of the amygdala (CeA) that is responsible for high levels of uncontrolled alcohol drinking. However, the neuronal phenotypes and circuits controlled by these neurons are unknown. We investigated the cellular identity of this CeA neuronal ensemble and found that most neurons expressed corticotropin-releasing factor (CRF). Using Crh-Cre transgenic rats combined with in vivo optogenetics, we tested the role of CeA CRF neurons and their projections in excessive alcohol self-administration during withdrawal. Rats were injected with AAV-DIO-NpHR-eYFP or AAV-DIO-eYFP and implanted with optical fibers over the CeA. Animals were then exposed to chronic intermittent ethanol vapor to induce alcohol dependence. Inactivation of CeA CRF neurons decreased alcohol drinking in dependent rats to non-dependent levels and completely suppressed activation of the CeA neuronal ensemble (Fos+ neurons) during withdrawal. No effects were observed on water or saccharin self-administration. In a second experiment, CeA CRF neurons were infected with AAV-DIO-NpHR-eYFP and optical fibers were implanted into downstream projection regions, including the bed nucleus of the stria terminalis (BNST), lateral hypothalamus (LH), parasubthalamic nucleus (pSTN), substantia innominata (SI), and parabrachial nuclei (PBN). Optogenetic inactivation of CRF terminals in the BNST reduced alcohol drinking and withdrawal signs, whereas inactivation of all other projections had no effect. These results demonstrate that CeA CRF neurons and their projections to the BNST drive excessive alcohol drinking and withdrawal in dependent rats.