Aboagyewaah Oppong-Damoah1, Kristen E Curry1,2, Bruce E Blough3, Kenner C Rice4, Kevin S Murnane5. 1. Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, 3001 Mercer University Dr., Atlanta, GA, 30341, USA. 2. University of Texas College of Pharmacy, Austin, TX, USA. 3. Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA. 4. Section on Drug Design and Synthesis, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. 5. Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, 3001 Mercer University Dr., Atlanta, GA, 30341, USA. murnane_ks@mercer.edu.
Abstract
RATIONALE: Approximately 20 million adults in the USA have an alcohol use disorder (AUD). There are clinical and preclinical data suggesting that psychedelics may have benefits for AUD. OBJECTIVE: To investigate the effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on the behavioral effects of ethanol. METHODS: The effects of DOI were examined using ethanol-induced place conditioning (1.8 g/kg ethanol) and 2-bottle choice ethanol drinking (20% v/v), using a dose of DOI (3 mg/kg) that produced the maximal response in the serotonin 2A (5-HT2A) receptor-dependent head-twitch assay. Interactions between DOI and ethanol (3 g/kg) were examined using the ethanol-induced loss of righting reflex procedure and blood-ethanol analysis. To examine additional mechanisms by which psychedelics may interact with ethanol, we determined whether DOI reverses ethanol-induced nitric oxide release in macrophages, a marker of inflammation. RESULTS: DOI significantly attenuated ethanol-induced place conditioning and ethanol drinking. DOI-induced suppression of alcohol drinking depended upon 5-HT2A receptors, was selective for alcohol over water, and was selective for high alcohol-preferring subjects. DOI had no apparent pharmacokinetic interactions with ethanol, and DOI reduced ethanol-induced nitric oxide release. CONCLUSIONS: Our findings demonstrate that DOI blocks ethanol place conditioning and selectively reduces voluntary ethanol consumption. This may be related to modulation of the effects of ethanol in the reward circuitry of the brain, ethanol-induced neuroinflammation, or a combination of both. Additional studies to elucidate the mechanisms through which psychedelics attenuate the effects of ethanol would inform the pathophysiology of AUD and potentially provide new treatment options.
RATIONALE: Approximately 20 million adults in the USA have an alcohol use disorder (AUD). There are clinical and preclinical data suggesting that psychedelics may have benefits for AUD. OBJECTIVE: To investigate the effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on the behavioral effects of ethanol. METHODS: The effects of DOI were examined using ethanol-induced place conditioning (1.8 g/kg ethanol) and 2-bottle choice ethanol drinking (20% v/v), using a dose of DOI (3 mg/kg) that produced the maximal response in the serotonin 2A (5-HT2A) receptor-dependent head-twitch assay. Interactions between DOI and ethanol (3 g/kg) were examined using the ethanol-induced loss of righting reflex procedure and blood-ethanol analysis. To examine additional mechanisms by which psychedelics may interact with ethanol, we determined whether DOI reverses ethanol-induced nitric oxide release in macrophages, a marker of inflammation. RESULTS: DOI significantly attenuated ethanol-induced place conditioning and ethanol drinking. DOI-induced suppression of alcohol drinking depended upon 5-HT2A receptors, was selective for alcohol over water, and was selective for high alcohol-preferring subjects. DOI had no apparent pharmacokinetic interactions with ethanol, and DOI reduced ethanol-induced nitric oxide release. CONCLUSIONS: Our findings demonstrate that DOI blocks ethanol place conditioning and selectively reduces voluntary ethanol consumption. This may be related to modulation of the effects of ethanol in the reward circuitry of the brain, ethanol-induced neuroinflammation, or a combination of both. Additional studies to elucidate the mechanisms through which psychedelics attenuate the effects of ethanol would inform the pathophysiology of AUD and potentially provide new treatment options.
Entities:
Keywords:
2,5-Dimethoxy-4-iodoamphetamine; Alcohol use disorder; Ethanol; Neuroinflammation; Psychedelic; Serotonin 2A
Authors: James E Goeders; Kevin S Murnane; Matthew L Banks; William E Fantegrossi Journal: Pharmacol Biochem Behav Date: 2009-04-17 Impact factor: 3.533
Authors: Zheng-Ming Ding; Jamie E Toalston; Scott M Oster; William J McBride; Zachary A Rodd Journal: Psychopharmacology (Berl) Date: 2009-01-23 Impact factor: 4.530
Authors: Blake A Kimmey; Ruthie E Wittenberg; Alexandra Croicu; Nikita Shadani; Alexey Ostroumov; John A Dani Journal: Addict Biol Date: 2022-03 Impact factor: 4.280
Authors: Alaina M Jaster; Harrison Elder; Samuel A Marsh; Mario de la Fuente Revenga; S Stevens Negus; Javier González-Maeso Journal: Psychopharmacology (Berl) Date: 2022-03-02 Impact factor: 4.530
Authors: Lucas Silva Rodrigues; Giordano Novak Rossi; Juliana Mendes Rocha; Flávia L Osório; José Carlos Bouso; Jaime E Cecílio Hallak; Rafael G Dos Santos Journal: Eur Arch Psychiatry Clin Neurosci Date: 2021-04-29 Impact factor: 5.270
Authors: Albert Garcia-Romeu; Alan K Davis; Earth Erowid; Fire Erowid; Roland R Griffiths; Matthew W Johnson Journal: Front Psychiatry Date: 2020-01-22 Impact factor: 4.157
Authors: Lauri V Elsilä; Juliana Harkki; Emma Enberg; Alvar Martti; Anni-Maija Linden; Esa R Korpi Journal: J Psychopharmacol Date: 2022-06-13 Impact factor: 4.562