Posttraumatic stress disorder (PTSD) is a highly heterogeneous psychiatric disorder, complicating efforts to identify consistent biological markers and develop targeted treatments for individuals exposed to trauma. Recen...Posttraumatic stress disorder (PTSD) is a highly heterogeneous psychiatric disorder, complicating efforts to identify consistent biological markers and develop targeted treatments for individuals exposed to trauma. Recent research has identified a distinct intrusive-hypervigilant (IH) phenotype, which is characterized by heightened intrusive reexperiencing and hypervigilance symptoms along with elevated levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide involved in stress response via amygdala signaling. In an independent sample of 172 symptomatic trauma-exposed adults, we replicated this IH phenotype using latent profile analysis of Clinician-Administered PTSD Scale for DSM-5 symptom severity ratings and expanded its biological characterization using resting-state functional magnetic resonance imaging (rs-fMRI). Consistent with prior work, the identified IH group demonstrated more severe intrusive reexperiencing (Cohen's d's = 0.61-6.93) and hypervigilance symptoms (d's = 0.57-0.88) and higher PACAP levels compared to groups with generally High (d = 0.35) or Low (d = 0.44) symptom severity. Additionally, the IH phenotype exhibited stronger functional connectivity of the centromedial, but not basolateral, amygdala with regions in the occipital cortex (d's = 0.78-0.95), precuneus (d's = 1.20-1.21), and medial prefrontal cortex (d's = 0.81-1.18)-areas primarily within the Default Mode and Visual Networks. Meta-analytic decoding linked these regions to mental imagery, memory processing, fear, and threat perception. These findings support the existence of an IH phenotype of posttraumatic stress that may exhibit a distinct biological profile, characterized by exaggerated interactions between memory, threat, and arousal systems that may be mediated by PACAP and its effects on amygdala connectivity. This phenotype may serve as a promising target for precision psychiatry approaches, including pharmacological and neurotherapeutic interventions that modulate PACAP signaling and amygdala connectivity.
Visual attention enables filtering of irrelevant stimuli and focus on information that is most pertinent to survival. While the locus coeruleus-noradrenaline (LC-NA) system is recognized as crucial in this process, the r...Visual attention enables filtering of irrelevant stimuli and focus on information that is most pertinent to survival. While the locus coeruleus-noradrenaline (LC-NA) system is recognized as crucial in this process, the role of temporally structured NA signaling in visual attentional performance remains unsettled. Here, by using the genetically encoded NA sensor GRAB together with fiber photometry in mice, we identify sub-second NA release signatures in the medial prefrontal cortex (mPFC) that correlate with visual attention accuracy in the rodent Continuous Performance Test (rCPT). The dual-peak release signatures were time-locked to correct, rewarded responses, preceded by a ramp-up after stimulus presentation and followed by a decline at reward collection. No such signatures accompanied misses, correct rejections and mistakes. Similar, albeit less pronounced, patterns were observed in the lateral hypothalamus (LH). Activation of the Gq-coupled DREADD (Designer Receptors Exclusively Activated by Designer Drugs) hM3DGq expressed in LC neurons dose-dependently increased tonic NA levels in both mPFC and LH, while simultaneously distorting phasic NA signatures and impairing rCPT performance without affecting locomotor activity. Summarized our data suggest that NA enhances alertness to reward-associated stimuli through precise, dynamic release patterns underscoring its role in modulating attentional performance beyond tonic signaling.
Neuropsychopharmacology
· 2026 Jul · PMID 41946855
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Evolutionarily conserved neural circuits evolved that mediate switching between feeding and foraging for food, depending on environmental conditions such as food scarcity and internal state [1-3]. Activity-based anorexia...Evolutionarily conserved neural circuits evolved that mediate switching between feeding and foraging for food, depending on environmental conditions such as food scarcity and internal state [1-3]. Activity-based anorexia is a phenomenon observed ubiquitously in normal mammals that emerges under conditions of time-restricted food availability and continuous access to running wheels. Under these experimental conditions, rodents progressively lose body weight and develop paradoxical hypophagia and compulsive wheel running, which can prove fatal if left unchecked. On the other hand, rodents survive indefinitely under conditions of either time-restricted food access or running wheel availability. In this review, we discuss preclinical studies within the past decade which used modern genetic circuit-dissecting tools including chemogenetic, optogenetic, and calcium imaging, to dissect the neural circuitry modulating activity-based anorexia. We highlight how circuits interconnecting the hypothalamus, prefrontal cortex, amygdala, mesolimbic system, and monoaminergic nuclei, interact to modulate animals' decision to feed or forage in the activity-based anorexia paradigm. We then highlight how these recent findings have aided in identifying pathophysiological mechanisms underlying neuropsychiatric disorders characterized by the maladaptive prioritization of exercise over feeding. Finally, we suggest approaches for the development of targeted therapeutics for anorexia nervosa, which has no approved pharmacological treatments.
Neurodevelopmental psychiatric diseases such as schizophrenia or affective disorders share common symptomatic dimensions, in particular reward processing dysfunctions, associated with dysregulation of dopamine (DA) trans...Neurodevelopmental psychiatric diseases such as schizophrenia or affective disorders share common symptomatic dimensions, in particular reward processing dysfunctions, associated with dysregulation of dopamine (DA) transmission. Retinoic acid (RA) homeostasis, the active metabolite of vitamin A, is altered across psychiatric disorders but whether impaired developmental RA signaling impacts the functionality of DA-related reward processing at adulthood remains poorly explored. Herein, we found that vitamin A (i.e., retinol) deficiency (VAD) from gestation to adulthood potentiates instrumental responding in motivational tasks and increases choice impulsivity in male, but not female mice. These behavioral alterations in males are coherent with reduced DA transporter (DAT) expression in the midbrain and increased mesolimbic DA dynamics associated with instrumental responding. In accordance, chemogenetic inhibition of midbrain DA neurons normalizes motivational performance in VAD males. Our results support that developmental VAD induces sex-specific reward processing alterations at adulthood through hyperactivity of the mesolimbic DA pathway. Such findings reinforce the idea that RA signaling is an important modulator of the brain reward system by shaping DA transmission.
Late-life depression is associated with greater disability, suicide risk and mortality than depression in mid-life, and is a risk factor/prodrome for neurodegenerative diseases such as Alzheimer's disease and Parkinson's...Late-life depression is associated with greater disability, suicide risk and mortality than depression in mid-life, and is a risk factor/prodrome for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Many depressed, older adults fail to respond to first line antidepressant treatment, experience relapse and exhibit persistent symptoms, including anxiety, apathy and cognitive impairment, that may reflect underlying neurodegenerative processes. Advances in molecular imaging, particularly positron emission tomography (PET) allow direct in-vivo investigation of neurobiological mechanisms underlying late-life depression symptom trajectories, treatment response and the potential links to neurodegenerative disease. Molecular imaging studies in late-life depression have revealed alterations across neurotransmitter systems and Alzheimer's disease pathology (beta-amyloid and Tau) and a potential role of neuroinflammation. In late-life depression, variability in symptom presentation and treatment response arises from interacting neurotransmitter, inflammatory, and neurodegenerative processes and potentially other molecular mechanisms that impair synaptic plasticity. Future directions include the application of next-generation PET tracers targeting glutamatergic signaling, mitochondrial function, histone deacetylase activity, and cell-type-specific inflammation, along with multi-modal image analysis methods to test mechanistic models . Molecular imaging holds significant promise for guiding the development of targeted, mechanism-based treatments that reduce the burden of late-life depression and its associated vulnerability to neurodegenerative disease.
Huckstep KL, Newton B, Bailey G
… +11 more, Charlton A, Pearl AJ, Maddern XJ, Brown RM, McNally GP, Lubman DI, Arunogiri S, Morley KC, Campbell EJ, Lawrence AJ, Walker LC
Neuropsychopharmacology
· 2026 Mar · PMID 41896695
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Comorbidity between post-traumatic stress disorder (PTSD) and alcohol use is common and mutually-reinforcing, yet there are no pharmacological strategies that specifically target trauma-linked escalation of alcohol intak...Comorbidity between post-traumatic stress disorder (PTSD) and alcohol use is common and mutually-reinforcing, yet there are no pharmacological strategies that specifically target trauma-linked escalation of alcohol intake. We evaluated whether 3,4-methylenedioxymethamphetamine (MDMA), given in a therapy-adjunctive fashion (30 min before fear extinction), could facilitate extinction of conditioned fear and reduce alcohol consumption in a rat model that combines fear conditioning, binge-like alcohol access, abstinence, and re-exposure. Inbred alcohol-preferring (iP) and outbred Wistar rats of both sexes underwent auditory fear conditioning, voluntary ethanol drinking, and subsequently fear extinction after MDMA or vehicle administration, with drug-free extinction recall and alcohol consumption assessed thereafter. Fear conditioning increased voluntary alcohol intake only in iP rats, suggesting a genotype-related fear-alcohol contingency. MDMA acutely reduced freezing during extinction, but ultimately reshaped across-session freezing patterns in a strain- and sex-dependent manner. There were no lasting MDMA treatment effects on next-day drug-free recall. MDMA also altered on-drug fear-expression during extinction without affecting later recall in an iP rat cohort without prior alcohol exposure, indicating the effect is not secondary to drinking history. Critically, MDMA prevented the shock-related increase in alcohol consumption but only in iP rats. These data suggest MDMA's most reliable action in this model is to disrupt trauma-linked escalation of alcohol intake in genetically- and experientially- vulnerable rats, rather than to globally enhance fear extinction.
Honan LE, Mason B, Owens WA
… +7 more, Shin S, Ju YH, Shi Y, Horton RE, Fenno LE, Collins GT, Daws LC
Neuropsychopharmacology
· 2026 Mar · PMID 41888538
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Afflicting over 50 million people worldwide and demonstrating growing global trends of abuse, amphetamine-type stimulant abuse poses a significant public health burden. No effective pharmacological treatments exist for a...Afflicting over 50 million people worldwide and demonstrating growing global trends of abuse, amphetamine-type stimulant abuse poses a significant public health burden. No effective pharmacological treatments exist for amphetamine-type stimulant use disorders, underscoring a critical need to identify novel, effective therapeutic targets. Amphetamine exerts its actions in part by targeting high-affinity, low-capacity monoamine transporters, particularly the dopamine transporter (DAT). However, therapeutic interventions targeting DAT have been so far unsuccessful. Emerging evidence supports a role for the low-affinity, high-capacity organic cation transporter 3 (OCT3) in the actions of amphetamine. Here we use in vivo electrochemical and behavioral approaches, as well as constitutive and temporally-inducible OCT3 knockout mice, to establish OCT3 as a critical mediator of neurochemical and behavioral actions of amphetamine. We demonstrate that OCT3 substantially contributes to amphetamine-evoked dopamine efflux in dorsal striatum and is key to reinforcing effects of amphetamine in intravenous self-administration assays. Our novel findings provide convergent evidence to suggest that OCT3 plays a central role in mediating abuse-related effects of amphetamine, establishing OCT3 as a potential novel target for the development of therapeutics to treat amphetamine-type stimulant use disorders.
Gómez-Pineda V, Huang D, Chen Y
… +2 more, Guo C, Ma YY
Neuropsychopharmacology
· 2026 Mar · PMID 41882122
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Cocaine use disorder is characterized by persistent relapse vulnerability, which escalates with prolonged withdrawal. Corticostriatal circuits are key substrates for relapse, yet the role of the secondary motor cortex (M...Cocaine use disorder is characterized by persistent relapse vulnerability, which escalates with prolonged withdrawal. Corticostriatal circuits are key substrates for relapse, yet the role of the secondary motor cortex (M2) and its distinct projections to the dorsolateral striatum (DLS) and dorsomedial striatum (DMS) remains poorly understood. Here, we combined intravenous self-administration, pathway-selective optogenetic inhibition, and ex vivo patch-clamp recordings to measure comprehensive synaptic responses during withdrawal. Relative to withdrawal day 1, rats exhibited cocaine seeking incubation on withdrawal day 45, which was therefore selected as the primary experimental time point. Whole-cell recordings revealed heightened intrinsic excitability of M2 cortical pyramidal neurons and increased frequency, but not amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in both DLS and DMS medium-sized spiny neurons (MSNs), suggesting the possibility of enhanced presynaptic glutamate release. Optogenetic inhibition of eNpHR-expressing M2 terminals produced opposite behavioral outcomes: suppression of cocaine seeking when targeted to the DLS, but paradoxical enhancement when targeted to the DMS. In cocaine-exposed, but not saline, rats, optogenetic inhibition increased sEPSC frequency in both DLS and DMS MSNs, suggesting altered integration of M2 or local inhibitory inputs and non-M2 excitatory afferents. Inhibitory adaptations diverged across striatal subregions: in the DLS, repeated inhibition persistently increased spontaneous inhibitory postsynaptic current (sIPSC) frequency, whereas in the DMS, sIPSC enhancement was transient, with frequency and amplitude increasing only during the first light-on period, but amplitude rapidly declined thereafter. Together, these findings suggest that M2-striatal projections contribute in a pathway-specific manner to relapse vulnerability and are associated with alterations in excitatory-inhibitory balance within M2-DLS and M2-DMS circuits.
Qi G, Zhang Y, Wang YL
… +5 more, Anjum F, Theberge J, Jiang Y, Khan A, Palaniyappan L
Neuropsychopharmacology
· 2026 Jul · PMID 41876826
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Schizophrenia is characterized by impaired brain health, including gray matter reductions and cognitive dysfunction, with vascular and glymphatic dysfunction emerging as key contributors. The glymphatic system, which cle...Schizophrenia is characterized by impaired brain health, including gray matter reductions and cognitive dysfunction, with vascular and glymphatic dysfunction emerging as key contributors. The glymphatic system, which clears metabolic waste via perivascular pathways, is measurable using Diffusion Tensor Imaging-Along the Perivascular Space (DTI-ALPS) and its dysfunction is suspected to increase extracellular free water (FW). Prior studies reported potential glymphatic impairment in schizophrenia, but its relationship to the stage of illness and impact on interstitial fluid dynamics remains unclear. This study employed ultra-high field (7-Tesla) DTI to quantify DTI-ALPS and FW in white and gray matter in 125 subjects, including clinical high-risk (CHR), untreated first-episode psychosis (FEP), established schizophrenia (>3 years), and healthy controls (HC). We investigated: (1) the presence of DTI-ALPS alterations in CHR and its relative magnitude across disease stages; (2) its association with symptom severity; (3) its correlation with FW; and (4) its relationship to likely origins of neuroanatomical progression in schizophrenia from the hippocampal region. Compared with HC, the established, FEP and CHR all showed lower DTI-ALPS (p < 0.01 for all, Hedge's g = 0.73-1.13) and higher white matter FW (p < 0.05 for all, g = 0.59-1.57). Lower DTI-ALPS was correlated with higher FW, longer duration of untreated psychosis, and was selectively pronounced in the FEP subgroup, whose structural changes may originate from the hippocampal region. Our findings suggested that the putative glymphatic dysfunction indexed by DTI-ALPS predates antipsychotics, drives interstitial fluid accumulation, and contributes to schizophrenia's structural and clinical progression, offering mechanistic insights into its pathophysiology.
Ojha A, Henry TR, Jones NP
… +2 more, Shirtcliff EA, Ladouceur CD
Neuropsychopharmacology
· 2026 Mar · PMID 41872357
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Puberty demarcates the start of adolescence, a critical period of marked changes in motivated behavior (e.g., approach, avoidance) and socio-affective processing supported by development of the mesocorticolimbic circuitr...Puberty demarcates the start of adolescence, a critical period of marked changes in motivated behavior (e.g., approach, avoidance) and socio-affective processing supported by development of the mesocorticolimbic circuitry-prefrontal cortex (PFC), amygdala, and nucleus accumbens (NAcc). Puberty-related increases in psychiatric risk have been linked to alterations in mesocorticolimbic circuitry function and sensitivity to rewards and punishments. Yet, how puberty influences the development of mesocorticolimbic circuitry supporting motivational traits remains unclear. We examined resting-state functional connectivity (RSFC) in 126 adolescents, studied longitudinally (216 total scans over 2 years), assessed reward/punishment sensitivity via questionnaires, and collected multimodal measures of puberty. As hypothesized, fronto-striatal RSFC was associated with reward sensitivity, but both fronto-striatal and fronto-amygdala RSFC were linked to punishment sensitivity. Puberty moderated several associations in males but not females: weaker fronto-striatal RSFC related to higher reward sensitivity in males more advanced in pubertal maturation. Further, whereas in early puberty stages stronger fronto-striatal RSFC related to higher punishment sensitivity in males, by late puberty stages, stronger fronto-amygdala RSFC was related to higher punishment sensitivity. Testosterone levels moderated the association between anterior ventromedial PFC - NAcc RSFC and reward sensitivity such that weaker RSFC related to higher reward sensitivity in males with lower testosterone levels than expected for their age and pubertal status. These data support sex-specific puberty effects on the relationship between mesocorticolimbic circuitry connectivity and reward/punishment sensitivity. Future research is needed to determine how these findings represent markers of risk for or resilience against psychiatric disorders.
Elvig SK, McGinn A, Li X
… +12 more, Vendruscolo JCM, Gomez JL, Pawlosky R, Mackowiak B, Gonzalez L, King MT, Michaelides M, Gao B, Volkow ND, Koob GF, Wiers CE, Vendruscolo LF
Neuropsychopharmacology
· 2026 Mar · PMID 41862734
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Previous work showed that rats that were exposed to a high-fat, low-carbohydrate/protein ketogenic diet (KD) exhibited elevated blood alcohol levels following alcohol exposure compared with rats fed regular chow. Additio...Previous work showed that rats that were exposed to a high-fat, low-carbohydrate/protein ketogenic diet (KD) exhibited elevated blood alcohol levels following alcohol exposure compared with rats fed regular chow. Additionally, the administration of a KD prior to alcohol exposure (i.e., a history of KD) reduced alcohol consumption in alcohol-dependent rats that were no longer on the diet. In the present study, we investigated the mechanisms by which a KD alters alcohol metabolism and tested whether ongoing KD exposure reduces alcohol consumption in rats. We hypothesized that chronic KD exposure alters hepatic alcohol-metabolizing enzymes, slows alcohol metabolism, and reduces alcohol self-administration in alcohol-dependent rats. We found that male and female rats maintained on a KD had higher blood alcohol levels, lower hepatic alcohol dehydrogenase 1 protein levels, and a higher nicotinamide adenine dinucleotide [NAD+]/[NADH] ratio in the liver cytoplasm compared with chow-fed control rats. Furthermore, KD-fed rats demonstrated lower brain glucose uptake relative to chow-fed control rats. In a model of alcohol dependence, the KD reduced alcohol consumption in male, but not female, rats compared with chow-fed rats. These findings suggest that a KD alters brain energetics and alcohol metabolism, which may contribute to reduced alcohol consumption in male rats.
Dick RM, Cunitz LB, Torres Pérez A
… +7 more, Ahmed H, Adke AP, Rivera Quiles C, Mitchell JS, Marron Fernandez de Velasco E, Grissom NM, Rothwell PE
Neuropsychopharmacology
· 2026 May · PMID 41826486
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N-methyl-D-aspartate receptors (NMDARs) in the prefrontal cortex (PFC) are critical regulators of neuronal excitability, synaptic plasticity, and cognitive function. NMDAR disruptions, including pharmacological blockade...N-methyl-D-aspartate receptors (NMDARs) in the prefrontal cortex (PFC) are critical regulators of neuronal excitability, synaptic plasticity, and cognitive function. NMDAR disruptions, including pharmacological blockade and anti-NMDAR encephalitis, can mimic symptoms of schizophrenia. These observations support the glutamate hypothesis of schizophrenia, which posits that symptoms arise from abnormal corticolimbic glutamatergic signaling. Further evidence for this theory includes abnormal expression of NMDARs and decreased dendritic spine density in the PFC of individuals with schizophrenia, as well as altered spine density and synaptic transmission caused by genetic manipulation of NMDARs. However, it is unknown how progressive loss of NMDAR function in the PFC during adolescence-a developmental time period associated with symptom onset in schizophrenia -affects excitatory synaptic structure and function. In this study, we used in vivo genome editing to ablate expression of the Grin1 gene, which encodes the obligate GluN1 subunit of NMDARs, in medial PFC neurons of female and male adolescent mice. We assessed synaptic density and function in layer V pyramidal neurons using whole-cell patch-clamp electrophysiology, integrated with confocal imaging of dendritic spine architecture in recorded neurons. NMDAR ablation caused an early decrease in basilar dendritic spine density, followed by a rebound in spine density and a corresponding increase in AMPAR-mediated synaptic transmission. These effects of pan-neuronal NMDAR ablation were not observed after a more specific manipulation of excitatory neurons. Our findings demonstrate that NMDAR ablation triggers a cascading reorganization of local PFC networks, which may include compensatory processes that maintain allostasis but are impaired in disease states.
Volf A, Brust TF, Kobylski RR
… +7 more, Czekner KM, Stahl EL, Cameron MD, Trojniak AE, Wood AB, Aubé J, Bohn LM
Neuropsychopharmacology
· 2026 Jul · PMID 41803417
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Kappa opioid receptor agonists are clinically used to treat pruritus and have therapeutic potential for the treatment of pain and neuropsychiatric disorders. We have previously shown that triazole 1.1 is a G protein sign...Kappa opioid receptor agonists are clinically used to treat pruritus and have therapeutic potential for the treatment of pain and neuropsychiatric disorders. We have previously shown that triazole 1.1 is a G protein signaling-biased KOR agonist, that can suppress itch without producing signs of sedation in mice. This profile was recapitulated in rats and non-human primates; however, triazole 1.1 had limited potency as an antipruritic. Here we describe a more potent, G protein signaling-biased agonist, triazole 187. Triazole 187 is a potent antipruritic agent and does not decrease spontaneous locomotor activity; interestingly, it produces anxiolytic-like behaviors in mice, an effect not observed for triazole 1.1. In addition to curbing sedation, triazole 187 produces only mild diuresis, resulting in 30% of urine output induced by U50,488H at a dose that is more than 100-fold the antipruritic potency dose. Compounds like triazole 187 may present a means to treat anxiety that is independent of or accompanied by persistent chronic itch while avoiding sedation and diuresis accompanied by typical KOR agonists.