Oxytocin reduces background anxiety in a fear-potentiated startle paradigm: peripheral vs central administration

Abstract

Oxytocin is known to have anti-anxiety and anti-stress effects. Using a fear-potentiated startle paradigm in rats, we previously demonstrated that subcutaneously administered oxytocin suppressed acoustic startle following fear conditioning compared with startle before fear conditioning (termed background anxiety), but did not have an effect on cue-specific fear-potentiated startle. The findings suggest oxytocin reduces background anxiety, an anxious state not directly related to cue-specific fear, but sustained beyond the immediate threat. The goal of the present study was to compare the effects of centrally and peripherally administered oxytocin on background anxiety and cue-specific fear. Male rats were given oxytocin either subcutaneously (SC) or intracerebroventricularly (ICV) into the lateral ventricles before fear-potentiated startle testing. Oxytocin doses of 0.01 and 0.1 μg/kg SC reduced background anxiety. ICV administration of oxytocin at doses from 0.002 to 20 μg oxytocin had no effect on background anxiety or cue-specific fear-potentiated startle. The 20 μg ICV dose of oxytocin did reduce acoustic startle in non-fear conditioned rats. These studies indicate that oxytocin is potent and effective in reducing background anxiety when delivered peripherally, but not when delivered into the cerebroventricular system. Oxytocin given systemically may have anti-anxiety properties that are particularly germane to the hypervigilance and exaggerated startle typically seen in many anxiety and mental health disorder patients.

Figure 1

Startle responses from three different trial types were used to analyze the effects of oxytocin. Background anxiety is the increase in startle amplitude in the noise trials during the fear-potentiated startle test compared with the amplitude during the last acclimation session (pre-fear startle). pre-fear startle occurs before both fear conditioning and oxytocin administration. Cue-specific fear-potentiated startle is the increase in startle amplitude in the light+noise trials compared with the startle amplitude in the noise trials during the fear-potentiated startle test (adapted from Missig et al, 2010).

Figure 2

The effect of oxytocin administered SC 30 min before fear-potentiated startle testing. (a) Oxytocin at two doses (0.01 and 0.1 μg/kg) significantly reduced startle during testing. (b) Percentage fear-potentiated startle. There was no effect of oxytocin. (c) Background anxiety. 0.001 and 0.01 μg/kg doses of oxytocin significantly reduced background anxiety compared with saline. ^*Indicates statistically significant from saline.

Figure 3

Oxytocin administered ICV at five doses (0.002–2.0 μg/rat) 30 min before fear-potentiated startle testing. (a) None of the doses had an effect on startle during testing. (b) Percentage fear-potentiated startle was unaffected by oxytocin. (c) There is no effect on background anxiety at any dose of oxytocin.

Figure 4

Oxytocin (0.1 and 1.0 μg) administered ICV 30 min before the observation of grooming behavior significantly enhanced the number of genital grooming bouts. ^*Indicates statistically significant from saline.

Figure 5

Oxytocin administered ICV at a high dose (20 μg) 30 min before fear-potentiated startle testing. (a) Oxytocin (20 μg) significantly reduced startle. (b) Percentage fear-potentiated startle was unaffected by this high dose of oxytocin. (c) Background anxiety was significantly reduced by 20 μg oxytocin. ^*Indicates statistically significant from saline.

Figure 6

Effects of oxytocin non-conditioned acoustic startle. (a) Oxytocin (20 μg) administered ICV significantly decreased startle elicited by the 115 dB noise burst (^*p<0.009). Startle elicited by 95 and 105 dB startle stimuli was not affected by oxytocin. (b) By comparison, oxytocin given SC at doses effective in reducing background anxiety did not affect acoustic startle in non-conditioned rats. Startle elicited by 115 dB noise burst is shown, but startle elicited by 95 and 105 dB noise bursts was also unaffected. Data from Figure 5 of Missig et al (2010).