The serotonin transporter: a primary target for antidepressant drugs.
The serotoninergic system is known to modulate mood, emotion, sleep and appetite and thus is implicated in the control of numerous behavioural and physiological functions. Decreased serotoninergic neurotransmission has been proposed to play a key role in the aetiology of depression. The concentration of synaptic serotonin is controlled directly by its reuptake into the pre-synaptic terminal and, thus, drugs blocking serotonin transport have been successfully used for the treatment of depression. In addition to tricyclic antidepressants (TCAs; e.g. imipramine) which also block noradrenaline reuptake, highly specific serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine have been developed, which are increasingly prescribed for depressed patients. The mode of action of these antidepressant drugs on their direct target, the serotonin transport protein, and possible regulatory mechanisms with respect to long-term alleviation of depression, although having been investigated both neurobiologically and clinically over the last years, are not yet understood. The cloning of the cDNA encoding the serotonin transporter has allowed a more precise characterization of this protein at the molecular level. This will show how antidepressants act at this target, thereby affecting the biochemical, pharmacological and electrophysiological properties of the serotoninergic system and give an introduction of how they might exert their therapeutic effect. This review gives an overview of the recent developments in this field, discusses mechanisms of antidepressant action on this target, and also possible interactions with other components of serotoninergic neurotransmission.
Schloss
P
P
Biochemistry Department, University of Dublin, Trinity College, Ireland. schlossp@mail.tcd.ie
Williams
D C
DC
D000928:Antidepressive Agents / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002352:Carrier Proteins / Q000187:drug effects* / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000502:physiology; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human