In the Ventral Tegmental Area, G-Proteins and cAMP Mediate the Neurosteroid 3α,5α-THP’s Actions at Dopamine Type 1 Receptors for Lordosis of Rats

Petralia, Sandra M.; Frye, Cheryl A.

doi:10.1159/000082752

Cited by 26 publications

(42 citation statements)

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“…I.V. or intra-VTA infusions of a D 1 antagonist attenuate, and of a D 1 agonist, enhance lordosis of naturally-receptive or hormone-primed rodents (Frye and Vongher, 1999a;Frye et al, 2000aPetralia and Frye, 2004). Thus, in the VTA, progestins may facilitate lordosis, in part, via actions at D 1 .…”

Section: Progestin-dopamine Receptor Interactionsmentioning

confidence: 99%

“…D 1 density is higher concomitant with elevated progestin levels during behavioral estrus than during diestrus (Levesque and Di Paolo, 1990). 3α,5α-THP and dopamine levels are greater in the midbrain of receptive compared with non-receptive rats, and are further increased with mating (Frye, 2001 Vongher, 1999a;Frye et al, 2000aPetralia and Frye, 2004 The data discussed above indicate effects, sources, and substrates of 3α,5α-THP-facilitated lordosis. Briefly: (1) 3α,5α-THP in the VTA facilitates lordosis of rodents.…”

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confidence: 98%

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3α-hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area mediates social, sexual, and affective behaviors

et al. 2006

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Progestins mediate the onset and duration of lordosis, the mating posture of female rodents, through actions in the hypothalamus and ventral tegmental area. In the hypothalamus, progesterone has traditional, "genomic" actions via intracellular progestin receptors. In the ventral tegmental area, 3α-hydroxy-5α-pregnan-20-one has "non-genomic" actions independent of progestin receptors to facilitate lordosis that involve GABA A /benzodiazepine receptors, NMDA type glutamate receptors, and/or dopamine receptors. 3α-Hydroxy-5α-pregnan-20-one levels also change with behavioral and/ or environmental stimuli and may have a role in other reproductively-relevant behaviors, such as affiliation, exploration, and anxiety (socio-sexual behaviors). Data are reviewed that support the notion that: 1) effects of 3α-hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area facilitate lordosis and other reproductively-relevant behaviors. 2) 3α-Hydroxy-5α-pregnan-20-one, formed in the ventral tegmental area from metabolism of progestins, produced peripherally by endocrine glands, or centrally from biosynthesis in glial cells mediates socio-sexual behaviors. 3) 3α-Hydroxy-5α-pregnan-20-one's actions at GABA A /benzodiazepine receptors, NMDA type glutamate receptors, and dopamine receptors in the ventral tegmental area are important for lordosis; however, effects at these substrates on socio-sexual behaviors have not been elucidated. Given 3α-hydroxy-5α-pregnan-20-one's involvement in stress responses, its putative role as a homeostatic regulator and in the pathophysiology and treatment of neuropsychiatric disorders is discussed. Keywords steroidogenesis; GABA A receptors; NMDA receptors; dopamine; stress response; mood Our research focuses on the mechanisms of progestins' actions in the midbrain ventral tegmental area (VTA) that mediate the onset and duration of sexual behavior of female rodents. To date, the majority of our investigations have utilized a model system in which progestins' mechanisms are manipulated in the VTA and/or the hypothalamus of ovariectomized (OVX), estrogen (E)-primed rodents. The effects on lordosis, the stereotypic posture which female * Correspondence to: C. A. Frye, Department of Psychology, Social Science 369, the University at Albany-SUNY, 1400 Washington Avenue, Albany, NY 12222, USA. Tel: +1-518-442-4836; fax: +1-518-442-4867. E-mail address: cafrye@cnsunix.albany.edu (C. A. Frye). NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 September 2. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript rodents assume to enable mating to occur (given appropriate hormonal and environmental stimulation), are then used as a bioassay to indicate which mechanisms of progestins are required for lordosis. This approach has revealed that progesterone (P) has classic actions through intracellular progestin receptors (PRs-"genomic" actions) in the hypothalamus to initiate lordosis, but P's metabolite, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP),...

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Section: Progestin-dopamine Receptor Interactionsmentioning

confidence: 99%

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confidence: 98%

3α-hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area mediates social, sexual, and affective behaviors

et al. 2006

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“…In the VMH, E 2 and P 4 initiate lordosis through classical actions at intracellular progestin receptors (PRs). However, in the VTA, P 4 modulates the duration and intensity of lordosis responses following metabolism to, and/or de novo synthesis of, 5α-pregnan-3α-ol-20-one (3α,5α-THP) and its subsequent actions at GABA A , dopamine-like type 1, and/or NMDA receptors and subsequent downstream signal transduction processes [5][6][7][8][9][10][11][12]. By using lordosis as a bioassay, we have elucidated that these are some of the mechanisms by which 3α,5α-THP has actions in the VTA to mediate mating.…”

Section: Introductionmentioning

confidence: 99%

Infusions of 3α,5α-THP to the VTA enhance exploratory, anti-anxiety, social, and sexual behavior and increase levels of 3α,5α-THP in midbrain, hippocampus, diencephalon, and cortex of female rats

Frye

Rhodes

2008

Behavioural Brain Research

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Abstract17β-Estradiol (E 2 ) and progesterone (P 4 ) influence the onset and duration of sexual behavior and are also associated with changes in behaviors that may contribute to mating, such as exploration, anxiety, and social behaviors (socio-sexual behaviors). In the midbrain ventral tegmental area (VTA), the P 4 metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), modulates lordosis of E 2 -primed rodents; 3α,5α-THP can also influence anxiety and social behaviors. To examine if 3α,5α-THP in the VTA mediates socio-sexual behaviors, we infused 3α,5α-THP to the VTA of diestrous and proestrous rats. As expected, proestrous, compared to diestrous, rats showed more exploratory (open field), anxiolytic (elevated plus maze), pro-social (partner preference, social interaction), and sexual (paced mating) behavior and had increased E 2 , P 4 , dihydroprogesterone (DHP), and 3α,5α-THP in serum, midbrain, hippocampus, diencephalon, and cortex. Infusions of 3α,5α-THP to the VTA, but not control sites, such as the substantia nigra (SN) or central grey (CG), of diestrous rats produced behavioral and endocrine effects akin to that of proestrous rats and increased DHP and 3α,5α-THP levels in midbrain, hippocampus, and diencephalon. Levels of DHP and 3α,5α-THP, but neither E 2 nor P 4 concentrations, in midbrain, hippocampus, diencephalon, and/or cortex were positively correlated with socio-sexual behaviors. Thus, 3α,5α-THP infusions to the VTA, but not SN or CG, can enhance socio-sexual behaviors and increase levels in midbrain, hippocampus, and diencephalon.

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“…D 1 are well-known G-protein coupled receptors and GBRs can also activate G-proteins and 2nd messengers (Fancsik et al 2000;Stoof and Kebabian 1984). Indeed, progestins' actions at D 1 and/or GBRs in the VTA require activation of G-proteins, cyclic AMP (cAMP)-dependent protein kinase A, phospholipase C, and/ or PKC for lordosis (Frye et al 2006b;Petralia and Frye 2004;Petralia et al 2006;Frye and Walf 2007, papers submitted for publication). Modulating these signal transduction pathways only had effects when administered to E 2 -and progestinprimed hamsters and rats, and there was little evidence for effects for E 2 -faciliated lordosis.…”

Section: Discussionmentioning

confidence: 99%

“…Dopamine-like type 1 receptors (D 1 ) in the VTA are another target of 3α,5α-THP for its rapid effects to mediate lordosis. Administration of the D 1 agonist, SKF38393, or the D 1 antagonist, SCH23390, respectively, increase and decrease progestin-facilitated lordosis of E 2 -primed, ovariectomized (ovx) rats and hamsters Petralia and Frye 2004;Sumida et al 2005). Indeed, there is an interaction between effects of 3α,5α-THP at both GBRs and D 1 receptors in the VTA for lordosis.…”

Section: Introductionmentioning

confidence: 99%

Effects of manipulating progesterone and NMDA receptors in the ventral tegmental area for lordosis of hamsters and rats

2008

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Rationale-Progesterone (P 4 ) has actions in the ventral tegmental area (VTA) to regulate female sexual behavior in rodents. However, there are few intracellular progestin receptors (PRs) that have been identified in the VTA through which P 4 may have its actions to facilitate lordosis. There are N-methyl-D-aspartate receptors (NMDARs) in the VTA that may be a substrate for P 4 's effects.Objective-We investigated the effects of pharmacologically manipulating NMDARs in the VTA for E 2 -and P 4 -facilitated lordosis of hamsters and rats.Materials and methods-We examined the effect of systemic injections (intraperitoneal; IP) and bilateral infusions to the VTA of the highly specific, competitive NMDAR antagonist, 9-0-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959); 0, 0.3, and 1 mg/kg IP and 0, 1.0, and 10 ng/μl intra-VTA), on lordosis of estradiol-primed (E 2 ; 10 μg) and P 4 -primed (0, 50, 250, or 500 μg) ovariectomized hamsters and rats.Results-Intra-VTA administration of the NMDAR antagonist, LY235959, produced similar effects as systemic administration to enhance lordosis, particularly in E 2 -primed rats or hamsters administered moderate P 4 levels (less than 500 μg). Administration of LY235959 to the substantia nigra did not produce similar effects as intra-VTA infusions for lordosis.Conclusions-Together, these data suggest that blocking NMDARs in the VTA enhances lordosis of hamsters and rats.

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In the Ventral Tegmental Area, G-Proteins and cAMP Mediate the Neurosteroid 3α,5α-THP’s Actions at Dopamine Type 1 Receptors for Lordosis of Rats

Cited by 26 publications

References 96 publications

3α-hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area mediates social, sexual, and affective behaviors

3α-hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area mediates social, sexual, and affective behaviors

Infusions of 3α,5α-THP to the VTA enhance exploratory, anti-anxiety, social, and sexual behavior and increase levels of 3α,5α-THP in midbrain, hippocampus, diencephalon, and cortex of female rats

Effects of manipulating progesterone and NMDA receptors in the ventral tegmental area for lordosis of hamsters and rats

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