PMID- 36526372 OWN - NLM STAT- MEDLINE DCOM- 20230203 LR - 20230802 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 43 IP - 5 DP - 2023 Feb 1 TI - Chronic Ethanol Exposure Modulates Periaqueductal Gray to Extended Amygdala Dopamine Circuit. PG - 709-721 LID - 10.1523/JNEUROSCI.1219-22.2022 [doi] AB - The bed nucleus of the stria terminalis (BNST) is a component of the extended amygdala that regulates motivated behavior and affective states and plays an integral role in the development of alcohol-use disorder (AUD). The dorsal subdivision of the BNST (dBNST) receives dense dopaminergic input from the ventrolateral periaqueductal gray (vlPAG)/dorsal raphe (DR). To date, no studies have examined the effects of chronic alcohol on this circuit. Here, we used chronic intermittent ethanol exposure (CIE), a well-established rodent model of AUD, to functionally interrogate the vlPAG/DR-BNST dopamine (DA) circuit during acute withdrawal. We selectively targeted vlPAG/DR(DA) neurons in tyrosine hydroxylase-expressing transgenic adult male mice. Using ex vivo electrophysiology, we found hyperexcitability of vlPAG/DR(DA) neurons in CIE-treated mice. Further, using optogenetic approaches to target vlPAG/DR(DA) terminals in the dBNST, we revealed a CIE-mediated shift in the vlPAG/DR-driven excitatory-inhibitory (E/I) ratio to a hyperexcitable state in dBNST. Additionally, to quantify the effect of CIE on endogenous DA signaling, we coupled optogenetics with fast-scan cyclic voltammetry to measure pathway-specific DA release in dBNST. CIE-treated mice had significantly reduced signal half-life, suggestive of faster clearance of DA signaling. CIE treatment also altered the ratio of vlPAG/DR(DA)-driven cellular inhibition and excitation of a subset of dBNST neurons. Overall, our findings suggest a dysregulation of vlPAG/DR to BNST dopamine circuit, which may contribute to pathophysiological phenotypes associated with AUD.SIGNIFICANCE STATEMENT The dorsal bed nucleus of the stria terminalis (dBNST) is highly implicated in the pathophysiology of alcohol-use disorder and receives dopaminergic inputs from ventrolateral periaqueductal gray/dorsal raphe regions (vlPAG/DR). The present study highlights the plasticity within the vlPAG/DR to dBNST dopamine (DA) circuit during acute withdrawal from chronic ethanol exposure. More specifically, our data reveal that chronic ethanol strengthens vlPAG/DR-dBNST glutamatergic transmission while altering both DA transmission and dopamine-mediated cellular inhibition of dBNST neurons. The net result is a shift toward a hyperexcitable state in dBNST activity. Together, our findings suggest chronic ethanol may promote withdrawal-related plasticity by dysregulating the vlPAG/DR-dBNST DA circuit. CI - Copyright (c) 2023 the authors. FAU - Pati, Dipanwita AU - Pati D AD - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. AD - Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751. FAU - Downs, Anthony M AU - Downs AM AD - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. AD - Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751. FAU - McElligott, Zoe A AU - McElligott ZA AUID- ORCID: 0000-0002-4717-5698 AD - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. AD - Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751. AD - Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751. FAU - Kash, Thomas L AU - Kash TL AD - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 tkash@email.unc.edu. AD - Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 2751. LA - eng GR - P60 AA011605/AA/NIAAA NIH HHS/United States GR - T32 AA007573/AA/NIAAA NIH HHS/United States GR - R21 AA027460/AA/NIAAA NIH HHS/United States GR - R01 NS122230/NS/NINDS NIH HHS/United States GR - R01 AA026363/AA/NIAAA NIH HHS/United States GR - R01 AA019454/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20221216 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 3K9958V90M (Ethanol) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Mice MH - Male MH - Animals MH - *Periaqueductal Gray MH - *Ethanol/toxicity MH - Dopamine/pharmacology MH - Amygdala MH - Neurons/physiology MH - Mice, Transgenic PMC - PMC9899080 EDAT- 2022/12/17 06:00 MHDA- 2023/02/04 06:00 PMCR- 2023/08/01 CRDT- 2022/12/16 21:06 PHST- 2022/06/09 00:00 [received] PHST- 2022/11/29 00:00 [revised] PHST- 2022/12/01 00:00 [accepted] PHST- 2022/12/17 06:00 [pubmed] PHST- 2023/02/04 06:00 [medline] PHST- 2022/12/16 21:06 [entrez] PHST- 2023/08/01 00:00 [pmc-release] AID - JNEUROSCI.1219-22.2022 [pii] AID - JN-RM-1219-22 [pii] AID - 10.1523/JNEUROSCI.1219-22.2022 [doi] PST - ppublish SO - J Neurosci. 2023 Feb 1;43(5):709-721. doi: 10.1523/JNEUROSCI.1219-22.2022. Epub 2022 Dec 16.