The question of feedback at the somadendritic region and antidepressant drug action

Presynaptic receptor theory has been expanded to encompass the regulation of the firing rate of serotonergic neurons through negative feedback mediated by the somadendritic release of transmitter. This has encouraged hypotheses as to the mechanisms of action of several classes of antidepressants and anxiolytics. One conspicuous example is the attribution of the clinical efficacy of 5-HT uptake inhibitors, such as fluoxetine and paroxetine, to desensitization of somadendritic 5-HT autoreceptors. An examination of the available evidence, mainly observations made with agonists, antagonists, monoamine oxidase inhibitors and uptake blockers, taken along with the theoretical expectations for a negative feedback loop, and the operational characteristics of inactivation pathways, indicates that negative feedback does not function at somadendritic sites to set firing rate or transmitter density, and suggests that the process may not function at all physiologically. The attribution of the effectiveness of neuroactive drugs to desensitization of raphe 5-HT inhibitory receptors, or to other interactions with feedback, is highly speculative and unlikely.