ABSTRACT
Progesterone and its metabolites (progestogens) mediate reproductive behaviors and social approach, which can involve reward functions and differences in stress/affective responses. In order to elucidate some of the mechanisms through which this may occur, we have focused on novel mechanisms of progestogens in the midbrain ventral tegmental area. The focus has been in the midbrain ventral tegmental area because this is an area of the brain with high concentrations of progestogens coincident with reproductive behavior and pregnancy of rodents, but lacking in progestin receptors (the traditional target of progestogens), unlike the hypothalamus. We have manipulated progestogens’ actions in this region of naturally cycling or ovariectomized, estrogen- and progestogen-primed rodents and used lordosis behavior as a bioassay. We were the first to use antibody haptens, as large macromolecules, to demonstrate that membrane actions of progesterone and its metabolite, allopregnanolone, in the midbrain, but not hypothalamus, were sufficient to facilitate lordosis. Allopregnanolone is produced as a metabolite of progesterone as well as produced de novo in the midbrain ventral tegmental area to facilitate and later sequentially inhibit lordosis. Recent studies have shown that in addition to steroidogenic enzymes involved for brain-derived progestogens, pregnane xenobiotic receptors are a cellular target for progestogen formation (as a response to, and to stimulate) social behaviors. Peripheral and brain-derived progestogens have actions at membrane receptors (GABAA and dopamine type 1 receptors, membrane progestin receptors). Mechanisms involved in lordosis are similar to those seen for attractivity, approach, and proceptivity, which notably results in increases in progestogens and termination of mating. Commensurate with changes in social approach are expected variations in anxiety and depression and stress. We have examined organizing effects of progestogens through prenatal stress, which decreases gestational length, and produces anxiety- and depression-like phenotypes and alters the HPA axis. Social buffers mitigate acute and chronic effects of stress via progestogens’ actions on the HPA axis and parasympathetic nervous system to enhance recovery. Thus, progesterone can have activational and organizational effects to alter broad aspects of social behavior of mammals.
