Fig. 4: Circuit diagrams for proposed effects of chronic social stress and GPR52-inverse agonism on dopamine signaling in nucleus accumbens.

The current findings are interpreted within the framework of the indirect NAc pathway of VTA regulation. It should be noted that the depiction that VP GABA neurons that are post-synaptic to NAc D2R MSNs themselves project to VTA or RMTg is an assumption, albeit widely accepted as an integral component of the indirect pathway. A Basal state: an adaptive level of firing by VTA DA neurons results in adaptive DA release on to NAc MSNs. NAc D2R-MSNs binding of DA reduces their firing and inhibition of VP GABA neurons. VP GABA neurons exert adaptive inhibition of VTA GABA interneurons and RMTg GABA neurons. VTA/RMTg GABA (inter)neurons exert adaptive inhibition on VTA DA neurons. Appetitive behavior leading to an incentive stimulus is processed as primarily rewarding by BA glutamate aversion neurons (A) and reward neurons (R) projecting to NAc D2R- and D1R-MSNs, respectively: phasic DA release is adaptive and incentive motivation is high. B Chronic stress state: a low level of firing by VTA DA neurons results in low DA release on to NAc MSNs. NAc D2R-MSNs binding low DA increases their firing and inhibition of VP GABA neurons. VP GABA neurons exert low inhibition of VTA GABA interneurons and RMTg GABA neurons. VTA/RMTg GABA (inter)neurons exert high inhibition of VTA DA neurons. Appetitive behavior leading to an incentive stimulus is processed as primarily aversive by BA A and R projecting to NAc D2R- and D1R-MSNs, respectively: phasic DA release is low and incentive motivation is low. C Chronic stress state and GPR52 inverse agonist: a low level of firing by VTA DA neurons results in reduced DA release. NAc D2R-MSNs binding low DA increase their firing but inhibition of VP GABA neurons is blocked by GPR52 inverse agonist. VP GABA neurons exert adaptive inhibition of VTA GABA interneurons and RMTg GABA neurons. VTA/RMTg GABA (inter)neurons exert low inhibition of VTA DA neurons. An adaptive level of firing by VTA DA neurons results in adaptive DA release on to NAc MSNs. Despite appetitive behavior leading to an incentive stimulus being processed as primarily aversive by BA A and R projecting to NAc D2R- and D1R-MSNs, respectively: phasic DA release is adaptive and incentive motivation is high. BA basal amygdala, R glutamate reward neuron, A glutamate aversion neuron, NAc nucleus accumbens, D1R medium spiny neuron expressing dopamine receptor 1, D2R medium spiny neuron expressing dopamine receptor 2, VP ventral pallidum, VTA ventral tegmental area, RMTg rostro-medial tegmentum.