Biased signaling at NTSR1 differentially regulates inhibitory synaptic transmission in the extended amygdala and suppresses motivated feeding in mice

Maladaptive consummatory behaviors can arise from dysregulated circuits, like the extended amygdala that governs motivation and feeding. Neurotensin (NTS) is expressed throughout the central, peripheral, and enteric nervous systems with well-established roles in energy balance and feeding. SBI-553, a β-arrestin-biased allosteric modulator of NTSR1, recruits β-arrestin while attenuating G q -mediated signaling. We used SBI-553 to examine NTS modulation of extended amygdala GABAergic signaling, and probed its effects on food consumption in mice. Ex vivo , we found that NTS and SBI-553 differentially modulates GABAergic neurotransmission across extended amygdala subregions. In vivo , SBI-553 reduces palatable food consumption in both fed and food-deprived mice, with greater reductions under fasted conditions. SBI-553 alters activation across CeA subregions in a sex- and feeding-state-dependent manner: SBI-553 increases cFos immunofluorescence in the CeA L and CeA C , but not the CeA M . This work supports neurotensinergic modulation as a compelling target for further investigation into the neural substrates of consummatory behaviors. Highlights NTS enhances GABAergic transmission in the CeA L and the ovBNST SBI-553 blocks NTS-induced modulation in the CeA L but not in the ovBNST SBI-553 attenuates feeding of a palatable high-carbohydrate food The effect of SBI-553 on feeding is driven by energy deficit/motivation to feed Graphical Abstract