, Volume 178, Issue 2–3, pp 174–182 | Cite as

In the ventral tegmental area picrotoxin blocks FGIN 1-27-induced increases in sexual behavior of rats and hamsters

  • Sandra M. Petralia
  • Cheryl A. Frye
Original Investigation


Rationale and objectives

There are two types of benzodiazepine receptors, mitochondrial benzodiazepine receptors (MBRs), and γ-aminobutyric acid (GABAA)/benzodiazepine receptor complexes (GBRs). MBR activation increases neurosteroidogenesis. Ventral tegmental area (VTA) infusions of the MBR agonist, FGIN 1-27, increase midbrain levels of the progesterone metabolite 5α-pregnan-3α-ol-20-one (3α,5α-THP) and lordosis of rats and hamsters. Activation of GBRs leads to membrane hyperpolarization. In the VTA, infusions of GBR agonists enhance 3α,5α-THP-facilitated lordosis. Thus, if, in the VTA, MBR-mediated increases in 3α,5α-THP enhance sexual responses via actions at GBRs, then blocking GBRs with picrotoxin will reduce FGIN 1-27-induced increases in sexual behavior of female rodents.


Ovariectomized rats and hamsters, with unilateral guide cannula to the VTA, received estradiol benzoate (10 μg; EB) at hour 0. Hamsters also received progesterone (100 μg) at hour 44. At hour 47.5, all animals were infused first with 10 ng or 20 ng picrotoxin or saline, vehicle to the VTA and, 30 min later, with 5 μg/11.4 nM FGIN 1-27 or saline, vehicle. Ten minutes later, animals were tested for sex and motor behavior.


Picrotoxin, but not vehicle, infusions blocked FGIN 1-27-mediated increases in lordosis of rats and hamsters, proceptivity of rats, and sexual responsiveness of hamsters. In addition, midbrain 3α,5α-THP levels were higher in animals that received VTA infusions of FGIN 1-27, compared to those infused with saline, vehicle.


In the VTA, GBRs are required for MBR-enhanced sexual behavior of EB-primed rats and EB- and progesterone-primed hamsters.


GABAA receptors 5α-Pregnan-3α-ol-20-one Lordosis Neurosteroidogenesis Non-genomic Mitochondrial benzodiazepine receptors 



This study was supported by grants from The National Science Foundation (IBN98-96263, IBN03-16083) and The National Institute of Mental Health (MH06769801). We thank Christine Gervasi for her help with the photomicrograph. The experiments within this study comply with current laws of the United States of America.


  1. Arnt J, Scheel-Kruger J (1979) GABA in the ventral tegmental area: differential regional effects on locomotion, aggression and food intake after microinjection of GABA agonists and antagonists. Life Sci 25:1351–1360CrossRefPubMedGoogle Scholar
  2. Bitran D, Foley M, Audette D, Leslie N, Frye CA (2000) Activation of peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-like effects in the rat. Psychopharmacology 151:64–71CrossRefPubMedGoogle Scholar
  3. Brown RC, Papadopoulos V (2001) Role of the peripheral-type benzodiazepine receptor in adrenal and brain steroidogenesis. Int Rev Neurobiol 46:117–143CrossRefPubMedGoogle Scholar
  4. Chiba T, Murata Y (1985) Afferent and efferent connections of the medial preoptic area in the rat: a WGA-HRP study. Brain Res Bull 14:261–272CrossRefPubMedGoogle Scholar
  5. Ciaccio LA, Lisk RD (1971) The role of progesterone in regulating the period of sexual receptivity in the female hamster. J Endocrinol 50:201–207PubMedGoogle Scholar
  6. Davidson JM, Rodgers CH, Smith ER, Bloch GJ (1968) Stimulation of female sex behavior in adrenalectomized rats with estrogen alone. Endocrinology 82:193–195PubMedGoogle Scholar
  7. DeBold JF, Martin JV, Whalen RE (1976) The excitation and inhibition of sexual receptivity in female hamsters by progesterone: time and dose relationships, neural localization and mechanisms of action. Endocrinology 99:1519–1527PubMedGoogle Scholar
  8. Fancsik A, Linn DM, Tasker JG (2000) Neurosteroid modulation of GABA IPSCs is phosphorylation dependent. J Neurosci 20:3067–3075PubMedGoogle Scholar
  9. Frye CA (2001a) The role of neurosteroids and nongenomic effects of progestins in the ventral tegmental area in mediating sexual receptivity of rodents. Horm Behav 40:226–233CrossRefPubMedGoogle Scholar
  10. Frye CA (2001b) The role of neurosteroids and non-genomic effects of progesterone and androgens in mediating sexual receptivity of rodents. Brain Res Brain Res Rev 37:201–222CrossRefPubMedGoogle Scholar
  11. Frye CA (2001c) Inhibition of 5α-reductase enzyme or GABAA receptors in the VMH and the VTA attenuates progesterone-induced sexual behavior in rats and hamsters. J Endocrinol Invest 24:399–407PubMedGoogle Scholar
  12. Frye CA, Bayon LE (1999) Mating stimuli influence endogenous variations in the neurosteroids 3α,5α-THP and 3α-diol. J Neuroendocrinol 11:839–848CrossRefPubMedGoogle Scholar
  13. Frye CA, DeBold JF(1992) Muscimol facilitates sexual receptivity in hamsters when infused into the ventral tegmentum. Pharmacol Biochem Behav 42:879–887CrossRefPubMedGoogle Scholar
  14. Frye CA, Gardiner SC (1996) Progestins can have a membrane-mediated action in rat midbrain for facilitation of sexual receptivity that is likely GABA mediated. Ital J Anat Embryol 100:162–163Google Scholar
  15. Frye CA, Petralia SM (2003a) Lordosis of rats is modified by neurosteroidogenic effects of membrane benzodiazepine receptors in the ventral tegmental area. Neuroendocrinology 77:71–82CrossRefPubMedGoogle Scholar
  16. Frye CA, Petralia SM (2003b) Mitochondrial benzodiazepine receptors in the ventral tegmental area modulate sexual behaviour of cycling or hormone-primed hamsters. J Neuroendocrinol 15:677–686CrossRefPubMedGoogle Scholar
  17. Frye CA, Petralia SM (2003c) 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. CRC, Boca Raton, pp 265–289Google Scholar
  18. Frye C, Seliga A (2003) Effects of olanzapine infusions to the ventral tegmental area on lordosis and midbrain 3α,5α-THP concentrations in rats. Psychopharmacology 170:132–139CrossRefPubMedGoogle Scholar
  19. Frye CA, Vongher JM (1999) Progestins’ rapid facilitation of lordosis when applied to the ventral tegmentum corresponds to efficacy at enhancing GABAA receptor activity. Neuroendocrinology 11:829–837CrossRefGoogle Scholar
  20. Frye CA, Vongher JM (2001) Ventral tegmental area infusions of inhibitors of the biosynthesis and metabolism of 3α,5α-THP attenuate lordosis of hormone-primed and receptive rats and hamsters. J Neuroendocrinol 13:1076–1086CrossRefPubMedGoogle Scholar
  21. Frye CA, Bayon LE, Pursnani NK, Purdy RH (1998) The neurosteroids, progesterone and 3α,5α-THP, enhance sexual motivation, receptivity, and proceptivity in female rats. Brain Res 808:72–83CrossRefPubMedGoogle Scholar
  22. Frye CA, Petralia SM, Rhodes M, Stein B (2003) Fluoxetine may influence lordosis of rats through effects on midbrain 3α,5α-THP concentrations. Ann N Y Acad Sci 1007:37–41CrossRefPubMedGoogle Scholar
  23. Griffin LD, Mellon SH (1999) Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci USA 9:13512–13517CrossRefGoogle Scholar
  24. Hall PE (1985) Trophic stimulation of steroidogenesis: in search of the elusive trigger. Recent Prog Horm Res 41:1–39PubMedGoogle Scholar
  25. Hardy DF, Debold JF(1971) Effects of mounts without intromission upon the behavior of female rats during the onset of estrogen-induced heat. Physiol Behav 7:643–645CrossRefPubMedGoogle Scholar
  26. Hoshina Y, Takeo T, Nakano K, Sato T, Sakuma Y (1994) Axon-sparing lesion of the preoptic area enhances receptivity and diminishes proceptivity among components of female rat sexual behavior. Behav Brain Res 61:197–204CrossRefPubMedGoogle Scholar
  27. Jahagirdar V, Petralia SM, Frye CA (2003) Infusions of P450 side-chain cleavage or 5α-reductase enzyme inhibitors to the ventral tegmental area decrease lordosis of rats in behavioral estrus. Horm Behav 44:46Google Scholar
  28. Jefcoate CR, McNamara BC, Artemenko I, Yamazaki T (1992) Regulation of cholesterol movement into mitochondrial cytochrome P450scc in steroid hormone synthesis. J Steroid Biochem 43:751–767CrossRefGoogle Scholar
  29. Kouri E, DeBold JF(1988) Lordosis relevant pathways near the ventral tegmentum in female hamsters. SFN Abstr 14:274Google Scholar
  30. Lisciotto CA, DeBold JF(1991) Ventral tegmental lesions impair sexual receptivity in female hamsters. Brain Res Bull 26:877–883CrossRefPubMedGoogle Scholar
  31. Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986) Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232:1004–1007PubMedGoogle Scholar
  32. Malsbury CW, Kow LM, Pfaff DW (1977) Effects of medial hypothalamic lesions on the lordosis response and other behaviors in female golden hamsters. Physiol Behav 19:223–237CrossRefPubMedGoogle Scholar
  33. Mathews D, Edwards DA (1977) Involvement of the ventromedial and anterior hypothalamic nuclei in the hormonal induction of receptivity in the female rat. Physiol Behav 19:319–326CrossRefPubMedGoogle Scholar
  34. McCarthy MM, Pfaff DW, Schwartz-Giblin S (1991) Midbrain central gray GABAA receptor activation enhances, and blockade reduces, sexual behavior in the female rat. Exp Brain Res 86:108–116PubMedGoogle Scholar
  35. Mellon SH, Griffin LD, Compagnone NA (2001) Biosynthesis and action of neurosteroids. Brain Res Brain Res Rev 37:3–12CrossRefPubMedGoogle Scholar
  36. Milton GV, Randall PK, Erickson CK (1995) Low-dose effect of ethanol on locomotor activity induced by activation of the mesolimbic system. Alcohol Clin Exp Res 19:768–776PubMedGoogle Scholar
  37. Morin LP, Wood RI (2001) A Stereotaxic atlas of the golden hamster brain. Academic, San DiegoGoogle Scholar
  38. Muntz JA, Rose JD, Shults RC (1980) Disruption of lordosis by dorsal midbrain lesions in the golden hamster. Brain Res Bull 5:359–364PubMedGoogle Scholar
  39. Noble RG (1973) Facilitation of the lordosis response of the female hamster (Mesocricetus auratus). Physiol Behav 10:663–666CrossRefPubMedGoogle Scholar
  40. Paxinos G, Watson C (1986) The rat brain. Academic, New YorkGoogle Scholar
  41. Plassart-Schiess E, Baulieu EE (2001) Neurosteroids: recent findings. Brain Res Brain Res Rev 37:133–140CrossRefPubMedGoogle Scholar
  42. Reddy DS, Kulkarni SK (1996) Role of GABAA and mitochondrial diazepam binding inhibitor receptors in the anti-stress activity of neurosteroids in mice. Psychopharmacology 128:280–292CrossRefPubMedGoogle Scholar
  43. Reddy DS, Kulkarni SK (1998) The role of GABAA and mitochondrial diazepam-binding inhibitor receptors on the effects of neurosteroids on food intake in mice. Psychopharmacology 137:391–400CrossRefPubMedGoogle Scholar
  44. Rodbard D, Hutt DM (1974) Statistical analysis of radioimmunoassay and immunoradiometric assays: a generalized weighted interactive least squares method for logistic curve fitting. In: International Atomic Energy Agency (ed) Symposium on radioimmunoassay and related procedures in medicine. Uniput, New York, pp 209–233Google Scholar
  45. Roeling TA, Veening JG, Kruk MR, Peters JP, Vermelis ME, Nieuwenhuys R (1994) Efferent connections of the hypothalamic “aggression area” in the rat. Neuroscience 59:1001–1024CrossRefPubMedGoogle Scholar
  46. Schumacher M, McEwen BS (1989) Steroid and barbiturate modulation of the GABAA receptor. Possible mechanisms. Mol Neurobiol 3:275–304PubMedGoogle Scholar
  47. Struthers WM (2001) Sex-induced fos in the medial preoptic area: projections to the midbrain. Neuroreport 12:3065–3068CrossRefPubMedGoogle Scholar
  48. Tanner T (1979) GABA-induced locomotor activity in the rat, after bilateral injection into the ventral tegmental area. Neuropharmacology 18:441–446CrossRefPubMedGoogle Scholar
  49. Whitney JF(1986) Effect of medial preoptic lesions on sexual behavior of female rats is determined by test situation. Behav Neurosci 100:230–235CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Department of PsychologyThe University at Albany-SUNYAlbanyUSA
  2. 2.Department of Biological SciencesThe University at Albany-SUNYAlbanyUSA
  3. 3.The Center for Neuroscience ResearchThe University at Albany-SUNYAlbanyUSA

Personalised recommendations