Rapid Anxiolytic Effects of RS67333, a Serotonin Type 4 Receptor Agonist, and Diazepam, a Benzodiazepine, Are Mediated by Projections From the Prefrontal Cortex to the Dorsal Raphe Nucleus.

Background: Activation of serotonin (5-HT) type 4 receptors (5-HTRs) has been shown to have anxiolytic effects in a variety of animal models. Characterizing the circuits responsible for these effects should offer insights into new approaches to treat anxiety.

Methods: We evaluated whether acute 5-HTR activation in glutamatergic axon terminals arising from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN) induced fast anxiolytic effects.

Prophylactic efficacy of 5-HTR agonists against stress.

Enhancing stress resilience could protect against stress-induced psychiatric disorders in at-risk populations. We and others have previously reported that (R,S)-ketamine acts as a prophylactic against stress when administered 1 week before stress. While we have shown that the selective 5-hydroxytryptamine (5-HT) (serotonin) reuptake inhibitor (SSRI) fluoxetine (Flx) is ineffective as a prophylactic, we hypothesized that other serotonergic compounds such as serotonin 4 receptor (5-HTR) agonists could act as prophylactics.

Optogenetic activation of granule cells in the dorsal dentate gyrus enhances dopaminergic neurotransmission in the Nucleus Accumbens.

The dentate gyrus (DG) has distinct roles along its dorso-ventral axis. In the mouse, we recently demonstrated that dorsal DG (dDG) stimulation enhances exploratory behavior (Kheirbek et al., 2013).

Neurobiological Mechanisms of Stress Resilience and Implications for the Aged Population.

Background: Stress is a common reaction to an environmental adversity, but a dysregulation of the stress response can lead to psychiatric illnesses such as major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and anxiety disorders. Yet, not all individuals exposed to stress will develop psychiatric disorders; those with enhanced stress resilience mechanisms have the ability to adapt successfully to stress without developing persistent psychopathology. Notably, the potential to enhance stress resilience in at-risk populations may prevent the onset of stress-induced psychiatric disorders.

S 38093, a histamine H antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice.

Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN.

Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior.

Background: Stress exposure is one of the greatest risk factors for psychiatric illnesses like major depressive disorder and posttraumatic stress disorder. However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual.

Serotonin 1A and Serotonin 4 Receptors: Essential Mediators of the Neurogenic and Behavioral Actions of Antidepressants.

Selective serotonin reuptake inhibitors are the mostly widely used treatment for major depressive disorders and also are prescribed for several anxiety disorders. However, similar to most antidepressants, selective serotonin reuptake inhibitors suffer from two major problems: They only show beneficial effects after 2 to 4 weeks and only about 33% of patients show remission to first-line treatment. Thus, there is a considerable need for development of more effective antidepressants.