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. Author manuscript; available in PMC: 2021 Mar 15.
Published in final edited form as: Neuropharmacology. 2019 Dec 24;165:107924. doi: 10.1016/j.neuropharm.2019.107924

Figure 5. Cellular and molecular mechanisms proposed to mediate corticosterone excitation within the ventral hippocampus.

Figure 5.

The ventral hippocampus is known to have an extensive interneuronal network (shown in red) responsible for regulating local excitation (Chamberland and Topolnik, 2012; Freund and Buzsaki, 1996; Leranth and Hajszan, 2007). Therefore, we propose the ventral hippocampus’ glutamatergic efferents responsible for stimulating accumbal dopamine release (shown in green) may be under tonic inhibition by GABAergic interneuron- and interneuron-inhibiting interneurons (called interneuron-specific interneurons, IS-Is) under basal conditions. We conclude that corticosterone activation of presynaptic membrane mineralocorticoid receptors (MR, purple circles) potentiates local glutamate release onto the ventral hippocampus’ glutamatergic efferents (Bekkers and Stevens, 1989; Karst et al., 2005). Membrane mineralocorticoid receptors also exist postsynaptically and can rapidly and reversibly potentiate glutamate release in the hippocampus; these have not been shown in the figure for the sake of simplicity. However, we propose activation of postsynaptic cytosolic glucocorticoid receptors (GR, blue circles) is also required to induce top-down disinhibition of the glutamatergic efferents whose terminal actions regulate accumbal dopamine output (Liu et al., 2010; Maggio and Segal, 2009; Zeise et al., 1992). The disinhibiting effects of GR activation are thought to occur through its induction of the retrograde signaling (RN: retrograde neurotransmitter) components 2-Arachidonoylglycerol (2-AG; an ester/lipid endocannabinoid), nitric oxide (NO; a gas), and/or serotonin (5-HT; an amino acid), which have been shown to act on inhibitory Gi/o-coupled Type I cannabinoid (CB1) receptors, NO-sensitive guanylyl cyclase, and inhibitory 5-HT1A- and excitatory 5-HT3 receptors (respectively) on the presynaptic terminals of presynaptic GABAergic interneurons (Barr and Forster, 2011; Di et al., 2016; Di et al., 2003; Hu et al., 2010; Li et al., 2014). Overall, we propose GR activation disinhibits GABAergic suppression of the ventral hippocampus’ principal glutamatergic efferents that project to the mesolimbic dopamine system, enabling MR-induced depolarizing events to regulate accumbal excitation/inhibition and dopamine release.