In a rat model of polydrug use where animals self-administered both intravenous heroin and oral alcohol, the psychedelic compound DOI (0.4 mg/kg) reduced motivation for heroin, measured as the break point in a progressive ratio test. This effect was blocked by a 5-HT2A receptor antagonist but not by a 5-HT2C antagonist, indicating the effect is mediated by 5-HT2A receptors. DOI did not affect motivation for alcohol. The findings suggest that psychedelic drugs acting as 5-HT2A agonists may reduce opioid motivation in individuals with opioid and alcohol co-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.