Increased expression of 5-HT1B receptor in dorsal raphe nucleus decreases fear-potentiated startle in a stress dependent manner.
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.
Clark
Michael S
MS
Department of Psychiatry and Behavioral Sciences and Harborview Medical Center, University of Washington, Box 359911, 325 Ninth Avenue, Seattle, WA 98195-2499, USA.
Vincow
Evelyn S
ES
Sexton
Timothy J
TJ
Neumaier
John F
JF
D000818:Animals; D001522:Behavior, Animal; D005239:Fear; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins; D006380:Helplessness, Learned; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D008959:Models, Neurological; D010881:Piperidones / Q000494:pharmacology; D011903:Raphe Nuclei / Q000378:metabolism* / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000378:metabolism*; D013216:Reflex, Startle / Q000235:genetics / Q000502:physiology*; D058829:Serotonin 5-HT1 Receptor Antagonists; D013141:Spiro Compounds / Q000494:pharmacology; D013312:Stress, Physiological / Q000378:metabolism* / Q000821:virology
D008164:Luminescent Proteins; D010881:Piperidones; D044302:Receptor, Serotonin, 5-HT1B; C108518:SB 22489G; D058829:Serotonin 5-HT1 Receptor Antagonists; D013141:Spiro Compounds; D049452:Green Fluorescent Proteins