A psychedelic 5-HT2A/2C agonist, DOI, increases dopamine signals in the nucleus accumbens core of rats during a learned reward task. The drug boosts dopamine responses to rewards and the cues that directly precede them, but not to earlier, distal cues. This effect occurs independently of changes in reward value, suggesting DOI amplifies prediction error signaling—a mechanism that may help disrupt entrenched associations or facilitate new learning. The findings point toward psychedelic strategies that engage error-driven learning for therapeutic benefit.
Psychedelics may help treat neuropsychiatric disorders by disrupting entrenched associations and promoting new learning. In rats performing a Pavlovian task where sequential cues predict rewards, the psychedelic DOI (a 5-HT2A/2C agonist) increased dopamine signaling in the nucleus accumbens core to rewards and to cues immediately preceding them, but not to more distal predictive cues. This elevated dopamine occurred independently of changes in reward value and supports increased prediction error signaling. The findings suggest psychedelics could engage error-driven learning mechanisms to disrupt or form new associations.