The links between stress and deleterious health consequences such as depression and drug abuse are well-documented. However, the mechanisms underlying these phenomena remain elusive, preventing effective treatments from reaching the public. This proposal aims to determine the role of the serotonin-1 B receptor (5-HT1 B) in modulating the behavioral and physiological responses to chronic social stress, as previous studies have established a link between 5-HT1B receptors, stress states, and drug effects. 5- HT1B receptors are richly expressed in brain regions that are important in mediating psychomotor sensitization and drug reward, and emerging data from our lab suggest that these receptors may be important mediators of the interactions between stress and hedonic elements of reward mechanisms. In the shell of the nucleus accumbens (NaccSh), 5-HT1B receptors are expressed on the terminals of GABAergic projection neurons that synapse on dopaminergic cells in the ventral tegmental area. These dopaminergic neurons project back to the NaccSh, and participate in determining the rewarding properties of incoming stimuli. These proposed experiments will investigate the role of the 5-HT1B receptor in the stress-drug interface. Our stress model will be the resident intruder model of social defeat. This method of social stress causes robust changes in behavior that have been well-documented in the literature, including dramatic changes in cocaine-related behaviors.
In Specific Aim 1, we will determine whether chronic social stress increases 5-HT1B receptor mRNA levels in the NaccSh, as previous studies suggest that stress may impact 5-HT1B receptor expression. Next, Specific Aim 2 will determine if increased levels of 5-HT1B receptors, via viral-mediated gene transfer, will predispose an organism to the deleterious effects of chronic stress. We will overexpress 5-HT1B mRNA in the NaccSh during stress exposure and measure anhedonia and conditioned place preference to cocaine (CPP) after dissipation of viral expression. We predict that increased 5-HT1B mRNA expression during stress will cause subsequent enhanced hedonic state and CPP. In our final aim, we will use siRNA mediated-knockdown of 5-HT1B receptor mRNA during stress exposure to reverse and possibly decrease hedonic state and CPP. The proposed experiments offer excellent training potential as I will be exposed to several new techniques (viral-mediated gene transfer, RNA intereference, and in situ hybridization), while gaining experience with establishing and troubleshooting a new behavioral paradigm.
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