Serotonin-7 receptors and Alcohol-seeking Behaviors

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ABSTRACT: Drug addiction can be characterized as a chronic reoccurring illness. The relapse rate of alcoholism is particularly high (75-95%). It has been hypothesized that drug craving is a critical precipitating factor to relapse and drug craving is influenced by the amount of time abstinent, the exposure to the drug-paired environment, or drug-paired cues. Convergent data in rodents and humans have indicated that drug-paired environment or drug-paired cues' ability to elicit drug-craving intensifies with the passage of time during early abstinence, which can be referred to as ‘cue incubation of drug craving’. The serotonin (5-HT) system is thought to play a role in the development of alcohol addiction as well as play an important role in the control of drug-seeking and sensitivity to drug reward and drug cues. The 5-HT7 receptor has been researched as a potential therapeutic target for various conditions such as anxiety, depression, neuropathic pain, Alzheimer’s disease, and drug addiction. The activation of 5-HT7 receptors can regulate ‘behavior control,’ drug-withdrawal symptoms, and cognitive behaviors. However, there is a gap in knowledge of the involvement of the 5-HT7 receptor in mediating alcohol (EtOH)-seeking behaviors. Extensive preliminary data conducted in our laboratory have indicated that the systemic and site-specific, specifically in the nucleus accumbens shell (AcbSh), pharmacological manipulation of 5-HT7 receptor bidirectionally mediates context- and cue-induced EtOH-seeking. There is a critical need for therapeutic treatments for EtOH- seeking behaviors and we propose that the 5-HT7 receptors need to be further researched as potential targets for treatments of alcohol ‘craving’ behaviors. Understanding 5-HT7 mechanisms contributing to the ‘incubation’ of cue-induced EtOH-seeking is very important for developing strategies to reduce or prevent relapse. The Pavlovian Spontaneous Recovery (PSR) model of EtOH seeking, pharmacological techniques, and viral vectors will be used to examine the temporal effects of ‘incubation’ of cue-induced EtOH-seeking behaviors and determine 5-HT7 receptors' involvement in regulating these behaviors. Western blot techniques will be used to examine cellular mechanisms in ‘behavioral control’ neural circuitry and the alterations of 5-HT7 receptors expression. Microdialysis and pharmacological techniques will be used to examine the involvement of 5-HT7 receptors' effects on DA and 5-HT release within the AcbSh associated with temporal aspects of ‘incubation’ of cue-induced EtOH-seeking. Therefore, we propose to test the hypothesis that 5-HT7 receptors mediate the incubation’ of cue-induced EtOH-seeking during abstinence by regulating extracellular levels of DA and 5-HT in the AcbSh and that this response is mediated by the regulation of 5HT7 receptor expression in the AcbSh dorsal raphe circuit.