| Current antidepressants require weeks to months of treatment to exert therapeutic relief in depressed patients. Delay in therapeutic onset is particularly debilitating for this class of mood disorders marked by high prevalence, low remission rates, high relapse rates, and high incidence of suicide. To date, no fast-acting antidepressants are available to the clinically depressed patient.;Recent clinical trials have identified that ketamine, an N-methyl-d-aspartate receptor antagonist, and scopolamine, a non-selective muscarinic receptor antagonist, produce rapid (within hours) antidepressant-effects in treatment-resistant depressed patients. However, ketamine and scopolamine remain unapproved for the treatment of depression due to serious side effects. Importantly, ketamine and scopolamine do not act through serotonergic or noradrenergic mechanisms, suggesting the development of fast-acting antidepressants should focus on compounds with novel mechanisms of action.;One potential class of compounds is selective serotonin 2C (5-HT2C) antagonists. Many typical antidepressants antagonize 5-HT2C receptors with nanomolar affinity and the recently approved atypical antidepressant agomelatine, a 5-HT2C receptor antagonist and melatonin receptor agonist, has been reported to induce faster-onset therapeutic relief in depressed patients. Similar to ketamine and scopolamine, 5-HT2C receptor antagonists do not mediate serotonergic or noradrenergic signaling; rather 5-HT2C antagonists stimulate dopaminergic signaling. Given the role of disrupted dopaminergic signaling in anhedonic states, which is a core feature of depression, and clinical observations that agomelatine exerts faster-acting effects, we hypothesized that 5-HT2C antagonists could be compounds with fast-acting antidepressant potential.;To test this hypothesis, we assessed the time course of therapeutic onset of 5-HT2C receptor antagonists in chronic animal models of depressive-like behavior. Here, we show that 5-HT2C antagonists exert fast-acting (5 days) antidepressant effects in 4 behavioral paradigms: chronic forced swim test, olfactory bulbectomy, chronic mild stress, and social defeat stress.;Next, we examined the molecular mechanisms underlying the fast-acting antidepressants effects of 5-HT2C antagonists. Here, we show that 5-HT2C receptor antagonists elevate brain derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC), which depends on components of mammalian target of rapamycin (mTOR) signaling, similar to ketamine and scopolamine. In local infusion studies, we show this mechanism relies on blocking 5-HT2C receptors in the ventral tegmental area, the origin of dopaminergic signaling. Dopamine antagonists blocked 5-HT2C receptor antagonist-induced fast-acting antidepressant effects. Additionally, we made the discovery that typical antidepressants also activate components of mTOR signaling, which were proposed to be separate from faster-acting agents.;Lastly, we determined the fast-acting antidepressant effects of 5-HT2C receptor antagonists on stress-induced neuronal atrophy in the mPFC, given that many typical antidepressants reverse these changes after chronic treatment. Here, we show that 5-HT2C antagonists reverse some of the morphological neuronal changes induced by stress, including increased dendritic length, spine density, and dendritic arborization in the mPFC.;The studies presented in this thesis identify 5-HT2C receptor antagonists as putative fast-acting antidepressants with a novel mechanism of action. These findings reinforce the notion that activation of BDNF is critical to the onset of the antidepressant response and disprove the notion that mTOR signaling is required for antidepressant onset. We believe 5-HT2C antagonists should be investigated in clinical trials. |
