PMID- 37773223 OWN - NLM STAT- MEDLINE DCOM- 20240108 LR - 20240429 IS - 1435-1463 (Electronic) IS - 0300-9564 (Print) IS - 0300-9564 (Linking) VI - 131 IP - 1 DP - 2024 Jan TI - The GlyT1-inhibitor Org 24598 facilitates the alcohol deprivation abolishing and dopamine elevating effects of bupropion + varenicline in rats. PG - 95-106 LID - 10.1007/s00702-023-02701-x [doi] AB - Alcohol Use Disorder (AUD) is a relapsing brain disorder that involves perturbations of brain dopamine (DA) systems, and combined treatment with varenicline + bupropion produces additive effects on accumbal DA output and abolishes the alcohol deprivation effect (ADE) in rats. Also, direct and indirect glycine receptor (GlyR) agonists raise basal DA, attenuate alcohol-induced DA release in the nucleus Accumbens (nAc) and reduce alcohol consumption in rats. This study in rats examines whether the GlyT1-inhibitor Org 24598, an indirect GlyR agonist, enhances the ADE-reducing and DA elevating action of the combined administration of varenicline + bupropion in lower doses than previously applied. Effects on voluntary alcohol consumption, the ADE and extracellular levels of glycine and DA in nAc were examined following treatment with Org 24598 6 and 9 mg/kg i.p., bupropion 3.75 mg/kg i.p. and varenicline 1.5 mg/kg s.c., in monotherapy or combined, using a two-bottle, free-choice alcohol consumption paradigm with an ADE paradigm, and in vivo microdialysis in male Wistar rats. Notably, all treatment regimens appeared to abolish the ADE but only the effect produced by the triple combination (Org24598 + varenicline + bupropion) was significant compared to vehicle. Hence, addition of Org 24598 may enhance the ADE-reducing action of varenicline + bupropion and appears to allow for a dose reduction of bupropion. Treatment with Org 24598 raised accumbal glycine levels but did not significantly alter DA output in monotherapy. Varenicline + bupropion produced a substantial elevation in accumbal DA output that was slightly enhanced following addition of Org 24598. Conceivably, the blockade of the ADE is achieved by the triple combination enhancing accumbal DA transmission in complementary ways, thereby alleviating a hypothesized hypodopaminergia and negative reinforcement to drink. Ultimately, combining an indirect or direct GlyR agonist with varenicline + bupropion may constitute a new pharmacological treatment principle for AUD, although further refinement in dosing and evaluation of other glycinergic compounds are warranted. CI - (c) 2023. The Author(s). FAU - Olsson, Yasmin AU - Olsson Y AUID- ORCID: 0000-0003-4547-3584 AD - Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, PO Box 410, 405 30, Gothenburg, SE, Sweden. yasmin.olsson@gu.se. AD - Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden. yasmin.olsson@gu.se. AD - Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden. yasmin.olsson@gu.se. FAU - Lido, Helga AU - Lido H AD - Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, PO Box 410, 405 30, Gothenburg, SE, Sweden. AD - Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden. FAU - Ademar, Karin AU - Ademar K AD - Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, PO Box 410, 405 30, Gothenburg, SE, Sweden. FAU - Cadeddu, Davide AU - Cadeddu D AD - Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, PO Box 410, 405 30, Gothenburg, SE, Sweden. FAU - Ericson, Mia AU - Ericson M AD - Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, PO Box 410, 405 30, Gothenburg, SE, Sweden. FAU - Soderpalm, Bo AU - Soderpalm B AD - Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, PO Box 410, 405 30, Gothenburg, SE, Sweden. AD - Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden. LA - eng GR - 2020-01346/Vetenskapsradet/ GR - 2020-02105/Vetenskapsradet/ GR - 2020-00607/Fredrik och Ingrid Thurings Stiftelse/ GR - GLS-985839/Goteborgs Lakaresallskap/ GR - GLS-960721/Goteborgs Lakaresallskap/ GR - 2022-4085/Stiftelserna Wilhelm och Martina Lundgrens/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230929 PL - Austria TA - J Neural Transm (Vienna) JT - Journal of neural transmission (Vienna, Austria : 1996) JID - 9702341 RN - 0 (org 24598) RN - W6HS99O8ZO (Varenicline) RN - VTD58H1Z2X (Dopamine) RN - 01ZG3TPX31 (Bupropion) RN - TE7660XO1C (Glycine) RN - 3K9958V90M (Ethanol) RN - 0 (Receptors, Glycine) SB - IM MH - Rats MH - Male MH - Animals MH - Rats, Wistar MH - Varenicline/pharmacology MH - *Dopamine MH - Bupropion/pharmacology MH - Glycine/pharmacology MH - Ethanol MH - Receptors, Glycine MH - *Alcoholism PMC - PMC10769923 OTO - NOTNLM OT - Alcohol addiction OT - Dopamine OT - Ethanol consumption OT - Glycine receptor OT - In vivo microdialysis OT - nucleus Accumbens EDAT- 2023/09/29 18:41 MHDA- 2024/01/08 06:41 PMCR- 2023/09/29 CRDT- 2023/09/29 13:28 PHST- 2023/04/04 00:00 [received] PHST- 2023/09/18 00:00 [accepted] PHST- 2024/01/08 06:41 [medline] PHST- 2023/09/29 18:41 [pubmed] PHST- 2023/09/29 13:28 [entrez] PHST- 2023/09/29 00:00 [pmc-release] AID - 10.1007/s00702-023-02701-x [pii] AID - 2701 [pii] AID - 10.1007/s00702-023-02701-x [doi] PST - ppublish SO - J Neural Transm (Vienna). 2024 Jan;131(1):95-106. doi: 10.1007/s00702-023-02701-x. Epub 2023 Sep 29.