|Title||Time-dependent modulation of glutamate synapses onto 5-HT neurons by antidepressant treatment.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Geddes, Sean D., Saleha Assadzada, Alexandra Sokolovski, Richard Bergeron, Samir Haj-Dahmane, and Jean-Claude Béïque|
|Date Published||2015 Aug|
|Keywords||Animals, Antidepressive Agents, Second-Generation, Bacterial Proteins, Carrier Proteins, Dorsal Raphe Nucleus, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Immunohistochemistry, Patch-Clamp Techniques, Rats, Sprague-Dawley, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Serotonergic Neurons, Serotonin Uptake Inhibitors, Synapses, Time Factors, Tissue Culture Techniques|
Antidepressants, including the selective serotonin reuptake inhibitors (SSRIs), are thought to exert their clinical effects by enhancing serotonin (5-HT) transmission. However, animal studies show that the full magnitude of this enhancement is reached only following prolonged treatments with SSRIs, consistent with the well-described therapeutic delay of this class of medications. Thus, the clinical efficacy of SSRIs most likely does not emerge from their acute pharmacological actions, but rather indirectly from cellular alterations that develop over the course of a sustained treatment. Here, we show that sustained administration of the SSRI citalopram leads to a homeostatic-like increase in the strength of excitatory glutamate synapses onto 5-HT neurons of the dorsal raphe nucleus that was apparent following one week of treatment. A shorter treatment with citalopram rather induced a paradoxical decrease in the strength of these synapses, which manifested itself by both pre- and postsynaptic mechanisms. As such, these results show that an SSRI treatment induced a concerted and time-dependent modulation of the synaptic drive of 5-HT neurons, which are known to be critically involved in mood regulation. This regulation, and its time course, provide a mechanistic framework that may be relevant not only for explaining the therapeutic delay of antidepressants, but also for the perplexing increases in suicide risks reportedly occurring early in the course of antidepressant treatments.
|Grant List||/ / Canadian Institutes of Health Research / Canada|