The hippocampus and PFC send glutamatergic projections (red) to the NAc where they excite D1R-expressing GABAergic MSNs. These cells inhibit a population of interneurons within the VTA that form GABAergic inhibitory synapses (blue) onto dopaminergic VTA cells (green) projecting back to the NAc, hippocampus, and PFC. When the hippocampus or PFC are active, they excite D1R cells, thereby disinhibiting VTA dopaminergic cells and promoting dopamine release (left panel). There is a distinct circuit mediating responses to negative stimuli in which glutamatergic cells in the LHb project to GABAergic neurons in the rostromedial tegmentum (RMTg), which in turn inhibit dopaminergic neurons in the VTA. Chronic stress induces anhedonia and other reward-related symptoms of depression because of a weakening of excitatory synapses in the hippocampus and PFC and because of a weakening of excitatory synapses on D1R MSNs. There is also a potentiation of excitatory inputs onto LHb neurons, resulting in an increase in the excitation of RMTg neurons and subsequent increase in the inhibition of VTA cells. These changes synergistically increase the inhibition of VTA dopaminergic cells thereby impairing dopamine release (center panel). Effective antidepressant therapies (SSRIs, ketamine, DBS, or ECT) can all trigger an activity- and/or serotonin-dependent strengthening of excitatory synapses in the hippocampus, PFC, and NAc, thereby restoring the normal release of dopamine in response to rewarding stimuli (right panel). Evidence of changes in synaptic excitation: 1. (Lim et al., 2012 []); 2. (Yuen et al., 2012; Li et al., 2011; Liston et al., 2006; Radley et al., 2008; Liu and Aghajanian, 2008 [–,,]); 3. (Kallarackal et al., 2013; Alfarez et al., 2003; Schmidt et al., 2010; Watanabe et al., 1992; Sousa et al., 2000 [,,,,]). 4. (Li et al., 2011 []); 5. (Stamatkis and Stuber, 2012 []). Evidence of synaptic strengthening by ADs: 6. (Cai et al., 2013, SSRI []; Conrad et al., 1996, tricyclic []). 7. (Li et al., 2011, ketamine []); 8. (Covington et al., 2010, LTP? []).