Selective serotonin reuptake inhibitors induce spontaneous interneuronal activity in the leech nervous system

Serotonin [5-hydroxytryptamine (5-HT)] is a conspicuous neuromodulator of sensory-motor networks that affects a variety of neurons at different levels of the network hierarchy. Because of its many possible targets, it has been difficult to obtain a comprehensive picture of how 5-HT achieves its final modulatory output on any given network. Our hypothesis is that the profile of 5-HT actions is dictated by its pattern of release from endogenous sites. We tested this hypothesis in the leech nervous system by means of a selective serotonin reuptake blocker (SSRI), fluoxetine. Fluoxetine evoked barrages of synaptic potentials in identified sensory, motor, and interneurons. This effect was mimicked by the tricyclic antidepressants imipramine and clomipramine, and by the SSRI citalopram, with relative efficacies that matched their known relative selectivities for the 5-HT transporter. The synaptic responses evoked by fluoxetine in different neurons were temporally correlated, suggesting that they had a common origin. The profile of the synaptic responses matched that expected from the activation of the mechanosensory pressure cells, known to act by polysynaptic pathways. The results suggest that endogenous 5-HT acted on cord spanning interneurons. On the other hand, bath-applied 5-HT evoked an effect different from that of the SSRI. Taken together, the results evidenced that the pattern of action of the monoamine is dictated by the spatial distribution of the 5-HT release sites.