Tabernanthalog Reduces Motivation for Heroin and Alcohol in a Polydrug Use Model

Jasper A Heinsbroek; Giuseppe Giannotti; Joel Bonilla; David E Olson; Jamie Peters

doi:10.1089/psymed.2023.0009

Tabernanthalog Reduces Motivation for Heroin and Alcohol in a Polydrug Use Model

Psychedelic Med (New Rochelle). 2023 Jun 1;1(2):111-119. doi: 10.1089/psymed.2023.0009. Epub 2023 Jun 14.

Authors

Jasper A Heinsbroek¹, Giuseppe Giannotti^{1

2}, Joel Bonilla¹, David E Olson^{3

4

5

6}, Jamie Peters^{1

7}

Affiliations

¹ Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
² Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, USA.
³ Department of Chemistry, University of California, Davis, Davis, California, USA.
⁴ Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
⁵ Center for Neuroscience, University of California, Davis, Davis, California, USA.
⁶ Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, California, USA.
⁷ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

PMID: 37360328
PMCID: PMC10286262 (available on 2024-06-22)
DOI: 10.1089/psymed.2023.0009

Abstract

Background: The potential use of psychedelic drugs as therapeutics for neuropsychiatric disorders has been limited by their hallucinogenic properties. To overcome this limitation, we developed and characterized tabernanthalog (TBG), a novel analogue of the indole alkaloids ibogaine and 5-methoxy-N,N-dimethyltryptamine with reduced cardiac arrhythmogenic risk and a lack of classical psychedelic drugs-induced sensory alterations. We previously demonstrated that TBG has therapeutic efficacy in a preclinical model of opioid use disorder (OUD) in rats and in a binge model of alcohol drinking in mice. Alcohol is commonly co-used in ∼35-50% of individuals with OUD, and yet, preclinical models that recapitulate this comorbidity are lacking.

Methodology: Here we employed a polydrug model of heroin and alcohol couse to screen the therapeutic efficacy of TBG on metrics of both opioid and alcohol seeking. We first exposed rats to alcohol (or control sucrose-fade solution) in the home-cage (HC), using a two-bottle binge protocol, over a period of 1 month. Rats were then split into two groups that underwent self-administration training for either intravenous heroin or oral alcohol, so that we could assess the impact of HC alcohol exposure on the self-administration of each substance separately. Thereafter, rats began self-administering both heroin and alcohol in the same sessions. Finally, we tested the effects of TBG on break points for heroin and alcohol in a progressive ratio test, where the number of lever presses required to obtain a single reward increased exponentially.

Results and conclusion: TBG effectively reduced motivation for heroin and alcohol in this test, indicating its efficacy is preserved in animals with a history of heroin and alcohol polydrug use.

Keywords: alcohol; break point; heroin; polydrug use; self-administration; tabernanthalog.

Abstract

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