Neurobiological mechanisms involved in antidepressant therapies.
Selective serotonin reuptake inhibitors (SSRIs) are effective in alleviating the symptoms of depression. However, clinical improvement is only obtained after several weeks of treatment. SSRIs, when administered acutely to animals, have little effect on synaptic levels of serotonin. This suggests the existence of one or more regulatory mechanisms controlling serotonergic neurotransmission. The firing rate of dorsal raphe serotonergic neurons is under the control of somatodendritic 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, the release of serotonin from nerve terminals is under the control of 5-HT autoreceptors (5-HT1B subtype in rodents, 5-HT1D in other species), whereas the control of the activity of tryptophan hydroxylase, the rate-limiting enzyme of serotonin synthesis, is complex, involving 5-HT1A but possibly other 5-HT receptors including the 5-HT1B/D subtype. During prolonged administration with a SSRI, these three feedback systems become desensitized and their regulatory effects on serotonergic neurotransmission are weakened or lost. This has the effect of allowing the synaptic levels of serotonin to rise with a consequently increased stimulation of one or more types of postsynaptic 5-HT receptor. Thus, it is only after prolonged administration that the pharmacological activity of SSRI is fully expressed in terms of synaptic serotonin levels. This may explain the latency of antidepressant action seen with these drugs in humans. Various other classes of antidepressant therapies (tricyclic antidepressants and monoamine oxidase inhibitor drugs, electroconvulsive therapy) have long-term effects on one or more of the feedback mechanisms such that an increase in synaptic concentrations of serotonin may be a common mechanism of many antidepressant therapies.
Briley
M
M
Neurobiology Division I, Centre de Recherche Pierre Fabre, Castres, France.
Moret
C
C
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D006801:Humans; D009474:Neurons / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
D000928:Antidepressive Agents; D017367:Selective Serotonin Reuptake Inhibitors