Effects and Mechanisms of 3α,5α,-THP on Emotion, Motivation, and Reward Functions Involving Pregnane Xenobiotic Receptor

Abstract

Progestogens [progesterone (P4) and its products] play fundamental roles in the development and/or function of the central nervous system during pregnancy. We, and others, have investigated the role of pregnane neurosteroids for a plethora of functional effects beyond their pro-gestational processes. Emerging findings regarding the effects, mechanisms, and sources of neurosteroids have challenged traditional dogma about steroid action. How the P4 metabolite and neurosteroid, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), influences cellular functions and behavioral processes involved in emotion/affect, motivation, and reward, is the focus of the present review. To further understand these processes, we have utilized an animal model assessing the effects, mechanisms, and sources of 3α,5α-THP. In the ventral tegmental area (VTA), 3α,5α-THP has actions to facilitate affective, and motivated, social behaviors through non-traditional targets, such as GABA, glutamate, and dopamine receptors. 3α,5α-THP levels in the midbrain VTA both facilitate, and/or are enhanced by, affective and social behavior. The pregnane xenobiotic receptor (PXR) mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. The role of PXR to influence 3α,5α-THP production from central biosynthesis, and/or metabolism of peripheral P4, in the VTA, as well as its role to facilitate, or be increased by, affective/social behaviors is under investigation. Investigating novel behavioral functions of 3α,5α-THP extends our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate affect and motivated processes, such as those important for stress regulation and neuropsychiatric disorders (anxiety, depression, schizophrenia, drug dependence). Thus, further understanding of 3α,5α-THP’s role and mechanisms to enhance affective and motivated processes is essential.

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

“…PXR is a nuclear receptor that binds steroids, such as 3α,5α-THP, and influences transcription of cytochrome P450 enzymes that are involved in metabolism of many factors, including cholesterol and steroids (139-141). Although PXR is generally regarded for its role in the liver, it has been identified in brain regions, involved in motivation, affect and cognition, such as the ventral tegmental area, hippocampus, and cortex in mammals (9, 142-145). PXR is required for production of 3α,5α-THP and its actions for lordosis in the VTA, as well as for anxiety-related behaviours in the hippocampus (9, 143, 144, 146-149).…”

“…Although PXR is generally regarded for its role in the liver, it has been identified in brain regions, involved in motivation, affect and cognition, such as the ventral tegmental area, hippocampus, and cortex in mammals (9, 142-145). PXR is required for production of 3α,5α-THP and its actions for lordosis in the VTA, as well as for anxiety-related behaviours in the hippocampus (9, 143, 144, 146-149). Indeed, these effects of PXR may involve the well-known targets of 3α,5α-THP such as, NMDA and GABA A receptors (149).…”

“…3α,5α-THP also modulates serotonin type 3 receptors, neuronal nicotinic acetylcholine receptors, and voltage-activated calcium channels, although with micromolar potency (8). Another site of 3α,5α-THP action, the nuclear pregnane xenobiotic receptor (PXR) has been recently identified (9). In contrast, the sulfated derivative of pregnenolone inhibits GABA release, binds with high affinity to, and promotes trafficking of N-methyl-D-aspartate (NMDA) receptors, thus exerting excitatory actions (10).…”

“…It is still unclear how neuroactive steroids act on their membrane receptor targets, whether it is through paracrine or autocrine mechanisms or by intracellular lateral diffusion through the cell membrane (11). Further, in addition to 3α,5α-THP's action at the aforementioned pharmacodynamics targets, it may also have homeostatic pharmacokinetic effects through its actions at nuclear PXR (9). …”

Finasteride administration potentiates the disruption of prepulse inhibition induced by forced swim stress

“…However, chronic stress induces important reductions in cerebrocortical and plasma concentrations of ALLO [22], which seem related to several disturbances in emotional and motivational responses, and in reward functions [23]. In any case, whether acute or chronic stress, it seems that the maintenance of adequate levels of plasma and/or brain ALLO levels can be protective against the deleterious effects of environmental stress.…”