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 mug 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.

Figure 1.

Percentage change from baseline startle (± SEM) in OVX (gray circles; n = 5), OVX estrogen-replaced (E2; black circles; n = 6), and OVX estrogen-primed, P-replaced (E2P; white circles; n = 7) female rats after ICV CRF infusion. Data were collapsed into 10 min intervals of 20 startle stimuli.

Figure 2.

Percentage change from baseline startle (±SEM) after ICV CRF infusion in: A, OVX rats injected with oil alone (dark circles; n = 10) or progesterone (white circles; n = 10) (500 μg/100 μl oil) 4 hr before the CRF test; B, OVX rats implanted for 7 d with blank SILASTIC capsules (dark circles; n = 7) or P-filled capsules (white circles; n = 8); and C, intact virgin (dark circles; n = 6) and lactating (Xs; n = 7) female rats. Data from all three studies were collapsed into 10 min intervals of 20 startle stimuli.

Figure 3.

Percentage change from baseline startle (±SEM) in: A, OVX rats (n = 8) tested for CRF-enhanced startle with (dark squares) and without (white squares) intraperitoneal injection of THP (10 mg/kg, by weight); and B, changes in baseline startle over a 2 hr period in OVX rats (n = 8) after injection of THP (dark squares) or vehicle (veh; white squares).

Figure 4.

Percentage change from baseline startle (± SEM) after ICV CRF infusion in OVX rats implanted with MPA (dark squares; n = 6) or P (white squares; n = 7). Data were collapsed into 10 min intervals of 20 startle stimuli.

Figure 5.

Percentage change from baseline startle (± SEM) after ICV CRF infusion in OVX rats (white squares; n = 22) and those implanted with SILASTIC capsules filled with MPA (dark squares; n = 6). Data were collapsed into 10 min intervals of 20 startle stimuli.

Figure 6.

Fear-potentiated startle in: A, OVX rats implanted for 7 d with blank capsules (n = 8) or P-filled capsules (n = 9) and B, OVX rats (n = 8) tested 4 hr after either THP (10 μg/kg, by weight) injection or vehicle. Graph shows startle amplitude in the presence (light noise; white bars) and absence (noise alone; black bars) of the light cue. The difference between the two trial types (light-noise - noise alone = fear-potentiated startle; ±SEM) is depicted by gray bars.