Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology and Experimental Therapeutics

Abstract

The 5-HT1A receptor agonist, 8-OH-DPAT, improves recovery from hemorrhage by stimulating sympathetically-mediated venoconstriction and cardiac output. The sympathoexcitatory effect of 8-OH-DPAT is only observed in hypovolemic rats, and is attenuated by sinoaortic denervation. Lesion of serotonergic nerve terminals in the nucleus tractus solitarius (NTS) attenuates ventilatory and sympathetic responses to hemorrhage, and peripheral chemoreceptor stimulation. Thus, we propose that serotonin is released in the NTS during hemorrhage to activate 5-HT1A receptors which facilitate chemoreflex responses. We utilized viral-mediated knockdown of the rat 5-HT1A receptor in the caudal NTS (cNTS) to examine the role of 5-HT1A receptors on compensation following hemorrhage and ventilatory responses to hypoxic/hypercapnia. Sequences encoding a 5-HT1A shRNA or scrambled version of the same sequence were incorporated into adeno-associated viral vectors and injected into the cNTS of rats. After 4 weeks, rats injected with the 5-HT1A shRNA-encoding virus showed decreases in sympathetic recovery and elevated lactate accumulations following hemorrhage that were inversely correlated with 5-HT1A mRNA expression in the cNTS. We also found that knockdown of 5-HT1A receptors in the NTS attenuated the blood pressure recovery and sympathetic drive induced by systemic 8-OH-DPAT administration. 5-HT1A receptor mRNA in the NTS was inversely correlated with the latency to recover blood pressure and positively correlated with sympathetic activity induced by 8-OH-DPAT injection during hemorrhage. Lastly, we found that acidosis stimulated the activation of serotonin in regions that project to the NTS. The presence of acidosis also increased the number of NTS cells activated by hypoxia. We further found that 5-HT1A receptors in the cNTS mediate intermittent bouts of increased ventilatory frequency (sniffing behavior) that occur during combined exposure to acidosis and hypoxia. Together these data indicate that serotonin released in the NTS during hemorrhage activates 5-HT1A receptors to facilitate sympathetic-mediated compensation and tissue perfusion following severe blood loss. Our data further suggest that acidosis stimulates serotonin release in the NTS where it activates 5-HT1A receptors to increase arousal. This phenomenon may contribute to the beneficial hemodynamic effect of serotonin during hemorrhage.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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