Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT1A receptors but not 5-HT2A receptors

Atypical antipsychotic drugs (APDs) increase dopamine (DA) release in prefrontal cortex (PFC), an effect probably mediated by the direct or indirect activation of the 5-HT1A receptor (5-HT1AR). Given the very low in-vitro affinity of most APDs for 5-HT1ARs and the large co-expression of 5-HT1ARs and 5-HT2A receptors (5-HT2ARs) in the PFC, this effect might result from the imbalance of 5-HT1AR and 5-HT2AR activation after blockade of these receptors by APDs, for which they show high affinity. Here we tested this hypothesis by examining the dependence of the APD-induced DA release in medial PFC (mPFC) on each receptor by using in-vivo microdialysis in wild-type (WT) and 5-HT1AR and 5-HT2AR knockout (KO) mice. Local APDs (clozapine, olanzapine, risperidone) administered by reverse dialysis induced a dose-dependent increase in mPFC DA output equally in WT and 5-HT2AR KO mice whereas the DA increase was absent in 5-HT1AR KO mice. To examine the relative contribution of both receptors to the clozapine-induced DA release in rat mPFC, we silenced G-protein-coupled receptors (GPCRs) in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while 5-HT 1ARs or 5-HT2A/2CRs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving ∼70% of 5-HT2A/2CRs prevented the clozapine-induced DA rise in mPFC. In contrast, clozapine increased DA in mPFC of EEDQ-treated rats whose 5-HT1ARs were protected (∼50% of control rats). These results indicate that (1) 5-HT1ARs are necessary for the APDs-induced elevation in cortical DA transmission, and (2) this effect does not require 5-HT2AR blockade by APDs. © 2010 CINP.This work was supported by grants SAF 2007-62378 and SENY Fundació. A. B. is recipient of a Ramón y Cajal contract from MICINN-IDIBAPS. M. M. is a recipient of a predoctoral fellowship from CSIC (I3P program).Peer Reviewe

Effects of Serotonin Transporter Gene Variation on Impulsivity Mediated by Default Mode Network: A Family Study of Depression

Serotonergic neurotransmission, potentially through effects on the brain’s default mode network (DMN), may regulate aspects of attention including impulse control. Indeed, genetic variants of the serotonin transporter (5-HTT) have been implicated in impulsivity and related psychopathology. Yet it remains unclear the mechanism by which the 5-HTT genetic variants contribute to individual variability in impulse control. Here, we tested whether DMN connectivity mediates an association between the 5-HTT genetic variants and impulsivity. Participants (N = 92) were from a family cohort study of depression in which we have previously shown a broad distribution of 5-HTT variants. We genotyped for 5-HTTLPR and rs25531 (stratified by transcriptional efficiency: 8 low/low, 53 low/high, and 31 high/high), estimated DMN structural connectivity using diffusion probabilistic tractography, and assessed behavioral measures of impulsivity (from 12 low/low, 48 low/high, and 31 high/high) using the Continuous Performance Task. We found that low transcriptional efficiency genotypes were associated with decreased connection strength between the posterior DMN and the superior frontal gyrus (SFG). Path modeling demonstrated that decreased DMN–SFG connectivity mediated the association between low-efficiency genotypes and increased impulsivity. Taken together, this study suggests a gene-brain-behavior pathway that perhaps underlies the role of the serotonergic neuromodulation in impulse control

Dopamine Release Induced by Atypical Antipsychotics in Prefrontal Cortex Requires 5-HT(1A) Receptors but Not 5-HT(2A) Receptors

Atypical antipsychotic drugs (APDs) increase dopamine (DA) release in prefrontal cortex (PFC), an effect probably mediated by the direct or indirect activation of the 5-HT(1A) receptor (5-HT(1A)R). Given the very low in-vitro affinity of most APDs for 5-HT(1A)Rs and the large co-expression of 5-HT(1A)Rs and 5-HT(2A) receptors (5-HT(2A)Rs) in the PFC, this effect might result from the imbalance of 5-HT(1A)R and 5-HT(2A)R activation after blockade of these receptors by APDs, for which they show high affinity. Here we tested this hypothesis by examining the dependence of the APD-induced DA release in medial PFC (mPFC) on each receptor by using in-vivo microdialysis in wild-type (WT) and 5-HT(1A)R and 5-HT(2A)R knockout (KO) mice. Local APDs (clozapine, olanzapine, risperidone) administered by reverse dialysis induced a dose-dependent increase in mPFC DA output equally in WT and 5-HT(2A)R KO mice whereas the DA increase was absent in 5-HT(1A)R KO mice. To examine the relative contribution of both receptors to the clozapine-induced DA release in rat mPFC, we silenced G-protein-coupled receptors (GPCRs) in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while 5-HT(1A)Rs or 5-HT(2A)/2CRs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving ∼70% of 5-HT(2A)/(2C)Rs prevented the clozapine-induced DA rise in mPFC. In contrast, clozapine increased DA in mPFC of EEDQ-treated rats whose 5-HT(1A)Rs were protected (∼50% of control rats). These results indicate that (1) 5-HT(1A)Rs are necessary for the APDs-induced elevation in cortical DA transmission, and (2) this effect does not require 5-HT(2A)R blockade by APDs

Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis

Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1–PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.Fil: Fanibunda, S. E.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España. Kasturba Health Society; IndiaFil: Deb, Sukrita. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Maniyadath, Babukrishna. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Tiwari, Praachi. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Ghai, Utkarsha. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Gupta, Samir. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Figueiredo, Dwight. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Weisstaub, Noelia V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Gingrich, Jay A.. Columbia University; Estados UnidosFil: Vaidya, Ashok D.B.. Kasturba Health Society; IndiaFil: Kolthur Seetharam, Ullas. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Vaidya, Vidita A.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; Españ

Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy

Importance Selective serotonin reuptake inhibitor (SSRI) use among pregnant women is increasing, yet the association between prenatal SSRI exposure and fetal neurodevelopment is poorly understood. Animal studies show that perinatal SSRI exposure alters limbic circuitry and produces anxiety and depressive-like behaviors after adolescence, but literature on prenatal SSRI exposure in humans is limited and mixed. Objective To examine associations between prenatal SSRI exposure and brain development using structural and diffusion magnetic resonance imaging (MRI). Design, Setting, and Participants A cohort study conducted at Columbia University Medical Center and New York State Psychiatric Institute included 98 infants: 16 with in utero SSRI exposure, 21 with in utero untreated maternal depression exposure, and 61 healthy controls. Data were collected between January 6, 2011, and October 25, 2016. Exposures Selective serotonin reuptake inhibitors and untreated maternal depression. Main Outcomes and Measures Gray matter volume estimates using structural MRI with voxel-based morphometry and white matter structural connectivity (connectome) using diffusion MRI with probabilistic tractography. Results The sample included 98 mother (31 [32%] white, 26 [27%] Hispanic/Latina, 26 [27%] black/African American, 15 [15%] other) and infant (46 [47%] boys, 52 [53%] girls) dyads. Mean (SD) age of the infants at the time of the scan was 3.43 (1.50) weeks. Voxel-based morphometry showed significant gray matter volume expansion in the right amygdala (Cohen d = 0.65; 95% CI, 0.06-1.23) and right insula (Cohen d = 0.86; 95% CI, 0.26-1.14) in SSRI-exposed infants compared with both healthy controls and infants exposed to untreated maternal depression (P < .05; whole-brain correction). In connectome-level analysis of white matter structural connectivity, the SSRI group showed a significant increase in connectivity between the right amygdala and the right insula with a large effect size (Cohen d = 0.99; 95% CI, 0.40-1.57) compared with healthy controls and untreated depression (P < .05; whole connectome correction). Conclusions and Relevance Our findings suggest that prenatal SSRI exposure has an association with fetal brain development, particularly in brain regions critical to emotional processing. The study highlights the need for further research on the potential long-term behavioral and psychological outcomes of these neurodevelopmental changes

Adult Outcomes Of Childhood Disruptive Disorders In Offspring Of Depressed And Healthy Parents

Background: Longitudinal studies of children with disruptive disorders (DDs) have shown high rates of antisocial personality disorder (ASPD) and substance use in adulthood, but few have examined the contribution of parental disorders. We examine child-/adulthood outcomes of DDs in offspring, whose biological parents did not have a history of ASPD, bipolar disorder, or substance use disorders. Method: Offspring (N = 267) of parents with or without major depression (MDD), but no ASPD or bipolar disorders were followed longitudinally over 33 years, and associations between DDs and psychiatric and functional outcomes were tested. Results: Eighty-nine (33%) offspring had a DD. Those with, compared to without DDs, had higher rates of MDD (adjusted odds ratio, AOR = 3.42, p < 0.0001), bipolar disorder (AOR = 3.10, p = 0.03), and substance use disorders (AOR = 5.69, p < 0.0001) by age 18, as well as poorer school performance and global functioning. DDs continued to predict MDD and substance use outcomes in adulthood, even after accounting for presence of the corresponding disorder in childhood (MDD: hazards ratio, HR = 3.25, p < 0.0001; SUD, HR = 2.52, p < 0.0001). Associations were similar among the offspring of parents with and without major depression. DDs did not predict adulthood ASPD in either group. Limitations: Associations are largely accounted for by conduct disorder (CD), as there were few offspring with ADHD, and oppositional defiant disorder (ODD) was not diagnosed at the time this study began. Conclusion: If there is no familial risk for ASPD, bipolar disorder or substance use, childhood DDs do not lead to ASPD in adulthood; however, the children still have poorer prognosis into midlife. Early treatment of children with DD, particularly CD, while carefully considering familial risk for these disorders, may help mitigate later adversity

Advancing drug discovery for schizophrenia

Sponsored by the New York Academy of Sciences and with support from the National Institute of Mental Health, the Life Technologies Foundation, and the Josiah Macy Jr. Foundation, "Advancing Drug Discovery for Schizophrenia" was held March 9-11 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, all of which contribute to the overarching goal of enhancing the pharmaceutical armamentarium for treating schizophrenia. This report surveys work by the vanguard of schizophrenia research in such topics as genetic and epigenetic approaches; small molecule therapeutics; and the relationships between target genes, neuronal function, and symptoms of schizophrenia

5-HT2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress

Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A) receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS) on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC) and hippocampus in 5-HT2A receptor knockout (5-HT2Aâ/â) and wild-type mice of both sexes. While 5-HT2Aâ/â male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-HT2Aâ/â female mice with a hyperlipidemic baseline phenotype. 5-HT2Aâ/â male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2), trophic factors (Bdnf, Igf1) and immediate early genes (IEGs) (Arc, Fos, Fosb, Egr1-4) in the PFC and hippocampus were altered in 5-HT2Aâ/â mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic. Keywords: 5-HT2Aâ/â mice, Prefrontal cortex, Hippocampus, Gene expression, Sexual dimorphism, Despai

Gestational Exposure to Selective Serotonin Reuptake Inhibitors and Offspring Psychiatric Disorders : A National Register-Based Study

Objective: To investigate the impact of gestational exposure to selective serotonin reuptake inhibitors (SSRIs) on offspring neurodevelopment. Method: This is a cohort study using national register data in Finland between the years 1996 and 2010. Pregnant women and their offspring were categorized into 4 groups: SSRI exposed (n = 15,729); exposed to psychiatric disorder, no antidepressants (n = 9,651); exposed to SSRIs only before pregnancy (n = 7,980); and unexposed to antidepressants and psychiatric disorders (n = 31,394). We investigated the cumulative incidence of offspring diagnoses of depression, anxiety, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) for the 4 groups from birth to 14 years, adjusting for confounders. Results: The cumulative incidence of depression among offspring exposed prenatally to SSRIs was 8.2% (95% CI = 3.1-13.3%) by age 14.9 years, compared with 1.9% (95% CI = 0.9-2.9%) in the psychiatric disorder, no medication group (adjusted hazard ratio [HR] = 1.78; 95% CI = 1.12-2.82; p=.02) and to 2.8% (95% CI = 1.4-4.3%) in the SSRI discontinued group (HR = 1.84; 95% CI = 1.14-2.97; p=.01). Rates of anxiety, ASD, and ADHD diagnoses were comparable to rates in offspring of mothers with a psychiatric disorder but no medication during pregnancy. Comparing SSRI exposed to unexposed individuals, the HRs were significantly elevated for each outcome. Conclusion: Prenatal SSRI exposure was associated with increased rates of depression diagnoses in early adolescence but not with ASD or ADHD. Until confirmed, these findings must be balanced against the substantial adverse consequences of untreated maternal depression.Peer reviewe