Increased expression of 5-HT 1B receptor in dorsal raphe nucleus decreases fear-potentiated startle in a stress dependent manner

Abstract

5-HT 1B autoreceptors regulate serotonin release from terminals of dorsal raphe nucleus (DRN) projections. Due to postsynaptic 5-HT 1B receptors in DRN terminal fields, it has not previously been possible to manipulate 5-HT 1B autoreceptor activity without also changing 5-HT 1B heteroreceptor activity. We have developed a viral gene transfer strategy to express epitope-tagged 5-HT 1B and green fluorescent protein in vivo, allowing us to increase 5-HT 1B expression in DRN neurons. We have shown that increased 5-HT 1B autoreceptor expression reduced anxiety in unstressed animals but increased anxiety following inescapable stress. These findings suggest that effects of increased 5-HT 1B autoreceptor expression are dependent on stress context. To better understand the mechanisms underlying these observations, we have used fear-potentiated startle (FPS). FPS is especially sensitive to the activity of the amygdala, which shares reciprocal connections with DRN. In the absence of an inescapable stressor, increased 5-HT 1B autoreceptor expression attenuated FPS response compared with animals injected with a virus expressing only green fluorescent protein. Administration of the 5-HT 1B antagonist SB224289 (5 mg/kg i.p.) before startle testing blocked the effects of increased 5-HT 1B autoreceptor expression. Since SB224289 had no effect on FPS in the absence of viral gene transfer, these results suggest that the antagonist reversed the behavioral effects of increased 5-HT 1B autoreceptor expression through blockade of transgenic receptors. When tested 24 h following water-restraint stress, animals with increased 5-HT 1B autoreceptors demonstrated restoration of robust FPS response. These results extend our previous studies and suggest explanations for the complex relationship between 5-HT 1B autoreceptor expression, stress, and anxiety behavior.