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Using rodent models, researchers addressed the relationship between inhibition of the serotonin reuptake transporter (SERT) and the ability of selective serotonin reuptake inhibitors (SSRIs) to enhance synaptic plasticity and improve depression.
Long-term depression (LTD) induced in synapses in rat hippocampus was blocked by all available SSRIs in concentrations corresponding to brain levels in humans receiving therapeutic doses. The same result was found in SERT-knockout animals; LTD was also inhibited by an L-type calcium-channel blocker but not by an N-methyl-d-aspartate antagonist. Blockade of serotonin 1A receptors did not alter SSRIs' direct inhibition of L-type calcium currents.
In several validated animal models, fluvoxamine inhibited chronic, stress-induced, depression-like behaviors in both wild-type and SERT-knockout animals. In this model, LTD occurred in brains of depressed animals and was blocked by the SSRI, whether in wild-type or SERT-knockout animals.
Normann C et al. Antidepressants rescue stress-induced disruption of synaptic plasticity via serotonin transporter-independent inhibition of L-type Ca2+-channels. Biol Psychiatry 2017 Oct 19; [e-pub]. (http://dx.doi.org/10.1016/j.biopsych.2017.10.008)
Comment
This research shows that, independent of serotonin reuptake, SSRIs can ameliorate both depression and a fundamental change in neuronal communication associated with depression in the form of LTD, which reduces synaptic plasticity and the capacity to adapt to stress. The mechanism of improved plasticity seems to involve inhibition of voltage-gated L-type calcium channels. Interestingly, at therapeutic brain concentrations, SSRIs inhibit calcium channels but not SERT, supporting the observation that the antidepressant effect of SSRIs involves altered calcium influx as much as or more than serotonin reuptake. Further development of monoamine neurotransmitter “me-too drugs” should be replaced by a search for medications affecting other mechanisms, such as the intracellular calcium-signaling cascade.