Effects of psychedelic, DOI, on nucleus accumbens dopamine signaling to predictable rewards and cues in rats

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.

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Abstract

Psychedelics produce lasting therapeutic responses in neuropsychiatric diseases suggesting they may disrupt entrenched associations and catalyze learning. Here, we examine psychedelic 5-HT2A/2C agonist, DOI, effects on dopamine signaling in the nucleus accumbens (NAc) core, a region extensively linked to reward learning, motivation, and drug-seeking. We measure phasic dopamine transients following acute DOI administration in rats during well learned Pavlovian tasks in which sequential cues predict rewards. We find that DOI (0.0-1.2 mg/kg, i.p.) increases dopamine signals, photometrically measured using GRABDA optical sensor, to rewards and proximal reward cues, but not to the distal cues that predict these events. We determine that the elevated dopamine produced by DOI to reward cues occurs independently of DOI-induced changes in reward value. The increased dopamine associated with predictable reward cues and rewards supports DOI-induced increases in prediction error signaling. These findings lay a foundation for developing psychedelic strategies aimed at engaging error-driven learning mechanisms to disrupt entrenched associations or produce new associations.