A new small-molecule compound that regulates the firing of serotonergic neurons is shown to have a fast-acting antidepressant effect, according to a new study in mice. The findings open a new avenue for developing a new class of therapeutics for major depressive disorder (MDD) and other difficult to treat mood disorders. MDD is one of the most common mental disorders and affects hundreds of millions of people worldwide. Most current antidepressants target the serotonin transporter (SERT). However, these drugs are limited. Not only do they take up to 4 weeks before they take effect, SERT-targeted antidepressants can have negative side effects, including suicide, and only a portion of those who take them recover from depression following treatment. And, while ketamine has been explored as an alternative, the drug’s potential addictive properties and risk for schizophrenia have raised concerns. As a result, there is a need for new, fast-acting antidepressant targets and compounds without these serious drawbacks. Here, Nan Sun and colleagues present one such solution. Sun et al. designed a fast-onset antidepressant that works by disrupting the interaction between SERT and neuronal nitric oxide synthase (nNOS). The authors found that disassociating SERT from nNOS in the brains of mice reduced intercellular serotonin in a brain region called the dorsal raphe nucleus. This enhanced serotonergic neuron activity in this area and dramatically increased serotonin release into the medial prefrontal cortex. According to the findings, this resulted in a fast-acting antidepressant effect in a mouse model of MDD.
Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN
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