Erasing m6A-dependent transcription signature of stress-sensitive genes triggers antidepressant actions.

Emerging evidence has shown that stress responsivity and psychiatric diseases are associated with alterations in N6-methyladenosine (m6A) mRNA epigenetic modifications. Fat mass and obesity-associated protein (FTO) is an m6A demethylase that has been linked to increased body mass and obesity. Here, we show that tricyclic antidepressants (TCAs) with weight-gain side effects, such as imipramine and amitriptyline, directly increased FTO expression and activated its epigenetic function in the ventral tegmental area (VTA). VTA-specific genetic disruption of FTO increased stress vulnerability and abolished the antidepressant activity of TCAs, whereas erasing m6A modification in the VTA by FTO overexpression or cycloleucine led to significant antidepressant activity. Mechanistically, both transcriptome sequencing and quantitative PCR revealed that overexpression of FTO in the VTA decreased the transcription of stress-related neuropeptides, such as cocaine- and amphetamine-regulated transcript peptide and urocortin, in the social defeat model, which was mimicked by imipramine, suggesting an m6A-dependent transcription mechanism of stress-related neuropeptides may underlie the responses to antidepressant. Collectively, our results demonstrate that inhibiting m6A-dependent transcription of stress-related genes may work as a novel antidepressant strategy and highlight a previously unrecognized activator of FTO-dependent epigenetic function that may be used for the treatment of other neurological diseases.

SKF83959, an agonist of phosphatidylinositol-linked dopamine receptors, prevents renewal of extinguished conditioned fear and facilitates extinction.

Fear-related anxiety disorders, such as social phobia and post-traumatic stress disorder, are partly explained by an uncontrollable state of fear. An emerging literature suggests dopamine receptor-1 (D1 receptor) in the amygdala is involved in the regulation of fear memory. An early study has reported that amygdaloid D1 receptor (D1R) is not coupled to the classic cAMP-dependent signal transduction. Here, we investigated whether SKF83959, a typical D1R agonist that mainly activates a D1-like receptor-dependent phosphatidylinositol (PI) signal pathway, facilitates fear extinction and reduces the return of extinguished fear. Interestingly, long-term loss of fearful memories can be induced through a combination of SKF83959 (1 mg/kg/day, i.p., once daily for one week) pharmacotherapy and extinction training. Furthermore, sub-chronic administration of SKF83959 after fear conditioning reduced fear renewal and reinstatement in the mice. We found that the activation D1R and PI signaling in the amygdala was responsible for the effect of SKF83959 on fear extinction. Additionally, SKF83959 significantly promoted the elevation of brain-derived neurotrophic factor (BDNF) expression, possibly by the cAMP response element binding protein (CREB) -directed gene transcription. Given the beneficial effects on extinction, SKF83959 may emerge as a candidate pharmacological approach for improving cognitive-behavioral therapy on fear-related anxiety disorders.

Angiotensin-Converting Enzyme Inhibitor Rapidly Ameliorates Depressive-Type Behaviors via Bradykinin-Dependent Activation of Mammalian Target of Rapamycin Complex 1.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed antihypertensive agents. Intriguingly, case reports and clinical trials have indicated that ACEIs, including captopril and lisinopril, may have a rapid mood-elevating effect in certain patients, but few experimental studies have investigated their value as fast-onset antidepressants. METHODS: The present study consisted of a series of experiments using biochemical assays, immunohistochemistry, and behavioral techniques to examine the effect and mechanism of captopril on depressive-like behavior in 2 animal models, the chronic unpredictable stress model and the chronic social defeat stress model. RESULTS: Captopril (19.5 or 39 mg/kg, intraperitoneal injection) exerted rapid antidepressant activity in mice treated under the chronic unpredictable stress model and mice treated under the chronic social defeat stress model. Pharmacokinetic analysis revealed that captopril crossed the blood-brain barrier and that lisinopril, another ACEI with better blood-brain barrier permeability, exerted a faster and longer-lasting effect at a same molar equivalent dose. This antidepressant effect seemed to be independent of the renin-angiotensin system, but dependent on the bradykinin (BK) system, since the decreased BK detected in the stressed mice could be reversed by captopril. The hypofunction of the downstream effector of BK, Cdc42 (cell division control protein 42) homolog, contributed to the stress-induced loss of dendritic spines, which was rapidly reversed by captopril via activating the mTORC1 (mammalian target of rapamycin complex 1) pathway. CONCLUSIONS: Our findings indicate that the BK-dependent activation of mTORC1 may represent a promising mechanism underlying antidepressant pharmacology. Considering their affordability and availability, ACEIs may emerge as a novel fast-onset antidepressant, especially for patients with comorbid depression and hypertension.

Preventive and Therapeutic Potential of Vitamin C in Mental Disorders.

In this review, we summarize the involvement of vitamin C in mental disorders by presenting available evidence on its pharmacological effects in animal models as well as in clinical studies. Vitamin C, especially its reduced form, has gained interest for its multiple functions in various tissues and organs, including central nervous system (CNS). Vitamin C protects the neuron against oxidative stress, alleviates inflammation, regulates the neurotransmission, affects neuronal development and controls epigenetic function. All of these processes are closely associated with psychopathology. In the past few decades, scientists have revealed that the deficiency of vitamin C may lead to motor deficit, cognitive impairment and aberrant behaviors, whereas supplement of vitamin C has a potential preventive and therapeutic effect on mental illness, such as major depressive disorder (MDD), schizophrenia, anxiety and Alzheimer's disease (AD). Although several studies support a possible role of vitamin C against mental disorders, more researches are essential to accelerate the knowledge and investigate the mechanism in this field.