Inhibition of the serotonin 5-HT3 receptor by nicotine, cocaine, and fluoxetine investigated by rapid chemical kinetic techniques

The 5-HT3 serotonin receptor plays an important role in regulating communic ation between cells in the central and peripheral nervous systems. It is th e tar-get of many different therapeutic agents and abused drugs. A rapid ch emical kinetic method with a time resolution of 10 ms in combination with t he whole-cell current-recording technique was employed to study the recepto r in NIE-115 mouse neuroblastoma cells. The mechanism of the channel-openin g process, receptor desensitization, and receptor inhibition by nicotine, c ocaine, and fluoxetine were investigated. Two different forms of the 5-HT3 serotonin receptor, each with a different desensitization rate, were observ ed. The inhibition of the receptor by nicotine has not previously been repo rted. Both nicotine and cocaine compete with serotonin for the receptor sit e that controls channel opening, with observed dissociation constants of 25 and 7 muM, respectively. Fluoxetine (Prozac), a widely used antidepressant , occupies a different regulatory site on the receptor with an apparent K-i value of 244 muM.