The auditory event-related potential (ERP) components N1 and P3 have been identified as potential neural markers of psychotic disorders. However, the literature has largely examined categorical disorders, and the auditor...The auditory event-related potential (ERP) components N1 and P3 have been identified as potential neural markers of psychotic disorders. However, the literature has largely examined categorical disorders, and the auditory N1 and P3 have also been associated with internalizing disorders. It is unclear whether the auditory N1 and P3 relate to specific features of psychosis, broad psychosis, or general psychopathology. The present study examined the relationship between the auditory N1, P3a, and P3b and dimensional representations of psychosis and comorbid psychopathology. We tested whether auditory ERPs (1) were associated with specific psychosis dimensions (thought disorder, detachment, cognition, functioning) or the psychosis superspectrum, and (2) demonstrated specificity to psychosis compared to comorbid internalizing psychopathology. Participants (M = 49.57, 45.2% female) were 202 individuals with a history of hospitalization for a psychotic disorder and 304 demographically matched comparisons. All participants completed an auditory oddball task while we recorded electroencephalography, diagnostic interviews, self-report questionnaires, and a neuropsychological battery. A more blunted auditory N1, P3a, and P3b were associated with greater scores on the psychosis superspectrum. After controlling for the psychosis superspectrum, the N1 and P3a were not independently related to any specific psychosis dimension, but a smaller P3b was associated with poorer cognition. The N1 and P3b, but not P3a, demonstrated specificity to the psychosis superspectrum compared to the internalizing spectrum. A blunted auditory N1 and P3b are uniquely associated with the psychosis superspectrum, while a blunted P3a was common to both the psychosis superspectrum and internalizing spectrum.
McLean TAB, Jin Z, Hategan LA
… +9 more, Creighton SD, Luo JQ, Pirri F, Dahi TA, Neira Diaz L, Winston SM, Brimble MA, Walters BJ, Zovkic IB
Neuropsychopharmacology
· 2026 Jun · PMID 42373913
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Histone variants are critical components of neuronal chromatin that are emerging as key regulators of long-term memory formation. We previously showed that depleting the macrodomain-containing histone variant macroH2A1 (...Histone variants are critical components of neuronal chromatin that are emerging as key regulators of long-term memory formation. We previously showed that depleting the macrodomain-containing histone variant macroH2A1 (mH2A1) in the mouse hippocampus impairs long-term memory, establishing this histone as essential for memory consolidation. However, mH2A1 undergoes alternative splicing to generate two isoforms, mH2A1.1 and mH2A1.2, which differ by a single exon within the macrodomain. Though mH2A1.1 and mH2A1.2 have been reported to regulate unique molecular processes in non-neuronal cells, distinct functional contributions of hippocampal mH2A1.1 and mH2A1.2 to long-term memory formation in the adult brain are unknown. Here, we characterized genomic localization of mH2A1 splice isoforms in the mouse hippocampus and evaluated how isoform-specific knockdown impacts hippocampal transcription and memory. Although both isoforms localize to and regulate memory-relevant genes, their depletion affected largely non-overlapping gene sets, and only loss of mH2A1.1 impaired long-term memory. Notably, mH2A1.1 depletion increased expression of several genes that negatively regulate memory formation, including the well-established memory suppressor calcineurin. Thus, under normal conditions, mH2A1.1 may promote memory by repressing transcriptional programs that constrain plasticity. Together, these findings reveal isoform-specific functions of mH2A1 in the hippocampus and identify alternative splicing of mH2A1 as a key epigenetic mechanism that fine-tunes neural chromatin composition to enable long-term memory formation.
Levy CC, Cuzon Carlson VC, Grant KA
… +1 more, Salinas AG
Neuropsychopharmacology
· 2026 Jun · PMID 42365095
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Alcohol use disorder (AUD) affects over 28 million people in the U.S and is associated with neurobiological alterations, including in the basal ganglia. Within the basal ganglia, the caudate nucleus (caudate) and putamen...Alcohol use disorder (AUD) affects over 28 million people in the U.S and is associated with neurobiological alterations, including in the basal ganglia. Within the basal ganglia, the caudate nucleus (caudate) and putamen are implicated in AUD due to their roles in ethanol reinforcement. The caudate receives inputs from cortico-associative areas, and the putamen receives inputs from somatosensory areas, supporting goal-directed and habitual behaviors, respectively. These distinct behavioral roles are supported by dopamine signaling, including phasic dopamine, which is involved in assessing action-outcome associations, and tonic dopamine, which reflects ongoing dopaminergic tone that biases action initiation. Intrastriatal dopamine release is modulated by cholinergic interneurons via nicotinic acetylcholine receptors. Dysregulation of these mechanisms can contribute to the transition from occasional to habitual ethanol drinking. Here, we used in-vitro fast-scan cyclic voltammetry to measure dopamine signaling in male and female rhesus macaques following six months of ethanol self-administration. In the putamen, ethanol increased tonic dopamine in both sexes, with females exhibiting greater release and faster dopamine uptake rates than males. In the caudate, ethanol self-administration enhanced dopamine uptake rates only in males. Phasic dopamine release was enhanced by ethanol in the caudate of both sexes, but only in the putamen in males. Further, nAChR blockade revealed that phasic dopamine release in ethanol males, but not females, was dependent on cholinergic modulation. These results demonstrate that basal and sex-specific dopamine release and uptake are uniquely altered in rhesus macaque caudate and putamen in conjunction with chronic ethanol drinking.
Rehg JJ, Olivares DE, Li Y
… +4 more, García R, Martinowich K, Carr GV, Miranda-Barrientos J
Neuropsychopharmacology
· 2026 Jun · PMID 42362777
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The medial prefrontal cortex (mPFC) plays a pivotal role in attention by exerting top-down control to allocate cognitive resources toward behaviorally relevant stimuli based on learned context and expectations. mPFC neur...The medial prefrontal cortex (mPFC) plays a pivotal role in attention by exerting top-down control to allocate cognitive resources toward behaviorally relevant stimuli based on learned context and expectations. mPFC neurons project to multiple cortical and subcortical regions, including the locus coeruleus (LC)-the brain's primary source of norepinephrine (NE). The mPFC also receives inputs from the LC, which release NE to modulate mPFC neuronal activity and downstream cellular signaling. While enhanced functional connectivity between the mPFC and LC in mice during sustained attention tasks suggest an important role for the mPFC-LC circuit, and in particular for mPFC neurons projecting to the LC (mPFC-LC projectors), functional evidence directly implicating this population in attention is lacking. Here, we investigated the role of the mPFC-LC projectors in attention by comparing selective chemogenetic manipulation of these neurons to broad chemogenetic manipulation of mPFC neurons. Selective activation of mPFC-LC projectors in mice performing the rodent continuous performance test (rCPT), a translational sustained attention task, robustly improves attentional performance by enhancing discrimination while non-selective activation of mPFC neurons increases attentional performance by increasing responsiveness. Behavioral effects of mPFC-LC projector activation were mediated by recruitment of a microcircuit involving LC-NE neurons and glutamate and GABA peri-LC neurons that resulted in an increase in NE tone within the mPFC. while effects of non-selective activation of mPFC neurons were mediated by engaging downstream targets such as the nucleus accumbens (NAc) as well as the LC/peri-LC region. These findings demonstrate that subpopulations of mPFC neurons engaging distinct downstream targets control different domains of attentional performance, providing a circuit-level framework for understanding the mechanisms of sustained attention and for developing targeted therapies for attentional deficits across neuropsychiatric disorders.
Klug ME, Décarie-Spain L, Lauer LT
… +10 more, Sortman BW, Mo B, Kao AE, Moody OP, Morano NR, Huang H, Arnold DB, Noble EE, Johnson AW, Kanoski SE
Neuropsychopharmacology
· 2026 Jun · PMID 42362776
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Heightened impulsivity is associated with substance abuse disorders, gambling, and obesity. The ventral hippocampus (vHPC) has recently been linked with impulse control, yet the neurobiological and behavioral mechanisms...Heightened impulsivity is associated with substance abuse disorders, gambling, and obesity. The ventral hippocampus (vHPC) has recently been linked with impulse control, yet the neurobiological and behavioral mechanisms through which this occurs are unknown. A subset of vHPC neurons projects to the nucleus accumbens shell (ACBsh), a brain region known for regulating reward and motivation. Here, we evaluated the role of vHPC-ACBsh signaling in food-directed impulsivity using fiber photometry and transsynaptic chemogenetic and behavioral approaches. Male and female rats were trained in the differential reinforcement of low rates of responding (DRL) test of impulsive action, where they learn to withhold lever presses for 20 s to obtain a palatable food reward. Photometry recordings during DRL revealed elevations in calcium-dependent activity in the vHPC during the 5 s immediately prior to a non-impulsive vs. an impulsive response in males but not females. Chemogenetic silencing of ACBsh-projecting vHPC neurons elevated impulsive responses in DRL relative to vehicle treatment in males but not females, yet had no effect on home cage food intake, operant-based motivation to work for palatable food, impulsive choice, or anxiety-like behavior. To determine whether this impulse control circuit requires vHPC->ACBsh communication independent of collateral targets of ACBsh-projecting vHPC neurons, we utilized a novel transsynaptic viral approach to selectively silence ACB neurons that receive synaptic glutamatergic signaling from the vHPC. Results reveal that inhibition of ACBsh neurons receiving vHPC signaling elevates impulsive action in the DRL task relative to vehicle treatment. Collective results reveal a sex-specific hippocampal-striatal circuit that regulates impulsivity.
Perry-Hauser NA, Torres-Herraez A, Boumhaouad S
… +8 more, Makowicz EA, Lowes DC, Jin M, Denny CA, Sulzer D, Mosharov EV, Kellendonk C, Javitch JA
Neuropsychopharmacology
· 2026 Jun · PMID 42362775
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Dopamine signaling is essential for regulating movement, learning, and reward processing, and its dysregulation has been implicated in neuropsychiatric conditions such as ADHD and substance use disorder. ADGRL3, an adhes...Dopamine signaling is essential for regulating movement, learning, and reward processing, and its dysregulation has been implicated in neuropsychiatric conditions such as ADHD and substance use disorder. ADGRL3, an adhesion G protein-coupled receptor enriched in the brain, has been genetically linked to these disorders, and Adgrl3 knockout in animals alters expression of dopaminergic markers and impacts dopamine-related behaviors. However, how ADGRL3 influences dopamine dynamics remains poorly understood. Here, we characterized striatal dopamine release in Adgrl3 knockout mice using complementary ex vivo and in vivo approaches. Fast-scan cyclic voltammetry in acute brain slices revealed increased electrically evoked dopamine release in both dorsal and ventral striatum of Adgrl3 knockout mice. In contrast, in vivo fiber photometry using the dopamine sensor dLight1.2 showed reduced cue-induced dopamine signals in the ventral striatum during an operant fixed interval task. This reduction was accompanied by longer latencies to lever press and retrieve rewards, consistent with altered cue-guided behavioral responses reminiscent of task-switching difficulties in individuals with ADHD. Amphetamine challenge experiments indicated that phasic release capacity was similar between genotypes, suggesting that dopamine stores are intact in Adgrl3 KO mice. Together, these findings reveal that ADGRL3 regulates striatal dopamine release and motivate mechanistic studies of how its loss may alter the spatial organization of dopaminergic terminals.
Gärtner M, Meiering MS, Weigner D
… +11 more, Hempel M, Gruzman R, Carstens L, Keicher C, Mennes M, Beckmann CF, Luippold G, Süssmuth SD, Popp M, Wunder A, Grimm S
Neuropsychopharmacology
· 2026 Jun · PMID 42350630
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Anhedonia, a core symptom of major depressive disorder (MDD), is linked to dysfunction in reward-related brain regions and impaired dopamine (DA) signaling. This study used arterial spin labeling (ASL) to investigate the...Anhedonia, a core symptom of major depressive disorder (MDD), is linked to dysfunction in reward-related brain regions and impaired dopamine (DA) signaling. This study used arterial spin labeling (ASL) to investigate the effects of a single low dose of amisulpride, a selective DA antagonist, on cerebral blood flow (CBF) in MDD patients and healthy volunteers (HVs). In a double-blind, placebo-controlled, randomized, parallel-group design, participants received either 100 mg amisulpride or placebo. N = 111 participants (MDD: n = 57; HV: n = 54) were included in the final analysis and group differences were assessed in core regions of the reward network, particularly the ventral striatum. Individual CBF values were analyzed in relation to self-reported anhedonia and depression severity. Amisulpride was associated with higher perfusion in the ventral striatum compared to placebo in both HVs and MDD patients, consistent with enhanced dopaminergic activity in this region. No significant CBF changes were observed in other areas of the reward network. Ventral striatal perfusion was significantly associated with self-reported anhedonia. Exploratory whole-brain analyses revealed higher CBF in the right frontal operculum in MDD patients compared to HVs under placebo, but not under amisulpride. In the placebo group, both anhedonia and depression severity were associated with CBF in the right frontal operculum; these associations were absent following amisulpride administration. In conclusion, we provide initial evidence of region-specific effects of amisulpride administration on CBF that are consistent with modulation of dopaminergic signaling. Increased perfusion in the ventral striatum suggests a potential dopaminergic mechanism relevant to anhedonia. These findings underscore the ventral striatum's role in reward processing and support its involvement in the pathophysiology of anhedonia across clinical and non-clinical populations.
Xiang J, Ran J, Zhu P
… +9 more, Wang Y, Deng X, Yang B, Zhang L, Chen X, Guo J, Liu J, Qin K, Chen W
Neuropsychopharmacology
· 2026 Jun · PMID 42350629
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Major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ) are generally categorized as distinct diagnoses, but shared clinical, biological and genetic features. Although rich neuroimaging evidence has...Major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ) are generally categorized as distinct diagnoses, but shared clinical, biological and genetic features. Although rich neuroimaging evidence has revealed brain functional alterations in each of these disorders, the transdiagnostic patterns remain poorly understood. A comprehensive literature search was conducted up to March 2025 for resting-state functional MRI studies reporting regional homogeneity (ReHo) abnormalities in MDD, BD or SZ patients, as compared to healthy controls (HC). Voxel-wise meta-analyses of ReHo abnormalities were conducted separately for each disorder using the Seed-based d Mapping toolbox, followed by conjunction and contrast analyses to further identify common and disorder-specific patterns. Our meta-analysis included a total of 90 studies, encompassing 3764 patients (MDD: n = 1703; BD: n = 872; SZ: n = 1189) and 3590 HC. A transdiagnostic pattern of common ReHo increase was identified in the right inferior frontal gyrus, while disorder-specific ReHo alterations were distributed across different large-scale brain networks. Specifically, MDD-specific abnormalities were primarily involved the default mode and subcortical networks; BD-specific abnormalities were mostly identified within the default mode network; SZ patients exhibited more widespread dysfunction spanning across the frontoparietal, and somatomotor networks. These transdiagnostic findings advance the current understanding of neurofunctional mechanisms underlying overlapping and different multi-dimensional features across affective and psychotic disorders, offering novel insights into precision diagnostics and therapeutic targets for individualized psychiatry in the future.
Choi BM, Zhang YQ, Kwon H
… +3 more, Han JS, Hwang BY, Yun J
Neuropsychopharmacology
· 2026 Jun · PMID 42350628
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The need for preclinical models that better reflect human substance use patterns has increased due to the rising misuse of electronic cigarettes (e-cigarettes) for drug inhalation. However, Self administration studies us...The need for preclinical models that better reflect human substance use patterns has increased due to the rising misuse of electronic cigarettes (e-cigarettes) for drug inhalation. However, Self administration studies using mice in this context remain limited. To address this, we developed a self-administration model in which mice voluntarily insert their nose into a nose poke port, where vaporized cocaine passes through an airway, allowing controlled inhalation. Mice were exposed to vaporized cocaine at 50, 100, 200, and 300 mg/mL, and active nose-poke response was significantly increased compared to vehicle across concentrations, except at 300 mg/mL. At 100 mg/mL, plasma cocaine was 284 nM, with no significant sex differences detected. During extinction, active responses decreased over time and were reinstated following exposure to cocaine vapor-associated cues and cocaine priming. We also observed differences between the cocaine and vehicle groups in rewards earned, and active nose-poke responding during the progressive-ratio (PR) sessions. This model provides a preclinical approach for studying vaporized cocaine self-administration. A key advantage of this system is that it enables temporally precise, self-administered bolus delivery of drug exposure. This feature allows for improved experimental control over the timing and pattern of drug intake, facilitating investigation of the reinforcing effects of vaporized cocaine.
Kapri D, Jayaprasad AB, Tiwari P
… +8 more, Sharma M, Balakrishnan A, Singla A, Mazumder I, Kolthur-Seetharam U, Fanibunda SE, Vaidya ADB, Vaidya VA
Neuropsychopharmacology
· 2026 Jun · PMID 42350627
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Neuronal mitochondria are central to not only maintaining cellular bioenergetics, calcium dynamics, and serving as signaling platforms, but are also critical for specialized functions including synaptic plasticity and ne...Neuronal mitochondria are central to not only maintaining cellular bioenergetics, calcium dynamics, and serving as signaling platforms, but are also critical for specialized functions including synaptic plasticity and neurotransmission. While mitochondria are postulated to have a fundamental role in the functioning of neurons, it is only recently that upstream factors that influence mitochondria in neurons have been systematically investigated. Here, we identify the critical role of the neurotransmitter, norepinephrine (NE) in modulating mitochondria in the rodent hippocampus. NE increases the expression of key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), enhances mitochondrial DNA content and ATP levels in hippocampal neurons in culture. These effects of NE are mediated via the recruitment of a β-adrenergic receptor-Gs-cAMP-PKA signaling cascade and are dependent on PGC-1α. We find that increasing noradrenergic signaling in vivo, either through direct administration of NE into the hippocampus via osmotic minipumps or treatment with the NE reuptake inhibitor, Atomoxetine, as well administration of the β-adrenergic receptor agonist, Formoterol, enhances mitochondrial DNA content in the hippocampus. Furthermore, increased spatial memory recall with Atomoxetine treatment was significantly correlated with both mitochondrial DNA content and ATP levels in the hippocampus. Our findings identify a novel role for NE in impacting mitochondrial biogenesis in the hippocampus, and suggest a link between bioenergetic status and spatial memory performance.
Lauer J, Poppke J, Nickl-Jockschat T
… +3 more, Dieterich DC, Fendt M, Afzal S
Neuropsychopharmacology
· 2026 Jun · PMID 42343111
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Cognitive deficits in executive functions such as working memory and cognitive flexibility are central to many brain disorders, yet effective treatments remain limited. Dysfunction of GluN2A-containing NMDA receptors (NM...Cognitive deficits in executive functions such as working memory and cognitive flexibility are central to many brain disorders, yet effective treatments remain limited. Dysfunction of GluN2A-containing NMDA receptors (NMDAR) contributes to these impairments, and positive allosteric modulators (PAM) that selectively enhance GluN2A function offer a promising strategy to rescue cognitive deficits while preserving physiological neurotransmission. However, it remains unclear whether PAM-driven GluN2A potentiation can rescue mechanistically distinct, pharmacologically induced impairments and whether the efficacy of GluN2A-PAMs differs across executive domains and sexes. Here, we assessed the effects of GNE-5729, a brain-penetrant GluN2A-selective PAM, on executive functions in mice. GNE-5729 showed no overall effect on working memory performance in the Y-maze, but improved performance in mice with low baseline spontaneous alternations, indicating a baseline-dependent effect. It also rescued working memory deficits induced by dl-amphetamine and scopolamine, which disrupt neuromodulatory regulation while leaving NMDAR channels functionally accessible. In contrast, GNE-5729 failed to reverse MK-801-induced impairments, consistent with MK-801's non-competitive pore blockade of NMDAR. Notably, GNE‑5729 effects showed sex‑dependent patterns, with female mice displaying more pronounced effects. GNE-5729 had no effects on cognitive flexibility in the attentional set-shifting task (ASST) and did not alter prefrontal GluN2A expression, though it disrupted the association between endogenous GluN2A levels and ASST performance observed in controls. Together, these findings indicate that GNE-5729 exerts effects under conditions of reduced baseline performance or disrupted neuromodulatory signaling and demonstrates differential effects across executive domains, supporting a state-dependent therapeutic profile of GluN2A-targeted modulation.
John MM, Gale JJ, Yaeger JDW
… +7 more, Gerberding HA, Meyer LS, Legner GL, Cox BS, Brummels RA, Segar SM, Summers CH
Neuropsychopharmacology
· 2026 Jun · PMID 42323509
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Social stress, beneficial for evaluating threats and resource opportunities, influences the development of anxious and depressive disorders. Stress responses are initiated via a pro-stress circuit in the anterior region...Social stress, beneficial for evaluating threats and resource opportunities, influences the development of anxious and depressive disorders. Stress responses are initiated via a pro-stress circuit in the anterior region of the basolateral amygdala (aBLA). This circuit contains pyramidal glutamatergic neurons that express genetic markers Camk2α, Rspo2, and Hcrtr1, which enhance stress-vulnerable behaviors via OrxR activity, and are inhibited directly by OrxR activation on Gad1, Hcrtr2, Cck GABAergic neurons. Our results have suggested stress circuitry in BLA is modulated by OrxR and OrxR activity, which counterbalance stress responsivity via Rspo2-positive glutamatergic neurons in aBLA, but whether these effects are consistent with systemic delivery is unknown. These receptor-dependent biases contribute to behavioral, physiological and molecular outcomes associated with psychiatric disorders, such as anxiety, depression, and post-traumatic stress disorder. Administration of a selective orexin receptor cross-over (SORCO; OrxR antagonist and OrxR agonist combination) treatment alleviates anxiogenic behavioral outputs in socially stressed mice, by decreasing escape latency in stress-vulnerable (Stay) mice (phenotypic reversal; vulnerable to resilient), and reducing the time spent freezing in response to the presence of a social aggressor (socially induced) in stress resilient (Escape) mice. Behavioral results coincided with a decrease in Rspo2 and an increase in Hcrtr2 gene expression in aBLA of SORCO-treated Stay mice, and an increase in Akt3 and Mtor transcription in Stay mice treated with an OrxR agonist (YNT-185). Our findings indicate that a combination of OrxR drugs (SORCO) provides potentially therapeutic outcomes through modifications of stress neurocircuitry, triggered by increasing expression of genes associated with neuroplasticity.
Calder AE, Diehl VJ, Lietz MP
… +7 more, Yousefi P, Friedli N, Coviello F, Rouaud A, Beichmann K, Eckert A, Hasler G
Neuropsychopharmacology
· 2026 Jun · PMID 42315644
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Preclinical studies suggest that lysergic acid diethylamide (LSD) may induce lasting changes in brain function and learning ability, but evidence in humans is uncertain. Motor learning, in particular, has clinical releva...Preclinical studies suggest that lysergic acid diethylamide (LSD) may induce lasting changes in brain function and learning ability, but evidence in humans is uncertain. Motor learning, in particular, has clinical relevance but has not been investigated in human studies of psychedelics. Forty-five healthy subjects (24 women) participated in this randomized crossover trial comparing 100 µg LSD with a placebo. For up to one week after dosing, we investigated LSD's post-acute neurophysiological effects using auditory tetanization with electroencephalography (EEG), paired associative stimulation (PAS) with transcranial magnetic stimulation (TMS), peripheral levels of brain-derived neurotrophic factor (BDNF). Additionally, online and offline motor learning were assessed one day after dosing with a sequence typing task. Questionnaires assessed perceived stress and cognitive flexibility one week after dosing. We found that offline motor learning significantly improved the day after LSD. One week after LSD, perceived stress was reduced and aspects of cognitive flexibility were increased. EEG data showed that LSD acutely decreased amplitudes of N1 and P2 auditory event-related potentials and still modulated P2 one week later. Motor-evoked potentials measured with TMS showed increased amplitude and faster latency under LSD. LSD did not alter BDNF levels. Our findings encourage future studies on LSD and learning and additionally highlight important challenges in the measurement of long-term potentiation in humans. The observed acute and lasting changes in neural signals provide insight into LSD's effects on the auditory and motor systems.
Mayer MR, Choo TH, Javitt DC
… +1 more, Kantrowitz JT
Neuropsychopharmacology
· 2026 Jun · PMID 42310370
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While both dopamine type 2 receptor antagonists and the muscarinic MR M/MR agonist xanomeline (KarXT) have shown to be effective in treating positive and total symptoms of schizophrenia, full or partial treatment resista...While both dopamine type 2 receptor antagonists and the muscarinic MR M/MR agonist xanomeline (KarXT) have shown to be effective in treating positive and total symptoms of schizophrenia, full or partial treatment resistance is common, particularly for negative symptoms and cognitive impairment associated with schizophrenia (CIAS). Based on the concept of targeting excitatory-inhibitory (E/I)-imbalance, serotonin type 3 receptor (5-HTR) antagonists may have utility as an adjunctive treatment for residual symptoms in schizophrenia. We present a meta-analysis of 5-HTR antagonists (setrons, CVN058 and the antidepressant vortioxetine) for CIAS and negative, positive and total symptoms. 12 active- vs. placebo-arm comparisons across 730 participants met the inclusion criteria. Meta-analyses of both negative symptoms [Cohen's d = -0.52 (95%CI: -0.78, -0.27), p = 0.012] and CIAS [Cohen's d = -0.53 (95%CI: 0.09, 0.97), p = 0.02] support a significantly greater effect for active drug at a moderate effect size. The results support the potential utility not only of "setron" type 5-HTR antagonists, but also of vortioxetine, which has significant 5-HTR antagonist properties along with more general anti-depressant features. Results argue for definitive multicenter studies of adjunctive 5-HTR antagonists in schizophrenia.
Hejazi N, Kheirkhah M, Riedner B
… +6 more, Yuan Q, Chholak R, Momenan R, Jones G, Goldman D, Zarate CA
Neuropsychopharmacology
· 2026 Jun · PMID 42304135
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Slow-wave activity (SWA), a key indicator of sleep homeostasis, is often diminished in individuals with treatment-resistant depression (TRD). Ketamine, a rapid-acting antidepressant, increases SWA during the first period...Slow-wave activity (SWA), a key indicator of sleep homeostasis, is often diminished in individuals with treatment-resistant depression (TRD). Ketamine, a rapid-acting antidepressant, increases SWA during the first period of non-rapid eye movement (NREM1) sleep. However, research into how ketamine affects sleep and its connection to treatment outcomes in TRD has been limited by small sample sizes and a lack of comparison with healthy volunteers (HVs). This placebo-controlled study compared the effects of ketamine on NREM1 SWA in a large sample of unmedicated TRD patients (n = 91; 51 F/40 M) and HVs (n = 42; 23 F/19 M). Linear mixed-effects models and regression analyses, with post-hoc testing (paired ttests and Wilcoxon matched-pairs signed rank tests), were used to assess condition-related effects across baseline, ketamine, and placebo in TRD and HV participants. Age-related moderation of ketamine-associated NREM1 SWA changes and condition-related changes in sleep variables were also examined. At baseline, TRD patients had lower NREM1 SWA than HVs. Ketamine, but not placebo, increased NREM1 SWA in TRD patients, particularly in responders. In contrast, ketamine had no effect on NREM1 SWA in HVs. Following ketamine, TRD patients also showed significant increases in total sleep time and sleep efficiency and a reduction in sleep latency. In TRD patients, the ketamine-related increase in NREM1 SWA diminished with increasing age. Together, the results indicate that ketamine's antidepressant effects appear closely associated with its ability to modulate early SWA. These effects may also be linked to ketamine's ability to improve sleep architecture in TRD. Clinical Trials Identifier: www.clinicaltrials.gov , NCT00088699, NCT01204918.
Neuropsychopharmacology
· 2026 Jun · PMID 42298085
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Dysregulated phospholipase A2 (PLA2) activity has been reported in multiple psychiatric disorders, yet its mechanistic contribution to pathological fear remains unclear. The 129S1/SvImJ (S1) mouse strain, which shows int...Dysregulated phospholipase A2 (PLA2) activity has been reported in multiple psychiatric disorders, yet its mechanistic contribution to pathological fear remains unclear. The 129S1/SvImJ (S1) mouse strain, which shows intact fear conditioning but profound deficits in fear extinction, provides a useful model for examining molecular pathways relevant to post-traumatic stress disorder. Using RNA sequencing, electrophysiology, and targeted pharmacological manipulation, we investigated whether altered PLA2 expression in amygdala circuits contributes to impaired extinction in S1 mice. S1 mice displayed markedly elevated Pla2g4e mRNA expression in both the basolateral amygdala (BLA) and the medial division of the central amygdala (CEm) compared with C57BL/6 controls. Electrophysiological analyses revealed reduced basal inhibitory transmission onto CEm neurons in S1, a deficit reversed by acute PLA2 inhibition in both naïve and behaviorally tested mice. PLA2 inhibition also normalized the diminished inhibitory/excitatory balance in the BLA→CEm pathway following extinction training. Behaviorally, selective infusion of a PLA2 inhibitor into the CEm robustly enhanced extinction learning and retrieval in S1mice. These findings identify PLA2 as a key regulator of inhibitory signaling within central amygdala circuits and suggest that heightened PLA2 activity contributes to extinction failure, highlighting a potential molecular target for therapeutic intervention in trauma-related disorders.
Neuropsychopharmacology
· 2026 Jun · PMID 42298084
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Many psychiatric disorders are associated with specific risk factors, including biological sex and adversity in childhood, but the mechanisms underlying these relationships are unknown. Multiple cognitive and affective p...Many psychiatric disorders are associated with specific risk factors, including biological sex and adversity in childhood, but the mechanisms underlying these relationships are unknown. Multiple cognitive and affective processes that are often disrupted in various psychiatric disorders are shaped by norepinephrine (NE) release throughout the brain, which is principally coordinated by noradrenergic locus coeruleus (LC) neurons with established sex differences in multiple properties, including stress sensitivity. Through application of a two-phase early life variable stress (ELVS) exposure to C57BL/6J mice to understand how early life adversity affects cognitive/affective behavior and LC physiology, we found that females displayed pronounced increases in novel environment exploration and reduced preference for sucrose. In addition, ELVS caused elevated activity in a familiar environment, modest deficits in Y-maze performance, and altered attention in an operant task in both sexes. A reduction in LC neuron sensitivity to corticotropin-releasing factor (CRF) and decreased excitability, partly due to an increase in action potential delay, was observed only in female mice exposed to ELVS, paralleling behavioral changes. CRF-induced changes in LC neuron activity were mediated by different preferential signaling pathways in naïve male and female mice - a potential mechanism for ELVS-induced sex-specific changes in LC physiology. Administration of the norepinephrine reuptake blocker reboxetine corrected ELVS-induced behavioral changes. Through this animal model of early life stress, we identified mechanisms involved in determining how stress and sex interact to cause LC activity dysregulation and related behavioral changes.