Endogenous neurotensin is involved in estrous cycle related alterations in prepulse inhibition of the acoustic startle reflex in female rats

Abstract

SummaryOvarian hormones regulate prepulse inhibition (PPI) of the acoustic startle reflex. Results from studies in intact female rodents investigating sex, estrous cycle and ovarian hormone regulation of PPI are inconsistent. In experiment #1, we investigated whether PPI in female rats is influenced by the time of day of testing and the estrous cycle stage of the rat. PPI was examined across the day of proestrus (P) and diestrus 1 (D1) in female rats and compared to males. PPI in males and P females was significantly higher than in D1 females. PPI in males and D1 females was significantly affected by the time of day of testing with PPI being reduced in the afternoon and evening compared to morning. PPI in P females was not significantly affected by the time of day of testing. Previous studies have demonstrated estrous cycle regulation of central nervous system neurotensin (NT) neurons and peripherally administered NT receptor agonists regulate PPI in a manner similar to antipsychotic drugs. Experiment #2 of this study was designed to examine whether endogenous NT is involved in estrous cycle regulation of PPI. The NT receptor antagonist SR 142948A reduced the high levels of PPI during D1 and P. In contrast, when tested at a time of day in which PPI was low in D1 females, administration of both the typical antipsychotic drug haloperidol and the NT receptor antagonist significantly increased PPI. These data support an effect of time of day and estrous cycle stage on PPI in female rats. The estrous cycle variations in PPI are mediated in part by endogenous NT.

Effects of estrous stage and time of day on prepulse inhibition in female rats

“…These findings indicate that not only did the time of day of testing affect PPI, but also these differences cannot be attributed to differences in startle behaviour. While some studies (Kinkead et al, 2008;Frankland and Ralph, 1995;Chabot and Taylor, 1992) have reported an increase in startle amplitude when testing animals during the dark cycle rather than the light cycle, others found no difference (Weiss et al, 1999), as was the result in this study.…”

“…Circadian fluctuations in hormones including corticosterone and adrenocorticotropin (Atkinson and Waddell, 1997) could be one such variable that interacts with estrous cycle. Kinkead et al (2008) have recently reported on the contribution of endogenous neurotensin to significant time of day effects on PPI in diestrous, females. The effects of estrous cycle however, can be minimized when PPI is assessed at a consistent time of day as reported here; within the window of 2-4 h following the onset of the dark phase of the light/dark cycle.…”

“…Male rats have shown higher PPI than females and female variations have been observed across the estrous cycle under certain testing conditions (Weiss and Feldon, 2001 observations, as with humans, have been attributed to estrogen induced increases of mesostriatal dopamine function (Koch, 1998). Other rodent studies have reported conflicting results in sex differences in PPI (Swerdlow et al, 1993;Koch, 1998;Bubenikova et al, 2005;Plappert et al, 2005) and estrous phase effects (Kinkead et al, 2008). These findings have obvious clinical connotations in understanding any gender differences and female cyclical changes in clinical course and treatment responsivity of gating family psychiatric disorders, as well as implications to the design of future PPI experiments.…”

Sex differences in animal models of psychiatric disorders

“…However in 1998, Koch found no difference in PPI between male and female rats, but PPI was reduced in female rats during prooestrous, in comparison with oestrous and dioestrous phases of the cycle (Koch, 1998). Other researchers have found opposite results, such as higher PPI in male and female rats in prooestrous, in comparison with female rats in dioestrous (Kinkead et al, 2008) or no differences across the oestrous cycle (Adams et al, 2008). These discrepancies have been attributed to different testing conditions, such as stimulus intensity and testing during the light or dark phase.…”

Exposure to repeated maternal aggression induces depressive-like behavior and increases startle in adult female rats

“…The acoustic startle reflex test was performed six days after the last maternal aggression stressor as previously described [25]. Briefly, during the light cycle, rats were placed in a ventilated startle chamber (San Diego Instruments, San Diego, CA) using an accelerometer to measure the startle reflex.…”