Progesterone Attenuates Corticotropin-Releasing Factor-Enhanced But Not Fear-Potentiated Startle via the Activity of Its Neuroactive Metabolite, Allopregnanolone

Abstract

Intact female rats and ovariectomized (OVX) rats with different ovarian steroid replacement regimens were tested for changes in corticotropin-releasing factor (CRF)-enhanced startle (increased acoustic startle amplitude after intracerebroventricular infusion of 1 g of CRF). OVX rats injected with estradiol (E) followed by progesterone (P) showed a blunted CRF-enhanced startle effect compared with OVX and E-injected rats. CRF-enhanced startle also was reduced significantly in lactating females (high endogenous P levels) compared with cycling rats (low to moderate P levels), as well as in non-E-primed rats when P was administered acutely (4 hr before testing) or chronically (7 d P replacement). The ability of P to attenuate CRF-enhanced startle was probably mediated by its metabolite allopregnanolone [tetrahydroprogesterone (THP)], because THP itself had a similar effect, and chronic administration of medroxyprogesterone, which is not metabolized to THP, did not blunt CRF-enhanced startle but instead slightly increased it. These data suggest that P blunts CRF-enhanced startle through a mechanism involving its neuroactive metabolite THP, although a role for the P receptor cannot be completely ruled out. Finally, neither chronic P replacement nor acute THP affected fear-potentiated startle, suggesting that P metabolites have an effect on the bed nucleus of the stria terminalis and anxiety rather than on the amygdala and stimulus-specific fear.

Luteal-Phase Accentuation of Acoustic Startle Response in Women with Premenstrual Dysphoric Disorder

“…A recent study in rodents suggests that fear-potentiated startle, which is mediated by the amygdala, is not modulated by estrogen, progesterone or allopregnanolone (ALLO). However, in a rodent model of stress/anxiety, ALLO and progesterone (presumably via ALLO) reversed the ASR accentuating effects of corticotropin releasing hormone (CRH) infused into the BNST (Toufexis et al, 2004). Compared to healthy controls and to themselves in the follicular phase, the PMDD subjects in our study were significantly more anxious/tense and irritable during the luteal phase and, as such, did not appear to require any external provocation (unpleasant picture viewing) to exhibit a heightened arousal.…”

GABA enhancement of maternal defense in mice: Possible neural correlates

“…A one-way analysis of variance (ANOVA) on difference scores was then performed between the vehicle and CDP groups. This approach is modeled after standard statistical method used in other behavioral paradigms (Toufexis et al, 2004;Walker et al, 2003). In cases were data were not normally distributed, a non-parametric Kruskal-Wallis One-Way ANOVA on Ranks was used.…”

Role of dopamine D1 and D2 receptors in CRF-induced disruption of sensorimotor gating

“…In rats, CRF effects on startle have been localized to a hippocampal-septal-bed nucleus stria terminalis circuit (for review see Davis et al, 1997), which expresses both CRF 1 and CRF 2 receptors (Van Pett et al, 2000). CRF-induced increases in startle are blocked by steroids such as progesterone treatment and alphaxalone (Swerdlow and Britton, 1994;Toufexis et al, 2004), blocked by GABAergic activation via chlordiazepoxide administration (Swerdlow et al, 1989), and enhanced by corticosterone and vasopressin treatment (Lee et al, 1994;Pelton et al, 1997). Recently, Meloni et al (2006) reported that SCH23390 attenuated CRF-induced increases in startle in rats (PPI was not tested).…”