The present study investigated the role of p11 in NAc CINs in dopamine responses to rewarding stimuli (cocaine, palatable food and female mouse encounter). The extracellular dopamine and acetylcholine (ACh) levels in the NAc were determined in freely moving male mice using in vivo microdialysis.
Rewarding stimuli induced an increase in dopamine efflux in the NAc of wild-type mice. The dopamine responses were attenuated in constitutive p11 KO mice. The dopamine response to cocaine was accompanied by an increase in ACh NAc efflux, whereas the attenuated dopamine response to cocaine in p11 KO mice was restored by pharmacological activation of ACh receptors in the NAc.
Dopamine response to cocaine and an increase in ACh were attenuated in mice with deletion of p11 from cholinergic neurons (ChAT-p11 cKO mice), whereas gene delivery of p11 to CINs and chemogenetic activation of CINs restored the dopamine responses.
Thus, p11 in NAc CINs plays a critical role in activating these neurons to mediate dopamine responses to rewarding stimuli. The dysregulation of mesolimbic dopamine system by dysfunction of p11 in NAc CINs may be involved in pathogenesis of depressive states.