N-Oleoyl Glycine and N-Oleoyl Alanine Attenuate Alcohol Self-Administration and Preference in Mice

N-Oleoyl Glycine and N-Oleoyl Alanine Attenuate Alcohol Self-Administration and Preference in Mice | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article N-Oleoyl Glycine and N-Oleoyl Alanine Attenuate Alcohol Self-Administration and Preference in Mice Rami Yaka, Samah Shahen-Zoabi, Reem Smoum, Alexey Bingor, Etty Grad, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2503793/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Jul, 2023 Read the published version in Translational Psychiatry → Version 1 posted 9 You are reading this latest preprint version Abstract The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain, and has an important role in the neurobiological processes underlying drug addiction. We have previously shown that an elevated ECS response to psychostimulant (cocaine) is involved in regulating the development and expression of cocaine-conditioned reward and cocaine sensitization. Here, we determine the involvement of ECS in alcohol addiction. We first measured the levels of endocannabinoids (eCBs) and eCB-like molecules in different regions of the brain reward system following chronic alcohol self-administration using LCMS. We found that following chronic intermittent alcohol consumption, N-oleoyl glycine (OlGly) levels were significantly elevated in the prefrontal cortex (PFC), and N-oleoyl alanine (OlAla) was significantly elevated in the PFC, nucleus accumbens (NAc) and ventral tegmental area (VTA) in a region-specific manner. We next tested whether exogenous administration of OlGly or OlAla would attenuate alcohol consumption and preference. We found that systemic administration of OlGly or OlAla (60mg/kg, intraperitoneal) during intermittent alcohol consumption significantly reduced alcohol intake and preference. These findings suggest that the ECS negatively regulates alcohol consumption and boosting selective endocannabinoids exogenously has beneficial effects against alcohol consumption and potentially in preventing relapse. Biological sciences/Neuroscience Biological sciences/Neuroscience/Molecular neuroscience Figures Figure 1 Figure 2 Figure 3 Figure 4 Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose Table 1 is available in the Supplementary Files section. Supplementary Files Table1.pdf Summary of region specific eCBs and eCB-Ls alterations following chronic EtOH selfadministration. Arrows indicate the alteration in the levels of eCBs and eCB-Ls in the various brain regions. Arrows do not represent the exact percent of change (detailed in figure 2). ns - not significant. SupplementaryTableS1.pdf SupplementaryTableS2.pdf SupplementaryTableS3.pdf Cite Share Download PDF Status: Published Journal Publication published 31 Jul, 2023 Read the published version in Translational Psychiatry → Version 1 posted Editorial decision: revise 17 Feb, 2023 Review # 2 received at journal 15 Feb, 2023 Review # 1 received at journal 06 Feb, 2023 Reviewer # 2 agreed at journal 02 Feb, 2023 Reviewer # 1 agreed at journal 31 Jan, 2023 Reviewers invited by journal 30 Jan, 2023 Submission checks completed at journal 23 Jan, 2023 Editor assigned by journal 22 Jan, 2023 First submitted to journal 22 Jan, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2503793","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":171933403,"identity":"75fece01-91cb-4a3f-9ad5-5f5f8b6b1560","order_by":0,"name":"Rami Yaka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYFACNgaGDwzMDAYMDAkHwHx2IrQwzkDRwkyEFmYeiBYoIKTF4PixxM+2OdYM5hIJDw8w1Ngx8BHUcibtsHTutnQGyxkJQIcdSybsMIMD6Q1ALYcZDG6AtLAdIELL+efNvy3hWv4Ro+VG2jFpRpgWxjYitEjeeJZm2bstncfgzIOEA4l9yTwEtfCdTzO+8XObtZzB8ZzkDx++2cnJtzfg16JwAELzAFECQwKYQQDII4xkP0BQ9SgYBaNgFIxMAACyb0Fcyk6CtAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-2372-2957","institution":"Hebrew University of Jerusalem","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Rami","middleName":"","lastName":"Yaka","suffix":""},{"id":171933404,"identity":"b8d6e2c5-0e8c-410d-840e-519bf4be1026","order_by":1,"name":"Samah Shahen-Zoabi","email":"","orcid":"https://orcid.org/0000-0003-2123-4351","institution":"Hebrew University of Jerusalem","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Samah","middleName":"","lastName":"Shahen-Zoabi","suffix":""},{"id":171933405,"identity":"b3b00b9e-9b1d-429e-9fd7-603f5da5a83a","order_by":2,"name":"Reem Smoum","email":"","orcid":"","institution":"Hebrew University of Jerusalem","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Reem","middleName":"","lastName":"Smoum","suffix":""},{"id":171933406,"identity":"6f9a7ea2-0034-4aae-af56-1feb621342eb","order_by":3,"name":"Alexey Bingor","email":"","orcid":"https://orcid.org/0000-0002-5498-2260","institution":"Hebrew University of Jerusalem","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexey","middleName":"","lastName":"Bingor","suffix":""},{"id":171933407,"identity":"3831ef4a-3953-4b13-b0e0-cc2d037e3e7b","order_by":4,"name":"Etty Grad","email":"","orcid":"","institution":"Hebrew University of Jerusalem","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Etty","middleName":"","lastName":"Grad","suffix":""},{"id":171933408,"identity":"88562997-98f7-4f86-864d-0047fdd95994","order_by":5,"name":"Alina Nemirovski","email":"","orcid":"","institution":"Hebrew University of Jerusalem","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alina","middleName":"","lastName":"Nemirovski","suffix":""},{"id":171933409,"identity":"3edc4197-e5fb-4fb6-99a1-790888c981a1","order_by":6,"name":"Tawfeeq Shekh-Ahmad","email":"","orcid":"","institution":"Hebrew University of Jerusalem","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tawfeeq","middleName":"","lastName":"Shekh-Ahmad","suffix":""},{"id":171933410,"identity":"0466a493-f6de-4271-9b63-c7668d7e8028","order_by":7,"name":"Raphael Mechoulam","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Raphael","middleName":"","lastName":"Mechoulam","suffix":""}],"badges":[],"createdAt":"2023-01-22 09:00:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2503793/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2503793/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41398-023-02574-4","type":"published","date":"2023-07-31T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":32354934,"identity":"33197fde-a105-49f6-bcb3-38b69d55f180","added_by":"auto","created_at":"2023-02-01 22:59:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":298441,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIntermittent access to EtOH induces an escalation of EtOH intake and preference in females and males\u003c/strong\u003e. \u003cstrong\u003e(A)\u003c/strong\u003eAlcohol intake in female and male mice exposed to intermittent access to 20% EtOH.\u003cstrong\u003e \u003c/strong\u003eFemale mice exhibited significantly increased EtOH consumption relative to males mice [\u003cem\u003eN \u003c/em\u003e= 13-15 mice/group; Mixed-effects analysis, followed by Sidak`s multiple comparisons test: \u003cem\u003eF\u003c/em\u003e(1,27) = 5.509, sex effect \u003cem\u003eP\u003c/em\u003e= 0.0265; \u003cem\u003eF\u003c/em\u003e(6.055, 160.1) = 20.6, session \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.0001; \u003cem\u003eF\u003c/em\u003e(16, 423) = 3.763, sex × session interaction \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.0001]. Sidak`s \u003cem\u003epost-hoc\u003c/em\u003e * \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, ** \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01. \u003cstrong\u003e(B) \u003c/strong\u003eCumulative intake of EtOH (per day) for female or male mice.\u003cstrong\u003e \u003c/strong\u003eInset, absolute EtOH intake for the two groups (\u003cem\u003eN \u003c/em\u003e= 13-15, \u003cem\u003eP \u003c/em\u003e= 0.0108, Student’s \u003cem\u003et\u003c/em\u003e-test).\u003cstrong\u003e \u003c/strong\u003e*\u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05. \u003cstrong\u003e(C) \u003c/strong\u003eThere were no differences in EtOH preference between female and male mice. [\u003cem\u003eN \u003c/em\u003e= 13-15; Mixed-effects analysis: \u003cem\u003eF\u003c/em\u003e(1,27) = 0.7908, sex effect \u003cem\u003eP\u003c/em\u003e = 0.3817; \u003cem\u003eF\u003c/em\u003e(6.117, 162.5) = 11.98, session \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.0001; \u003cem\u003eF\u003c/em\u003e(16, 425) = 2.673, sex × session interaction \u003cem\u003eP \u003c/em\u003e= 0.0005].\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-2503793/v1/9c1b7dc3c6e52b0f66c84e89.png"},{"id":32354936,"identity":"9ee3d50b-7568-443a-82d0-c8165ff70c41","added_by":"auto","created_at":"2023-02-01 22:59:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":376900,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLipidomic analysis of eCBs and eCB-Ls following chronic EtOH self-administration in female and male mice\u003c/strong\u003e. \u003cstrong\u003e(A-F) \u003c/strong\u003eOne day following the last EtOH self-administration session, animals were sacrificed and the PFC, NAc, VTA, HIP, AMY, and CER were dissected and analyzed for the expression levels of eCBs using LC-MS. The levels of OlGly, OlAla, 2-AG, AEA, PEA and OEA are expressed as ng/mg of tissue weight. Two-way ANOVA followed by Sidak`s multiple comparisons revealed that chronic EtOH self-administration significantly elevated OlGly level in the PFC of female mice [\u003cem\u003eN\u003c/em\u003e = 4-5 mice/group; \u003cem\u003eF\u003c/em\u003e(1,14) = 14.19, \u003cem\u003eP\u003c/em\u003e = 0.0021; Ctrl vs. EtOH, \u003cem\u003eP\u003c/em\u003e= 0.0230] and OlAla levels were elevated in PFC and NAc of male and PFC of female and male mice. * \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, ** \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01, *** \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001. Detailed statistical analysis for all the panels are presented in Supplementary Table S3. PFC - prefrontal cortex; NAc - nucleus accumbens; VTA - ventral tegmental area; HIP - hippocampus; AMY - amygdala; CER - cerebellum; eCBs - endocannabinoids; OlGly - \u003cem\u003eN\u003c/em\u003e-oleoyl glycine; OlAla - \u003cem\u003eN\u003c/em\u003e-oleoyl alanine; 2-AG - 2-arachidonoyl glycerol; AEA - \u003cem\u003eN\u003c/em\u003e-arachidonoyl ethanolamine; OEA - \u003cem\u003eN\u003c/em\u003e-oleoyl ethanolamide; PEA - \u003cem\u003eN\u003c/em\u003e-palmitoyl ethanolamide.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-2503793/v1/5a3d11cbad53be2962ec1492.png"},{"id":32354950,"identity":"c1c037d9-7f2a-4894-8be8-1583b9cc6d6b","added_by":"auto","created_at":"2023-02-01 22:59:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":338988,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOlGly attenuates EtOH self-administration and preference but not water consumption in male mice. (A)\u003c/strong\u003e Systemic administration of OlGly (60 mg/kg) before each EtOH self-administration session significantly attenuated EtOH intake [\u003cem\u003eN\u003c/em\u003e = 9-10; Mixed-effects analysis: \u003cem\u003eF\u003c/em\u003e(1,17) = 5.349, treatment effect \u003cem\u003eP\u003c/em\u003e = 0.0335; \u003cem\u003eF\u003c/em\u003e(5.896, 97.65) = 3.212, session \u003cem\u003eP\u003c/em\u003e = 0.0067; \u003cem\u003eF\u003c/em\u003e(16, 265) = 1.791, sex × session interaction \u003cem\u003eP\u003c/em\u003e = 0.0323]. Student`s \u003cem\u003et\u003c/em\u003e-test: * \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, ** \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01.\u003cstrong\u003e (B) \u003c/strong\u003eCumulative EtOH intake (per day) of animals injected with either OlGly (60 mg/kg) or vehicle. Inset, absolute EtOH intake for the two groups (\u003cem\u003eN\u003c/em\u003e = 9-10 mice/group,\u003cem\u003e \u003c/em\u003eStudent’s \u003cem\u003et\u003c/em\u003e-test,\u003cem\u003e P \u003c/em\u003e= 0.0238,).\u003cstrong\u003e \u003c/strong\u003e* \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.05.\u003cstrong\u003e (C) \u003c/strong\u003eMixedeffects analysis followed by Sidak`s multiple comparisons test revealed no difference in the water consumption between the two groups [\u003cem\u003eF\u003c/em\u003e(1,9) = 0.1972, \u003cem\u003eP\u003c/em\u003e = 0.6675]. \u003cstrong\u003e(D) \u003c/strong\u003eMixed-effects analysis, followed by Sidak`s multiple comparisons test revealed no difference in the total fluid intake between the two groups. [\u003cem\u003eF\u003c/em\u003e(1,9) = 1.322, \u003cem\u003eP\u003c/em\u003e = 0.2799].\u003cstrong\u003e (E) \u003c/strong\u003eOlGly attenuates EtOH preference. Inset, EtOH preference at the last session for the two groups was compared (\u003cem\u003eN\u003c/em\u003e = 9-10, Student’s \u003cem\u003et\u003c/em\u003e-test, \u003cem\u003eP\u003c/em\u003e = 0.0483), * \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-2503793/v1/fdcd20d750cffb35edf6b216.png"},{"id":32355265,"identity":"af5a618f-f37e-4c37-8733-b38680ca21c9","added_by":"auto","created_at":"2023-02-01 23:15:24","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":298744,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOlAla attenuates EtOH self-administration and preference but not water consumption in male mice. (A)\u003c/strong\u003e Systemic administration of OlAla (60 mg/kg) before each EtOH self-administration session significantly attenuated EtOH intake [\u003cem\u003eN\u003c/em\u003e = 10 mice/group; Mixed-effects analysis: \u003cem\u003eF\u003c/em\u003e(1,18) = 4.989, treatment effect \u003cem\u003eP\u003c/em\u003e = 0.0384; \u003cem\u003eF\u003c/em\u003e(6.118, 108.3) = 4.175, session \u003cem\u003eP\u003c/em\u003e = 0.0008; \u003cem\u003eF\u003c/em\u003e(10, 177) = 0.5726, sex × session interaction \u003cem\u003eP\u003c/em\u003e = 0.8349]. Student`s \u003cem\u003et\u003c/em\u003e-test: * \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05. \u003cstrong\u003e(B) \u003c/strong\u003eCumulative EtOH intake (per day) of animals injected with either OlAla or vehicle. Inset, absolute EtOH intake for the two groups (\u003cem\u003eN\u003c/em\u003e = 10,\u003cem\u003e \u003c/em\u003eStudent’s \u003cem\u003et\u003c/em\u003e-test,\u003cem\u003e P \u003c/em\u003e= 0.014).\u003cstrong\u003e \u003c/strong\u003e* \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05.\u003cstrong\u003e (C) \u003c/strong\u003eMixed-effects analysis, followed by Sidak`s multiple comparisons test revealed no difference in the water consumption between the two groups. [\u003cem\u003eF\u003c/em\u003e(1, 9) = 0.3549, \u003cem\u003eP\u003c/em\u003e = 0.5660].\u003cstrong\u003e (D) \u003c/strong\u003eMixed-effects analysis, followed by Sidak`s multiple comparisons test revealed no difference in the fluid intake\u003cstrong\u003e \u003c/strong\u003ebetween the two groups. [\u003cem\u003eF\u003c/em\u003e(1, 9) = 0.02550, \u003cem\u003eP\u003c/em\u003e = 0.8767].\u003cstrong\u003e (E) \u003c/strong\u003eOlAla attenuates EtOH preference\u003cstrong\u003e. \u003c/strong\u003eInset, EtOH preference at the last session for the two groups was compared (\u003cem\u003eN\u003c/em\u003e =10, Student’s \u003cem\u003et\u003c/em\u003e-test, \u003cem\u003eP\u003c/em\u003e = 0.0014). ** \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-2503793/v1/09d137abdfe5aa619657a2a1.png"},{"id":40864313,"identity":"2dd6eb33-f406-414d-8529-05d303394cc5","added_by":"auto","created_at":"2023-08-01 07:10:00","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":941583,"visible":true,"origin":"","legend":"","description":"","filename":"ShahenZoabietal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2503793/v1_covered_85cd1106-9b99-4e1f-a557-59a34da19eba.pdf"},{"id":32354935,"identity":"071f9a3b-e8e0-4ad8-8313-54760c55b2db","added_by":"auto","created_at":"2023-02-01 22:59:23","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":130757,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSummary of region specific eCBs and eCB-Ls alterations following chronic EtOH selfadministration. \u003c/strong\u003eArrows indicate the alteration in the levels of eCBs and eCB-Ls in the various brain regions. Arrows do not represent the exact percent of change (detailed in figure 2). ns - not significant.\u003c/p\u003e","description":"","filename":"Table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2503793/v1/2d641d4ce5b984ca6ab9376e.pdf"},{"id":32355161,"identity":"74222b81-d162-46fe-9e6a-e4595a73ea1e","added_by":"auto","created_at":"2023-02-01 23:07:24","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":368824,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2503793/v1/5c6cad7fc858575f13836e15.pdf"},{"id":32355266,"identity":"e8745b4b-ca0e-41b9-8434-cde8c526db2f","added_by":"auto","created_at":"2023-02-01 23:15:24","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":392562,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2503793/v1/e600cfa33d4df3336fd4c23d.pdf"},{"id":32354943,"identity":"1a05bb61-60b8-4193-9e5c-861fd57a08ff","added_by":"auto","created_at":"2023-02-01 22:59:24","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":704005,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2503793/v1/362c05048dbc1ac8e5c25583.pdf"}],"financialInterests":"\u003cp\u003eThe authors have declared there is \u003cstrong\u003eNO\u003c/strong\u003e conflict of interest to disclose\u003c/p\u003e\n\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e","formattedTitle":"N-Oleoyl Glycine and N-Oleoyl Alanine Attenuate Alcohol Self-Administration and Preference in Mice","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2503793/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2503793/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain, and has an important role in the neurobiological processes underlying drug addiction. We have previously shown that an elevated ECS response to psychostimulant (cocaine) is involved in regulating the development and expression of cocaine-conditioned reward and cocaine sensitization. Here, we determine the involvement of ECS in alcohol addiction. We first measured the levels of endocannabinoids (eCBs) and eCB-like molecules in different regions of the brain reward system following chronic alcohol self-administration using LCMS. We found that following chronic intermittent alcohol consumption, N-oleoyl glycine (OlGly) levels were significantly elevated in the prefrontal cortex (PFC), and N-oleoyl alanine (OlAla) was significantly elevated in the PFC, nucleus accumbens (NAc) and ventral tegmental area (VTA) in a region-specific manner. We next tested whether exogenous administration of OlGly or OlAla would attenuate alcohol consumption and preference. We found that systemic administration of OlGly or OlAla (60mg/kg, intraperitoneal) during intermittent alcohol consumption significantly reduced alcohol intake and preference. These findings suggest that the ECS negatively regulates alcohol consumption and boosting selective endocannabinoids exogenously has beneficial effects against alcohol consumption and potentially in preventing relapse.","manuscriptTitle":"N-Oleoyl Glycine and N-Oleoyl Alanine Attenuate Alcohol Self-Administration and Preference in Mice","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-02-01 22:59:19","doi":"10.21203/rs.3.rs-2503793/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2023-02-17T10:45:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-02-16T03:15:49+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-02-06T12:12:26+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-02-02T17:18:18+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-01-31T07:41:51+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2023-01-30T22:17:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-01-23T11:18:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-01-22T08:59:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Translational Psychiatry","date":"2023-01-22T08:59:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"32984773-e8b8-422f-af20-25935bd53fe8","owner":[],"postedDate":"February 1st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":18815907,"name":"Biological sciences/Neuroscience"},{"id":18815908,"name":"Biological sciences/Neuroscience/Molecular neuroscience"}],"tags":[],"updatedAt":"2023-09-25T13:14:12+00:00","versionOfRecord":{"articleIdentity":"rs-2503793","link":"https://doi.org/10.1038/s41398-023-02574-4","journal":{"identity":"translational-psychiatry","isVorOnly":false,"title":"Translational Psychiatry"},"publishedOn":"2023-07-31 04:00:00","publishedOnDateReadable":"July 31st, 2023"},"versionCreatedAt":"2023-02-01 22:59:19","video":"","vorDoi":"10.1038/s41398-023-02574-4","vorDoiUrl":"https://doi.org/10.1038/s41398-023-02574-4","workflowStages":[]},"version":"v1","identity":"rs-2503793","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2503793","identity":"rs-2503793","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}