Chronic Fluoxetine Treatment Desensitizes Serotoninergic Inhibition of GABAergic Inputs and Intrinsic Excitability of Dorsal Raphe Serotonin Neurons

<b>Background:</b> Dorsal raphe serotonin (5-hydroxytryptamine, 5-HT) neurons are spontaneously active and release 5-HT that is critical for normal brain function and regulates mood and emotion. Serotonin reuptake inhibitors (SSRIs) increase the synaptic and extracellular 5-HT level and are effective in treating depression. Treatment of two weeks or longer is often required for SSRIs to produce clinical benefits. The cellular mechanism underlying this delay is not fully understood. <b>Methods and Results</b>: Using whole-cell patch clamp recording in brain slices, here we show that the GABAergic inputs inhibit the spike firing of raphe 5-HT neurons. This GABAergic regulation was reduced by 5-HT; additionally, this 5-HT effect was prevented by the G-protein-activated inwardly rectifying potassium (GirK) channel inhibitor tertiapin-Q, indicating a contribution of 5-HT activation of GirK channels in GABAergic presynaptic axon terminals. Equally important, after 14 days of treatment with fluoxetine, a widely used SSRI type antidepressant, the 5-HT inhibition of GABAergic inputs was downregulated. Furthermore, chronic fluoxetine treatment downregulated the 5-HT activation of the inhibitory GirK current in 5-HT neurons. <b>Conclusions:</b> Taken together, our results suggest that chronic fluoxetine treatment, by blocking 5-HT reuptake and hence increasing the extracellular 5-HT level, can downregulate the function of 5-HT1B receptors on the GABAergic afferent axon terminals synapsing onto 5-HT neurons, allowing extrinsic GABAergic neurons to more effectively influence 5-HT neurons; simultaneously, chronic fluoxetine treatment also downregulated somatic 5-HT autoreceptor-activated GirK channel-mediated hyperpolarization and decrease in input resistance, rendering 5-HT neurons resistant to autoinhibition and leading to increased 5-HT neuron activity. These neuroplastic changes in raphe 5-HT neurons and their GABAergic afferents may contribute to the behavioral effect of SSRIs.