ORIGINAL ARTICLE Antagonists of the Protein Kinase A and Mitogen-Activated Protein Kinase Systems and of the Progestin Receptor Block the Ability of Vaginocervical/Flank-Perineal Stimulation to Induce Female Rat Sexual Behaviour O. Gonza ´lez-Flores,* A. M. Etgen, B. K. Komisaruk,à P. Go ´mora-Arrati,* A. Macias-Jimenez,§ F. J. Lima-Herna ´ndez,* M. Garcia-Jua ´rez* and C. Beyer* *Centro de Investigacio ´n en Reproduccio ´n Animal, CINVESTAV-Universidad Auto ´noma de Tlaxcala, Tlaxcala, Mexico.  Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA. àRutgers, The State University of New Jersey, Newark, NJ, USA. §Instituto de Ciencias de la Salud, Universidad Auto ´noma del Estado de Hidalgo, Pachuca, Hidalgo, Mexico. Vaginocervical stimulation (VCS) with a glass rod combined with manual flank-perineal stimulation (FS) elicits the lordosis response in ovariectomised (OVX) rats primed with oestrogens (1–4). The cel- lular mechanisms underlying this effect are not clear, although the short latency of the proceptive-receptive behavioural responses to VCS + FS implies the participation of nongenomic mechanisms (5–10). VCS + FS releases multiple neurotransmitters (noradrenaline, dopamine, nitric oxide) (11–19), neuromodulators (e.g. gonadotro- phin-releasing hormone; GnRH) and prolactin (20–22), which modulate proceptive-receptive behaviours in oestrogen-primed rats (5–11, 19, 22). Many of these agents activate intracellular signalling mechanisms through G protein linked membrane receptors. The participation of second messengers in the facilitation of lordosis behaviour by hormones in rodents has been well substantiated (5, 6, 9, 10, 23, 24). Thus, systemic or intracerebral administration of derivatives of cAMP or GMP facilitates lordosis behaviour in OVX, oestradiol (E 2 )-primed rats (5, 25–31). In addition, blockers of pro- tein kinase A (PKA), protein kinase G (PKG) or mitogen-activated protein kinase (MAPK) interfere with the stimulatory effect of progesterone and its ring A-reduced metabolites on proceptive- receptive behaviours in E 2- primed rats (31–34). Journal of Neuroendocrinology Correspondence to: O. Gonza ´lez-Flores, Centro de Investigacio ´n en Reproduccio ´n Animal, Apartado Postal No 62, Tlaxcala, Tlax. c.p. 90000, Me ´xico (e-mail: oglezflo@hotmail.com). Brief vaginocervical stimulation using a glass rod (VCS) combined with manual flank-perineal stimulation (FS) rapidly (within 5 min) induced both receptive and proceptive behavioural responses to males in ovariectomised, oestrogen-primed rats. This receptive-proceptive response to males, resulting from a single brief (5-s duration) instance of manual VCS + FS, declined markedly within 4 h. However, the decline was prevented if the females were mounted by males immediately after the manual VCS + FS and 2 h later. We tested the participation of the cAMP- dependent protein kinase A system and the mitogen-activated protein kinase (MAPK) system in the response to VCS + FS by infusing either 100 ng of Rp-adenosine 3¢,5¢-cyclic monophospho- rothiate triethylamonium salt (a protein kinase A blocker) or 3.3 lg of PD98059 (a MAPK blocker) i.c.v. 15 min prior to VCS + FS. Both inhibitors blocked the ability of VCS + FS to induce the proceptive-receptive responses to males at all testing intervals. In experiment 2, systemic administration of 5 mg of RU486 1 h before VCS + FS also blocked the ability of VCS + FS to induce the proceptive-receptive responses to males. The present findings suggest that both VCS + FS and mating stimuli provided by males release neurotransmitters and neuromodulators that trigger the protein kinase A and the MAPK signalling systems, which interact with the pro- gestin receptor to rapidly (within 5 min) induce proceptive-receptive behaviour in females. Key words: oestrous behaviour, vaginocervical stimulation, protein kinase A, MAPK, progestin receptor. doi: 10.1111/j.1365-2826.2008.01794.x Journal of Neuroendocrinology 20, 1361–1367 ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd Journal of Neuroendocrinology From Molecular to Translational Neurobiology