Abstract
RationaleThe prevalence of depression is ever-increasing throughout the population. However, available treatments are ineffective in around one-third of patients and there is a need for more effective and safer drugs.ObjectivesThe antidepressant-like and procognitive effects of the “biased agonists” F15599 (also known as NLX-101) which preferentially targets postsynaptic 5-HT1A receptors and F13714, which targets 5-HT1A autoreceptors, were investigated in mice.MethodsAntidepressant-like properties of the compounds and their effect on cognitive functions were assessed using the forced swim test (FST) and the novel object recognition (NOR), respectively. Next, we induced a depressive-like state by an unpredictable chronic mild stress (UCMS) procedure to test the compounds’ activity in the depression model, followed by measures of sucrose preference, FST, and locomotor activity. Levels of phosphorylated cyclic AMP response element-binding protein (p-CREB) and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) were also determined.ResultsF15599 reduced immobility time in the FST over a wider dose-range (2 to 16 mg/kg po) than F13714 (2 and 4 mg/kg po), suggesting accentuated antidepressant-like properties in mice. F15599 did not disrupt long-term memory consolidation in the NOR at any dose tested, while F13714 impaired memory formation, notably at higher doses (4–16 mg/kg). In UCMS mice, a single administration of F15599 and F13714 was sufficient to robustly normalize depressive-like behavior in the FST but did not rescue disrupted sucrose preference. Both F15599 and F13714 rescued cortical and hippocampal deficits in p-ERK1/2 levels of UCMS mice but did not influence the p-CREB levels.ConclusionsOur studies showed that 5-HT1A receptor biased agonists such as F13714 and especially F15599, due to its less pronounced side effects, might have potential as fast-acting antidepressants.
Highlights
Monika Głuch-Lutwin and Kinga Sałaciak contributed to this work.Depression is a severe mental condition, and according to the World Health Organization (WHO), more than 300 million people are affected by the disease globally, and by the end of 2030, they expect that depression will be the leading cause of disability worldwide (Lépine and Briley 2011)
We evaluated if F15599 and F13714 influence the levels of phosphorylated cyclic AMP response elementbinding protein (p-CREB) and phosphorylated ERK1/2 in the hippocampus and prefrontal cortex, two markers associated with antidepressant-like activity
The data sets for the experiments showed normal distribution as well as homogeneity of the variance (data sets for F15599, F13714 and ketamine: F(4,35) = 0.6841, ns; data sets for fluoxetine: F(2,21)=0.2567, ns)
Summary
Monika Głuch-Lutwin and Kinga Sałaciak contributed to this work.Depression is a severe mental condition, and according to the World Health Organization (WHO), more than 300 million people are affected by the disease globally, and by the end of 2030, they expect that depression will be the leading cause of disability worldwide (Lépine and Briley 2011). The drugs available for the treatment of depression are still inadequate: around 60% of patients do not respond to antidepressants, and nearly one-third of them, despite receiving pharmacotherapy, experience relapse. Another limiting factor of most current antidepressant drugs is their delayed onset of action-clinical efficacy generally requiring several weeks of treatment. Delayed onset of action is a common cause of drug discontinuation, with about 28% of patients ceasing to take. Scientists are still searching for new compounds that have a fast onset of action, increased efficacy, and additional properties
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