Progestins have multiple mechanisms of action in the central nervous system that are important for modulating lordosis of female rats. In the ventral tegmental area (VTA), progestins, such as the progesterone metabolite and neurosteroid 5α-pregnan-3α-ol-20-one (3α,5α-THP), regulate lordosis via actions independent of intracellular progestin receptors. We hypothesized that if, in the VTA, dopamine type 1 receptors (D1), G-proteins, and adenosine 3′,5′-monophosphate (cAMP) are downstream effectors of 3α,5α-THP’s actions for lordosis, then pharmacological manipulations of these signaling molecules will produce changes in 3α,5α-THP-facilitated lordosis of estradiol (E2)-primed rats. VTA infusions of 3α,5α-THP (50 ng) or 3α,5α-THP and the D1 agonist SKF38393 (100 ng) increased lordosis of ovariectomized, E2 (10 µg)- primed rats, compared to vehicle. Both 3α,5α-THP- and 3α,5α-THP plus SKF38393-facilitated lordosis was reduced by VTA infusions of the G-protein inhibitor guanosine 5′-O-(2-thiodiphosphate) (GDP-β-S; 50 µM), but not vehicle. Also, in the VTA, blocking D1 with SCH23390 (100 ng) decreased, or increasing cAMP with 8-bromo-cAMP (200 ng) enhanced, 3α,5α-THP-facilitated lordosis of E2-primed rats. Notably, SCH23390’s inhibitory effects on 3α,5α-THP-facilitated lordosis were reversed by 8-bromo-cAMP. Thus, in the VTA, 3α,5α-THP’s actions for lordosis may involve activation of D1 and initiation of the G-protein-mediated second messenger cAMP.

Etgen AM: Progestin receptors and the activation of female reproductive behavior: A critical review. Horm Behav 1984;18:411–430.
Molenda HA, Griffin AL, Auger AP, McCarthy MM, Tetel MJ: Nuclear receptor coactivators modulate hormone-dependent gene expression in brain and female reproductive behavior in rats. Endocrinology 2002;143:436–444.
Molenda HA, Kilts CP, Allen RL, Tetel MJ: Nuclear receptor coactivator function in reproductive physiology and behavior. Biol Reprod 2003;69:1449–1457.
Blaustein JD, King JC, Toft DO, Turcotte J: Immunocytochemical localization of estrogen-induced progestin receptors in guinea pig brain. Brain Res 1988;474:1–15.
Frye CA, Vongher JM: GABAA, D1, and D5, but not progestin receptor, antagonist and anti-sense oligonucleotide infusions to the ventral tegmental area of cycling rats and hamsters attenuate lordosis. Behav Brain Res 1999;103:23–34.
MacLusky NJ, McEwen BS: Progestin receptors in rat brain: Distribution and properties of cytoplasmic progestin-binding sites. Endocrinology 1980;106:192–202.
Lonstein JS, Blaustein JD: Immunocytochemical investigation of nuclear progestin receptor expression within dopaminergic neurones of the female rat brain. J Neuroendocrinol 2004;16:534–543.
Frye CA: The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents. Brain Res Brain Res Rev 2001;37:201–222.
Frye CA: The role of neurosteroids and nongenomic effects of progestins in the ventral tegmental area in mediating sexual receptivity of rodents. Horm Behav 2001;40:226–233.
Frye CA, Petralia SM: Lordosis of rats is modified by neurosteroidogenic effects of membrane benzodiazepine receptors in the ventral tegmental area. Neuroendocrinology 2003;77:71–82.
Frye CA, Petralia SM: Mitochondrial benzodiazepine receptors in the ventral tegmental area modulate sexual behaviour of cycling or hormone-primed hamsters. J Neuroendocrinol 2003;15:677–686.
McCarthy MM, Masters DB, Fiber JM, Lopez-Colome AM, Beyer C, Komisaruk BR, Feder HH: GABAergic control of receptivity in the female rat. Neuroendocrinology 1991;53:473–479.
Fancsik A, Linn DM, Tasker JG: Neurosteroid modulation of GABA IPSCs is phosphorylation dependent. J Neurosci 2000;20:3067–3075.
Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM: Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986;232:1004–1007.
Harrison NL, Majewska MD, Harrington JW, Barker JL: Structure-activity relationships for steroid interaction with the γ-aminobutyric acidA receptor complex. J Pharmacol Exp Ther 1987;241:346–353.
Frye CA, Vongher JM: Progestins’ rapid facilitation of lordosis when applied to the ventral tegmentum corresponds to efficacy at enhancing GABAA receptor activity. J Neuroendocrinol 1999;11:829–837.
Apostolakis EM, Garai J, Fox C, Smith CL, Watson SJ, Clark JH, O’Malley BW: Dopaminergic regulation of progesterone receptors: brain D5 dopamine receptors mediate induction of lordosis by D1-like agonists in rats. J Neurosci 1996;16:4823–4834.
Frye CA, Bayon LE, Vongher J: Intravenous progesterone elicits a more rapid induction of lordosis in rats than does SKF38393. Psychobiology 2000;28:99–109.
Mani SK, Allen JM, Clark JH, Blaustein JD, O’Malley BW: Convergent pathways for steroid hormone- and neurotransmitter-induced rat sexual behavior. Science 1994;265:1246–1249.
Foreman MM, Moss RL: Role of hypothalamic dopaminergic receptors in the control of lordosis behavior in the female rat. Physiol Behav 1979;22:283–289.
Boyson SJ, McGonigle P, Molinoff PB: Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine receptors in rat brain. J Neurosci 1986;6:3177–3188.
Huang Q, Zhou D, Chase K, Gusella JF, Aronin N, DiFiglia M: Immunohistochemical localization of the D1 dopamine receptor in rat brain reveals its axonal transport, pre- and postsynaptic localization, and prevalence in the basal ganglia, limbic system, and thalamic reticular nucleus. Proc Natl Acad Sci USA 1992;89:11988–11992.
Collado ML, Rodriguez-Manzo G, Cruz ML: Effect of progesterone upon adenylate cyclase activity and cAMP levels on brain areas. Pharmacol Biochem Behav 1985;23:501–504.
Frye CA, Petralia SM: 3α,5α-THP’s actions in the ventral tegmental area for lordosis: A model system for defining function and mechanisms of progestins; in Smith S (ed): Neurosteroids and the GABAA Receptor. Boca Raton, CRC Press, 2003, pp 265–290.
Mani SK, Fienberg AA, O’Callaghan JP, Snyder GL, Allen PB, Dash PK, Moore AN, Mitchell AJ, Bibb J, Greengard P, O’Malley BW: Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice. Science 2000;287:1053–1056.
Beyer C, Canchola E, Larsson K: Facilitation of lordosis behavior in the ovariectomized estrogen primed rat by dibutyryl cAMP. Physiol Behav 1981;26:249–251.
Petralia SM, Frye CA: Ventral tegmental are infusions of the cAMP analogue 8-bromo-cAMP increase lordosis of cycling and hormone-primed rats and hamsters. Horm Behav 2003;44:70.
Etgen AM, Chu HP, Fiber JM, Karkanias GB, Morales JM: Hormonal integration of neurochemical and sensory signals governing female reproductive behavior. Behav Brain Res 1999;105:93–103.
Etgen AM, Karkanias GB: Estrogen regulation of noradrenergic signaling in the hypothalamus. Psychoneuroendocrinology 1994;19:603–610.
Stoof JC, Kebabian JW: Two dopamine receptors: Biochemistry, physiology and pharmacology. Life Sci 1984;35:2281–2296.
Greengard P, Allen PB, Nairn AC: Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 1999;23:435–447.
Greengard P, Nairn AC, Girault JA, Ouinet CC, Snyder GL, Fisone G, Allen PB, Fienberg A, Nishi A: The DARPP-32/protein phosphatase-1 cascade: A model for signal integration. Brain Res Brain Res Rev 1998;26:274–284.
Hemmings HC Jr, Greengard P, Tung HY, Cohen P: DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. Nature 1984;310:503–505.
Hemmings HC Jr, Nairn AC, Greengard P: Protein kinases and phosphoproteins in the nervous system. Res Publ Assoc Res Nerv Ment Dis 1986;64:47–69.
Paxinos G, Watson C: The Rat Brain. New York, Academic Press, 1986.
Marshall JF, Teitelbaum P: Further analysis of sensory inattention following lateral hypothalamic damage in rats. J Comp Physiol Psychol 1974;86:375–395.
Frye CA, Walf AA, Sumida K: Progestins’ actions in the VTA to facilitate lordosis involve dopamine-like type 1 and 2 receptors. Pharmacol Biochem Behav 2004;78:405–418.
Sluka KA, Willis WD: The effects of G-protein and protein kinase inhibitors on the behavioral responses of rats to intradermal injection of capsaicin. Pain 1997;71:165–178.
Uphouse L, Maswood S, Jackson A: Factors elevating cAMP attenuate the effects of 8-OH-DPAT on lordosis behavior. Pharmacol Biochem Behav 2000;66:383–388.
Liu QY, Chang YH, Schaffner AE, Smith SV, Barker J: Allopregnanolone activates GABAA receptor/Cl channels in a multiphasic manner in embryonic rat hippocampal neurons. J Neurophysiol 2002;88:1147–1158.
Frye CA, Gardiner SG: Progestins can have a membrane-mediated action in rat midbrain for facilitation of sexual receptivity. Horm Behav 1996;30:682–691.
Hardy DF, Debold JF: Effects of mounts without intromission upon the behavior of female rats during the onset of estrogen-induced heat. Physiol Behav 1971;7:643–645.
Pfaus JG, Smith WJ, Byrne N, Stephens G: Appetitive and consummatory sexual behaviors of female rats in bilevel chambers. II. Patterns of estrus termination following vaginocervical stimulation. Horm Behav 2000;37:96–107.
Ahlenius S: Brain monoaminergic neurotransmission in the mediation of lordosis behavior in the female rat. Neurosci Biobehav Rev 1993;17:43–49.
Hamburger-Bar R, Rigter H: Apomorphine: Facilitation of sexual behaviour in female rats. Eur J Pharmacol 1975;32:357–360.
Beyer C, Gonzalez-Flores O, Gonzalez-Mariscal G: Progesterone receptor participates in the stimulatory effect of LHRH, prostaglandin E2, and cyclic AMP on lordosis and proceptive behaviours in rats. J Neuroendocrinol 1997;9:609–614.
Etgen AM, Barfield RJ: Antagonism of female sexual behavior with intracerebral implants of antiprogestin RU 38486: Correlation with binding to neural progestin receptors. Endocrinology 1986;119:1610–1617.
Gonzalez-Mariscal G, Gonzalez-Flores O, Beyer C: Intrahypothalamic injection of RU486 antagonizes the lordosis induced by ring A-reduced progestins. Physiol Behav 1989;46:435–438.
Lacey MG, Mercuri NB, North RA: On the potassium conductance increase activated by GABAB and dopamine D2 receptors in rat substantia nigra neurones. J Physiol 1988;401:437–453.
Johnson SW, North RA: Two types of neurone in the rat ventral tegmental area and their synaptic inputs. J Physiol 1992;450:455–468.
Rodriguez-Pallares J, Caruncho HJ, Lopez-Real A, Wojcik S, Guerra MJ, Labandeira-Garcia JL: Rat brain cholinergic, dopaminergic, noradrenergic and serotonergic neurons express GABAA receptors derived from the α3 subunit. Receptors Channels 2001;7:471–478.
Seabrook GR, Howson W, Lacey MG: Electrophysiological characterization of potent agonists and antagonists at pre- and postsynaptic GABAB receptors on neurones in rat brain slices. Br J Pharmacol 1990;101:949–957.
Bonci A, Malenka RC: Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area. J Neurosci 1999;19:3723–3730.
Kalivas PW, Duffy P: D1 receptors modulate glutamate transmission in the ventral tegmental area. J Neurosci 1995;15:5379–5388.
Steffensen SC, Svingos AL, Pickel VM, Henriksen SJ: Electrophysiological characterization of GABAergic neurons in the ventral tegmental area. J Neurosci 1998;18:8003–8015.
Kalivas PW, Duffy P, Eberhardt H: Modulation of A10 dopamine neurons by γ-aminobutyric acid agonists. J Pharmacol Exp Ther 1990;253:858–866.
MacNeil D, Gower M, Szymanska I: Response of dopamine neurons in substantia nigra to muscimol. Brain Res 1978;154:401–403.
Walters JR, Lakoski JM: Effect of muscimol on single unit activity of substantia nigra dopamine neurons. Eur J Pharmacol 1978;47:469–471.
Grace AA, Bunney BS: Paradoxical GABA excitation of nigral dopaminergic cells: Indirect mediation through reticulata inhibitory neurons. Eur J Pharmacol 1979;59:211–218.
Waszczak BL, Walters JR: Intravenous GABA agonist administration stimulates firing of A10 dopaminergic neurons. Eur J Pharmacol 1980;66:141–144.
Klitenick MA, DeWitte P, Kalivas PW: Regulation of somatodendritic dopamine release in the ventral tegmental area by opioids and GABA: An in vivo microdialysis study. J Neurosci 1992;12:2623–2632.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.