Influence of the estrous cycle on some non reproductive behaviors and on brain mechanisms in the female rat

ABSTRACT

Sex hormone fluctuations in females are involved in some behavioral states such as mood, anxiety, aggression and stress response, due to functional changes in the central nervous system (CNS) activity induced by the cyclic sex hormone fluctuation. This review includes three sections. 1.- A description of the three major hormone fluctuations in the estrous cycle estrogens (E2), progesterone (P4) and prolactine (PRL). E2 achieves the maximum circulation levels during P.E2 is mainly excitatory and has been considered to have an antidepressive action. The highest plasma levels of P4 and its metabolite allopregnenolone(ALLO) occur in P. Ovulation takes place in the night of P, and the resulting corpora lutea produces a secondary increase in P4 (and ALLO) on D. The P4 peak level occurring in D1 and in the evening of P was shown to exert benzodiazepine-like effects, including sedation. It has been proposed that ALLO, rather than P4 is the one acting on GABA systems. Circulating levels of ALLO parallel those of P4 across the estrous cycle and is known to have anxiolytic properties. PRL is produced mainly in the adenohypophysis, though synthesis in other sites of the brain also occurs. Its regulation is mostly inhibitory and is exerted by dopamine (DA) released in the hypothalamus. A surge in PRL secretion occurs during P. PRL would be a modulator of the HPA-axis, and is considered as a stress hormone. 2.- Some behavioral and neural changes occur at each stage of the cycle. Lower anxiety level in P females was described. This has been correlated with increased circulating levels of endogenous ALLO in P. PRL is another hormone that may cause the lower scores of anxiety observed at P, since the peak of plasma PRL is observed at this stage. A novel peptide, the Prolactin Releasing Peptide (PrRP), which is sensitive to E2 fluctuation, has also been linked to the lower activity of the HPA axis. Stress-induced activation of PrRP neurons is significantly decreased in E compared with P and D, suggesting that E2 suppresses the activation of PrRP neurons. The late luteal phase (D) correlates with the premenstrual phase in women, commonly associated with psychological disturbances, including mood disorders and increased aggression. Consistently, increased levels of anxiety and aggression have been detected in rats during D. 3.- Findings about cyclic hormone influences on the CNS neurotransmitters and on the stress mediator, prolactine-releasing peptide (PrRP) were described. GABA is the main inhibitory system in the brain. Estrous-cycle-dependent increases in -GABA A receptors were reported; this subtype underlying a tonic inhibitory current, is the most sensitive target of P4 and ALLO. E2 causes a reduction in GABAergic inhibition, leading to an increase in the excitatory tone. It also acts on hippocampus causing a transient lowering of GABA synthesis in the interneuron. These findings suggest an excitatory role for E2 through inhibition of the GABA system. The serotonin system, involved in behavioral responses such as stress, anxiety and depression, also exhibits variations along the estrous cycle, in part dependant of GABA-receptor changes. Gender differences were described for DA function in the brain, due to E2 and P4 modulation. DA release and reuptake fluctuate with changes in circulating steroid levels. E2 enhances DA release and DA-mediated behaviors, such as general activity stimulation, food seeking behavior and sexual motivation. PrRP is produced in hypothalamic and extra hypothalamic structures. It has been proposed as a mediator of stress responses. Though gender differences have been shown, distribution of PrRP does not change during the estrous cycle. We hope this review may contribute to understand the mechanism of female behavioral variations and their pharmacological and diagnostic implications.(AU)

RESUMEN

El rol de las hormonas sexuales sobre el comportamiento reproductivo ha sido extensamente documentado. La fluctuación periódica de hormonas sexuales en hembras de numerosas especies ha sido relacionada con cambios comportamentales no sexuales tales como humor, ansiedad, agresión y respuesta a estrés. El sustrato biológico-neural de estos cambios se basa en los cambios que estas hormonas inducen en el Sistema Nervioso Central. Este trabajo resume algunos cambios que afectan a receptores y neurotrasmisores de los sistemas GABAérgico, serotoninérgico, dopaminérgico y péptido liberador de prolactina del SNC de la rata. La rata hembra posee un ciclo sexual de 4 días de duración, denominado ciclo estrual. La presente revisión se informa en tres secciones. (1) Se presenta una breve descripción de la variación de tres hormonas sexuales principales con acción directa sobre el SNC estrógenos (E2), progesterona (P4) y prolactina (PRL). Se han descripto propiedades ansiolíticas para P4 y anti-estrés para PRL; para E2, la bibliografía es controvertida, describiéndose acciones excitatorias y anti-estrés. (2) Se informan algunos cambios cerebrales y comportamentales que tienen lugar en cada estadio del ciclo estrual. Las fluctuaciones hormonales se consideran básicas para la interpretación de tales cambios. (3) Se mencionan algunos hallazgos acerca de la influencia hormonal cíclica sobre los sistemas de neurotransmisión del SNC y sobre un nuevo péptido propuesto como mediador de la respuesta a estrés, el péptido liberador de prolactina (PrRP). Esperamos que este trabajo contribuya a un mejor entendimiento de los mecanismos del comportamiento de las hembras y sus variaciones, y sus implicancias farmacológicas y diagnósticas.(AU)