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The 26S Proteasome Participates in the Sequential Inhibition of Estrous Behavior Induced by Progesterone in Rats

Department of Neuroscience (A.M.E.), Albert Einstein College of Medicine, Bronx, New York 10461; Centro de Investigación en Reproducción Animal (O.G.-F.), Centro de Investigacion y de Estudios Avanzados-Universidad Autonoma de Tlaxcala, Tlaxcala 90140, Mexico; and Departamento de Biología (C.G.-A., M.C., I.C.-A.), Facultad de Química, Universidad Nacional Autónoma de México, Coyoacan 04510, México

Address all correspondence and requests for reprints to: Dr. Anne M. Etgen, Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, F113, Bronx, New York 10461. E-mail: etgen{at}aecom.yu.edu.

Estrous behavior induced by progesterone (P) treatment of estradiol-primed rats is followed by a period in which females do not respond behaviorally to a second administration of P [sequential inhibition (SI)]. SI is thought to involve P-dependent down-regulation of hypothalamic P receptor (PR) content. This study tested the hypothesis that the 26S proteasome participates in the regulation of SI and brain PR content in female rats. Ovariectomized, estrogen-primed (estradiol benzoate, 2 µg sc) adult rats were injected with P (1 mg sc) alone or P with the proteasome inhibitors Z-Ile-Glu (OBu¹)-Ala-Leu-H (PSI, 300 µg/100 g sc) or N-tosyl-lysyl chloromethyl ketone (TLCK, 200 µg ip) administered 48 h after estradiol priming. Sexual behavior was assessed in all animals 4 h later. These two agents inhibit 26S proteasome-mediated protein degradation by different mechanisms. To explore SI, the animals received a second P injection 24 h after the first, and a second sexual behavior test was performed 4 h later. After this test, brains were excised, and proteins were extracted from the preoptic area and the hypothalamus and processed for semiquantitative immunoblotting. In the first sexual behavior test (facilitation test), all animals treated with estradiol + P exhibited intense lordosis behavior. In the second sexual behavior test (inhibition test), both lordosis and proceptivity were significantly reduced in response to the second administration of P (SI). The magnitude of SI was significantly attenuated by the administration of either PSI or TLCK concurrently with the first P injection. The first P injection reduced PR content in the hypothalamus but not in the preoptic area. In contrast, PSI and TLCK significantly increased PR content in both structures. Our results suggest that PR degradation by the 26S proteasome participates in the expression of P-induced SI in female rats.

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				O. Gonzalez-Flores, J. Shu, I. Camacho-Arroyo, and A. M. Etgen Regulation of Lordosis by Cyclic 3',5'-Guanosine Monophosphate, Progesterone, and Its 5{alpha}-Reduced Metabolites Involves Mitogen-Activated Protein Kinase Endocrinology, December 1, 2004; 145(12): 5560 - 5567. [Abstract] [Full Text] [PDF]