Bi-directional interaction between nicotine and serotonin (5-HT)2C receptors - behavioural and molecular aspects
Recent data point to a role of serotonin (5-HT) and its receptors, mainly 5-HT2C receptor subtype, in the effects of nicotine - the key addictive component in cigarettes. Our series of studies performed on rats showed that pharmacological blockade of 5-HT2C receptors augmented the locomotor responses to acute nicotine, while activation of these receptors diminished nicotine-induced hyperactivity, the expression of behavioural sensitisation and conditioned locomotor activity as well as depression-like behaviour evoked by nicotine withdrawal. Our more recent studies demonstrated that nicotine challenge to nicotine-sensitised rats decreased [3H]mesulergine binding to 5-HT2C receptors in the prefrontal cortex, while nicotine withdrawal reduced receptor labelling in the ventral dentate gyrus and thalamic nuclei. To identify the mechanism associated with changes in radioligand binding, we analysed the pattern of 5-HT2C receptor mRNA editing (a posttranscriptional modification that may result in functionally different receptor isoforms) following repeated nicotine administration. Interestingly, our preliminary deep sequencing data showed significant decreases in 5-HT2C receptor mRNA editing in the hippocampus of nicotine-withdrawn animals. Such an alteration in editing may affect the availability of binding sites for 5-HT2C receptor radioligand and could partially explain changes in radioligand binding noted in this brain region. Taken together, our data support the existence of bi-directional interaction between 5-HT2C receptors and nicotine. Clear effects of 5-HT2C receptor agonists to ameliorate symptoms associated with nicotine dependence have been shown. On the other hand, the ability of nicotine to affect 5-HT2C receptor binding and editing has also been reported. Present data show a new direction in the search for efficient anti-nicotinic drugs and the possibility of using 5-HT2C receptor agonists as adjuncts to smoking cessation therapy.
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