Skip to main content
. Author manuscript; available in PMC: 2019 Feb 6.
Published in final edited form as: Annu Rev Pharmacol Toxicol. 2018 Oct 8;59:213–236. doi: 10.1146/annurev-pharmtox-010617-052811

Figure 2.

Figure 2

Circuits implicated in rapid antidepressant action. Simplified diagram of circuits promoting reward behavior in response to rewarding stimuli (a) and limiting reward behavior in response to aversive stimuli (b). Locations of key nodes in the reward circuitry are shown (i) superimposed on a parasagittal section of the mouse brain and (ii) in schematic form. Excitatory glutamatergic neurons and projections (green), inhibitory GABAergic neurons and projections (red), and dopaminergic neurons and projections (black) are shown. (a) Critical features of rewarding stimuli are perceived in the HPC and PFC and relayed by excitatory projections to the NAc. GABAergic medium spiny neurons in the NAc synapse onto VTA GABAergic interneurons reducing their inhibition of dopamine back to the telencephalon, overall promoting behaviors that combine to signal reward via dopaminergic connections. (b) Aversive stimuli decrease dopamine output by the VTA as the result of projections from the LHb to the RMTg. As shown in Figure 1, ketamine and hydroxynorketamines may act by strengthening excitatory synapses weakened in depression (5, 122). Ketamine may also act as an NMDAR antagonist to reduce depression-induced high-frequency burst firing of LHb neurons (78). Abbreviations: GABA, γ-aminobutyric acid; HPC, hippocampus; LHb, lateral habenula; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; PFC, prefrontal cortex; RMTg, rostromedial tegmentum; VTA, ventral tegmental area.