Cortico-Striatal-Midbrain Circuit Dysregulation Underlying MK-801 Induced Impulsivity and the Ameliorative Effects of SEP

Impulsivity is a core pathological feature of various psychiatric disorders including obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, and schizophrenia, which is conceptualized as dysregulated motivational and inhibitory processes. However, the underlying neural mechanism is poorly known. Using an olfactory cued Go/No-Go task, this work finds increased false alarm rate, shortened licking onset latency, elevated licking frequency and reduced inter-trial consistency in mice treated by the NMDAR antagonist (MK-801). Fiber optic recordings reveal MK-801 enhanced cue-evoked neuronal responses in the olfactory bulb (OB), orbitofrontal cortex (OFC), ventral tegmental area (VTA), and nucleus accumbens (NAc), while reducing reward-predictive cue selectivity and increasing NAc dopamine release. Additionally, in vivo electrophysiological recordings demonstrate that theta oscillation power in the NAc and its coherence with OB, OFC, and VTA are also amplified. MK-801 treatment enhances the correlation between firing rates of NAc neurons and cue, decreases the association with reward, strengthens the correlation with licking and increases the probability of firing peak preceding lick onset. Furthermore, this work confirms that the application of the trace amine-associated receptor 1 agonist SEP-363856 could correct the abnormal responses of NAc neurons and behavioral deficits. These findings elucidate the neural basis of impulsivity and support the potential therapeutic effect of SEP.

NMDAR antagonists; dopamine; impulsivity; schizophrenia; trace amine‐associated receptor.