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

• DOI: 10.1523/jneurosci.1386-04.2004
• Publication Date: 2004-11-10T21:49:03Z
• Authors: Donna J. Toufexis; Carrie Davis; Alexis Hammond; Michael Davis
• Keywords: Medroxyprogesterone; Reflex, Startle; Estradiol; Corticotropin-Releasing Hormone; Hormone Replacement Therapy; Ovariectomy; Fear; Pregnanolone; Anxiety; Rats; Rats, Sprague-Dawley; 03 medical and health sciences; 0302 clinical medicine; Acoustic Stimulation; Pregnancy; Animals; Lactation; Female; Septal Nuclei; Progesterone

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 μg 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.