Heinsbroek Jasper A, Giannotti Giuseppe, Bonilla Joel, Olson David E, Peters Jamie
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, USA.
Psychedelic Med (New Rochelle). 2023 Jun 1;1(2):111-119. doi: 10.1089/psymed.2023.0009. Epub 2023 Jun 14.
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--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.
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.
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.
致幻药物作为神经精神疾病治疗药物的潜在用途因其致幻特性而受到限制。为克服这一限制，我们开发并表征了一种新型吲哚生物碱类似物——瑞香狼毒碱（TBG），它是伊博格碱和5-甲氧基-N,N-二甲基色胺的类似物，具有降低的心律失常风险，且不会引起经典致幻药物所导致的感觉改变。我们之前证明，TBG在大鼠阿片类药物使用障碍（OUD）的临床前模型以及小鼠酒精暴饮模型中具有治疗效果。在约35%至50%的OUD患者中，酒精通常与阿片类药物共同使用，然而，目前缺乏能够概括这种共病情况的临床前模型。
在这里，我们采用海洛因和酒精联用的多药模型，以筛选TBG对阿片类药物和酒精觅求指标的治疗效果。我们首先在家笼（HC）中使用两瓶暴饮方案，让大鼠在1个月的时间内接触酒精（或对照蔗糖消退溶液）。然后将大鼠分为两组，分别接受静脉注射海洛因或口服酒精的自我给药训练，以便我们能够分别评估HC酒精暴露对每种物质自我给药的影响。此后，大鼠开始在同一实验环节中自我给药海洛因和酒精。最后，我们在渐进比率测试中测试了TBG对海洛因和酒精断点的影响，在该测试中，获得单次奖励所需的杠杆按压次数呈指数增加。
在该测试中，TBG有效降低了对海洛因和酒精的觅求动机，表示其疗效在有海洛因和酒精多药使用史的动物中得以保留。
