Dual serotonergic signals: a key to understanding paradoxical effects?

Neuroscientists have been puzzled by the fact that acute administration of a selective serotonin reuptake inhibitor (SSRI) produces results that are, at times, compatible with either decreases or increases in serotonergic neurotransmission. Furthermore, the underlying cause of the delayed onset of antidepressant effects of SSRI treatment has remained obscure. It has recently been reported that serotonergic raphe neurons co-release glutamate and that serotonergic and glutamatergic components constitute a dual signal with behaviorally distinct effects. We discuss the consequences of these novel findings and propose a framework for understanding the controversial effects of acute SSRI administration. Furthermore, we suggest that the delayed remedial onset of SSRI treatment could be explained by an initial reduction of the glutamatergic component of the dual serotonergic signal.