The serotonin system in the brain plays an important role in determining the responses to environmental stressors. The interaction between stress and serotonin is complex, however, since acute increases in serotonin can be anxiogenic, while chronic increases can actually reduce anxiety and depressive symptoms, depending on the context and the brain region. Since the 5-HT1B autoreceptor regulates the release and possibly the reuptake of 5-HT at axon terminals, it is strategically placed to modulate extracellular 5-HT in brain regions that mediate fear, anxiety, and stress-induced depression. The effects of 5-HT1B autoreceptors are challenging to study, though, because 5-HT1B heteroreceptors are localized in axon terminals of other neuron types throughout the brain, necessitating the use of anatomically specific techniques. Previously we developed a viral mediated gene transfer strategy to manipulate 5-HT1B autoreceptors in dorsal raphe nucleus and increase the expression of 5-HT1B autoreceptors selectively. We have found that 5-HT1B- overexpressing animals are less anxious when not exposed to environmental stressors, but more anxious when stressed. We have recently constructed a serotonin selective viral vector based on the serotonin transporter promoter to increase expression of 5-HT1B receptors only in serotonergic neurons. We now propose to pursue the function of 5-HT1B autoreceptors in dorsal raphe in four ways. We will examine the neuroanatomical contribution of 5-HT1B autoreceptors to behavior in rostral vs. caudal dorsal raphe, subregions that appear to mediate anxiety and depression, respectively. We will investigate the temporal role of 5-HT1B autoreceptors in modulating fear learning by examining their effects on acquisition, expression, and extinction of conditioned fear. We will study the mechanism by which these autoreceptors regulate extracellular 5-HT levels, and whether they do so by modulating serotonin transporter function. We will examine the modulation of 5-HT1B autoreceptor effects on behavior by stress and the CRF related peptides. These questions will be addressed using a combination of novel molecular, pharmacological, and behavioral strategies that we have developed in our lab, allowing us to isolate the role of 5-HT1B autoreceptors in these animal models of stress-associated illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063303-08
Application #
7753231
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Winsky, Lois M
Project Start
2001-03-09
Project End
2010-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
8
Fiscal Year
2010
Total Cost
$315,994
Indirect Cost
Name
University of Washington
Department
Psychiatry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Liu, Y; Kelly, M A; Sexton, T J et al. (2015) 5-HT1B autoreceptors differentially modulate the expression of conditioned fear in a circuit-specific manner. Neuroscience 298:436-47
Hagan, Catherine E; McDevitt, Ross A; Liu, Yusha et al. (2012) 5-HT(1B) autoreceptor regulation of serotonin transporter activity in synaptosomes. Synapse 66:1024-34
Schindler, Abigail G; Messinger, Daniel I; Smith, Jeffrey S et al. (2012) Stress produces aversion and potentiates cocaine reward by releasing endogenous dynorphins in the ventral striatum to locally stimulate serotonin reuptake. J Neurosci 32:17582-96
Hagan, Catherine E; Schenk, James O; Neumaier, John F (2011) The contribution of low-affinity transport mechanisms to serotonin clearance in synaptosomes. Synapse 65:1015-23
McDevitt, Ross A; Hiroi, Ryoko; Mackenzie, Scott M et al. (2011) Serotonin 1B autoreceptors originating in the caudal dorsal raphe nucleus reduce expression of fear and depression-like behavior. Biol Psychiatry 69:780-7
McDevitt, Ross A; Neumaier, John F (2011) Regulation of dorsal raphe nucleus function by serotonin autoreceptors: a behavioral perspective. J Chem Neuroanat 41:234-46
Hiroi, R; McDevitt, R A; Morcos, P A et al. (2011) Overexpression or knockdown of rat tryptophan hyroxylase-2 has opposing effects on anxiety behavior in an estrogen-dependent manner. Neuroscience 176:120-31
Hiroi, Ryoko; Neumaier, John F (2011) Complex roles of estrogen in emotion: sex matters. Biol Psychiatry 70:908-9
Hagan, Catherine E; Neumaier, John F; Schenk, James O (2010) Rotating disk electrode voltammetric measurements of serotonin transporter kinetics in synaptosomes. J Neurosci Methods 193:29-38
Mitchell, Ellen S; McDevitt, Ross A; Neumaier, John F (2009) Adaptations in 5-HT receptor expression and function: implications for treatment of cognitive impairment in aging. J Neurosci Res 87:2803-11

Showing the most recent 10 out of 24 publications