Chronic antidepressant treatment alters serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons.

The serotonin system is highly involved in the pathophysiology of mood disorders such as depression and anxiety. Currently, the most widely used treatment for these illnesses is selective serotonin (5-HT)reuptake inhibitors, such as fluoxetine. Because of the multiplicity of 5-HT receptors and their different adaptive properties, the chronic effects of fluoxetine have remained unclear. In this study, we investigated the alteration of 5-HT functions by long-term antidepressant treatment in pyramidal neurons of prefrontal cortex (PFC), a brain region crucial for the control of emotion and cognition. One prominent function of serotonin in PFC is to regulate GABAergic inhibitory transmission. Application of 5-HT induced a large, desensitizing enhancement of the amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSC), as well as a potent reduction of electrically evoked IPSC (eIPSC). Chronic fluoxetine treatment did not alter basal sIPSC, but reduced eIPSC in response to different stimulus strengths. Moreover, chronic (but not acute) fluoxetine treatment caused a much faster desensitization of the 5-HT effect on sIPSC, and significantly attenuated the 5-HT effect on eIPSC. Application of a 5-HT(2) receptor agonist produced similar effects as 5-HT on sIPSC and eIPSC, and these effects were similarly altered by long-term fluoxetine treatment. These electrophysiological results suggest that chronic antidepressant treatment resulted in a down-regulation of the synaptic function of forebrain 5-HT(2) receptors. Given the key role of GABAergic inhibitory transmission in controlling PFC functions, its altered regulation by serotonin after chronic fluoxetine treatment may provide a mechanism underlying the therapeutic action of antidepressants.