Tabernanthalog (TBG), a novel analogue of ibogaine and 5-methoxy-N,N-dimethyltryptamine, lacks classical psychedelic effects and cardiac arrhythmogenic risk. In a polydrug model of heroin and alcohol co-use in rats, TBG reduced motivation for both substances in a progressive ratio test, where the number of lever presses required for a reward increased exponentially. The study used a two-bottle binge protocol for alcohol exposure, followed by self-administration training for intravenous heroin or oral alcohol, and then sessions with both substances. TBG's efficacy was preserved in animals with a history of heroin and alcohol polydrug use.
Heroin self-administration increases the density of perineuronal nets (PNNs) in the ventral pallidum (VP) of mice. Depleting these PNNs with an enzyme prevents cue-induced reinstatement of heroin seeking, reduces the intrinsic excitability of parvalbumin-expressing VP neurons, strengthens inhibitory synaptic inputs onto them, and lowers Fos expression in those neurons after reinstatement. Chemogenetic activation of VP parvalbumin neurons rescues the suppressive effect of PNN depletion on heroin seeking, while chemogenetic inhibition mimics it. VP parvalbumin neurons and their PNNs are critical drivers of opioid seeking, and targeting PNNs in the VP may offer a novel therapeutic approach for relapse in opioid use disorder.