Neuropsychopharmacology
· 2026 Jan · PMID 41540228
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A persisting debate exists on whether physical processes can fully account for the personal experience of reality or whether subjectivity transcends physical processes. However, scientists and philosophers agree that the...A persisting debate exists on whether physical processes can fully account for the personal experience of reality or whether subjectivity transcends physical processes. However, scientists and philosophers agree that the subjective experience is influenced by information received from the body and the environment, modulated by emotions, concepts, skills, and memories acquired throughout life. Aging compromises aspects of cognition. However, many older adults develop emotion regulation strategies, experience their environment with a positivity bias, and use earlier successful predictive models of reality to compensate. Life events, personalized integration of perspectives of others, and an ever-changing social context, accelerated by the digital revolution, influence the older person's experience. Loss of loved ones, disability, pain, sensory compromise, the ravages of terminal illness, and the realization of approaching death become part of the older person's lifeworld. These experiences are integrated into a personal narrative through which older adults interpret reality and satisfy the fundamental need for creating meaning out of one's life. As we learn about the subjective experience of older adults, we can advance an agenda of research and advocacy that promotes their mental health, increases their participation in social processes, and enables them to contribute to the transgenerational continuity of society to everybody's benefit.
Neuropsychopharmacology
· 2026 Jan · PMID 41535633
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Publisher ↗
The purpose of this narrative review was to examine the efficacy and effectiveness of psychotherapy for older adults with depressive disorders or clinically significant depressive symptoms; describe extensions of psychot...The purpose of this narrative review was to examine the efficacy and effectiveness of psychotherapy for older adults with depressive disorders or clinically significant depressive symptoms; describe extensions of psychotherapy across populations, settings, providers, and modalities; review mechanisms and predictors of treatment response; and consider future directions. Numerous systematic reviews and meta-analyses demonstrate that psychotherapy benefits many depressed older adults, with the strongest evidence for a variety of cognitive-behavioral therapy (CBT) approaches, including problem-solving therapy (PST) and behavioral activation (BA), and consistent evidence for interpersonal, reminiscence, and life review therapies as well. Great advances have been made extending these interventions, particularly CBT-based interventions, such as adaptations for older adults with psychiatric, physical, or cognitive comorbidities; in primary care, aging services, and residential settings; and low-intensity, often technology-based interventions. Several neurobiological, psychological, behavioral, social, and treatment-related mechanisms and predictors of psychotherapy response have been identified, which may explain heterogeneity of treatment effects and may lead towards more personalized, tailored interventions to achieve better outcomes for more older adults. More research is needed in all areas, including expanding from traditional psychotherapy models to novel technology-based, neuroscience-informed interventions, and implementation research to continue expanding the reach, feasibility, and acceptability of evidence-based psychotherapy.
Huang Y, Michalski C, Zhou Y
… +7 more, Xu C, Niu W, Lucido MJ, Wang J, Feng Y, Miller AH, Wen Z
Neuropsychopharmacology
· 2026 Apr · PMID 41535632
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Increased inflammation has been linked to behavioral pathogenesis in depression. Previous studies have shown that administration of inflammatory stimuli induces motivational deficits associated with reduced activation of...Increased inflammation has been linked to behavioral pathogenesis in depression. Previous studies have shown that administration of inflammatory stimuli induces motivational deficits associated with reduced activation of the ventral striatum in association with reduced dopamine (DA) availability and release. However, the underlying mechanisms of inflammation-induced DA dysfunction remain largely unknown. Here, we investigated the in vitro effects of the inflammatory cytokine interleukin (IL)-6 on female and male human induced pluripotent stem cell (iPSC)-derived DAergic neurons from healthy volunteers. We identified inhibitory effects of IL-6 on female DA neurons, including reduced DA release, neuronal firing, velocity of synaptic vesicle (SV) transport, and density of docked SV, which was further supported by transcriptomic analyses. In contrast, male DA neurons exhibited an IL-6-induced compensatory phenotype, including increased velocity and density of SV and increased presynaptic terminal density. The long noncoding RNA (lncRNA) MIAT mediated these differences in male DA neurons, potentially via interaction with genes involved in the IL-6 signaling pathway and DA regulation. Moreover, by knocking out MIAT expression in male DA neurons, IL-6-induced deficits emerged, including reduced DA release, neuronal firing, and SV docking. Lastly, we found that the Janus kinase (JAK) inhibitor baricitinib reversed the inhibitory effects of IL-6 on female DA neurons. This work extends our understanding of the impact of inflammation on DA neurons, while identifying important sex differences and pharmacologic targets, ultimately laying the foundation for anti-inflammatory treatments of depressed patients with increased inflammation.
Taylor WD, Gerlach AR, Szymkowicz SM
… +2 more, Gujral S, Andreescu C
Neuropsychopharmacology
· 2026 Jan · PMID 41530554
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While achieving remission is the goal of acute antidepressant treatment, recurrence of new depressive episodes following remission is unfortunately common in clinical populations with Major Depressive Disorder, including...While achieving remission is the goal of acute antidepressant treatment, recurrence of new depressive episodes following remission is unfortunately common in clinical populations with Major Depressive Disorder, including older adults with Late-Life Depression (LLD). The neurobiological factors underlying this risk are poorly understood, limiting our ability to identify potential preventive mechanistic targets. Beyond the limited prognostic utility achieved from individual psychiatric history, it remains challenging to clinically stratify individual risk. This review examines factors influencing the recurrence of depressive episodes following remission in LLD, focusing on cognitive, behavioral, social, and environmental aspects. It additionally considers neuroimaging-based biomarkers related to recurrence risk as well as discussing evidence for and limits of maintenance treatment to prevent recurrence. The paper proposes possible mechanisms contributing to recurrence, including physiological and behavioral responses to stressors, the influence of Alzheimer's disease neuropathology, and conceptualizing repeat depressive episodes within the accelerated aging hypothesis of LLD. A dynamical landscape model of depression recurrence is proposed to elucidate the interplay between different mood states, resilience, and treatment response. This synthesis then highlights avenues for future research, focusing on areas of potential significance ranging from risk stratification to tertiary prevention efforts that may improve both long-term affective and cognitive symptoms.
Biernacki K, Zhai T, Hill J
… +4 more, McConnell E, Salmeron BJ, Kaiser RH, Janes AC
Neuropsychopharmacology
· 2026 Apr · PMID 41530553
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Dynamic resting-state brain activity provides insight into intrinsic neural function and holds promise for predicting individual responses to cognitive demands and pharmacological interventions. This research could ultim...Dynamic resting-state brain activity provides insight into intrinsic neural function and holds promise for predicting individual responses to cognitive demands and pharmacological interventions. This research could ultimately guide medication selection, yet links between network dynamics and medication effects on cognitive function require further validation. Here, we examined whether dynamic activity of an attentional network at rest relates to task-evoked brain activation on the Multi Source Interference Task (MSIT) following administration of methylphenidate (20 mg) and haloperidol (2 mg), which have opposing effects on attention and catecholaminergic function. Fifty-nine healthy adults completed resting-state and task-based fMRI on three separate days on which they received methylphenidate, haloperidol, or placebo in a double-blind placebo-controlled design. Coactivation pattern analysis determined time spent in the dorsal attention network (DAN) under placebo at rest. Linear mixed-effects modeling assessing the relationship between MSIT task activation under drug and time spent in DAN at rest under placebo and MSIT task activation under drug identified a significant interaction in the dorsolateral prefrontal cortex (dlPFC; p < 0.001). Post-hoc analyses indicated that more time in the DAN at rest under placebo was associated with decreased MSIT dlPFC activation under methylphenidate and increased dlPFC activation under haloperidol. Findings demonstrate that resting dynamics of an attentional network are linked to task-related brain responses under different drug conditions within a region implicated in attentional control and sensitive to catecholaminergic variance. Resting-state dynamics may predict pharmacological modulation of goal-directed cognition, highlighting the potential clinical utility of resting-state dynamics in predicting medication response and supporting individualized treatment.
He Y, Zhu J, Liu X
… +10 more, Xu N, Hong S, Wang J, Li Z, Cai Q, Luo Z, Ye F, Yang X, Chen JF, Li Y
Neuropsychopharmacology
· 2026 May · PMID 41530552
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Parkinson's disease (PD) is characterized pathologically by the aggregation of alpha-synuclein (α-Syn) and dopaminergic degeneration and clinically by motor and non-motor deficits, including executive dysfunction and a r...Parkinson's disease (PD) is characterized pathologically by the aggregation of alpha-synuclein (α-Syn) and dopaminergic degeneration and clinically by motor and non-motor deficits, including executive dysfunction and a reduction in the speed of information processing. The neuronal mechanisms underlying executive dysfunction in PD has yet to be elucidated; consequently, there is no effective treatment. In this study, we combined a hierarchical motor sequence learning paradigm, composed of multiple layers of action organization, to simulate the planning, initiation, termination and transition of motor sequence learning, with the focal aggregation of α-Syn in the substantial nigral compacta (SNc). Our goal was to investigate how α-Syn and the adenosine A receptor modulate executive functions. Our analysis revealed that the expression of A53T-α-Syn in SNc impaired executive function, as evidenced by (1) a deficiency in action element learning, (2) a reduction in the intermediate subsequence chunking accuracy of initiation, transition, termination, (3) a decline in high-order sequence execution efficiency, and (4) a reduction in processing speed. Furthermore, pharmacological blockade of the AR improved information processing speed and also reversed α-Syn-induced motor sequence learning deficit. The focal knockdown of ARs in the dorsolateral striatum reversed the α-Syn-induced impairment in motor sequence learning. Collectively, these findings suggest that the aggregation of α-Syn in SNc impaired hierarchical motor sequence learning, thus providing a behavioral model to investigate the executive dysfunction associated with PD. Additionally, the pharmacological blockade of AR reversed hierarchical motor sequence-learning deficit in PD, proposing a promising therapeutic target on PD-associated executive dysfunction.
Gruber M, Schulte J, Mauritz M
… +43 more, Ahrens KF, Rehm P, von Werthern NM, Staub H, Fischer S, Timm F, Libedinsky I, Grumbach P, Bonnekoh LM, Goltermann J, Winter NR, Thiel K, Winter A, Borgers T, Klug M, Meinert H, Hubbert J, Krieger J, Jurischka C, Thomas-Odenthal F, Usemann P, Teutenberg L, Pawlitzki M, Förster K, Sindermann L, Böhnlein J, Meinert S, Grotegerd D, Stein F, Straube B, Alexander N, Jamalabadi H, Jansen A, Nenadić I, Opel N, Hahn T, Bauer J, van den Heuvel MP, Reif A, Kircher T, Leehr EJ, Dannlowski U, Repple J
Neuropsychopharmacology
· 2026 Apr · PMID 41526712
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Current psychiatric neuroimaging supports the view that major depressive disorder (MDD) is a dysconnection syndrome, characterized by structural brain dysconnectivity. Recent studies investigating this question, however,...Current psychiatric neuroimaging supports the view that major depressive disorder (MDD) is a dysconnection syndrome, characterized by structural brain dysconnectivity. Recent studies investigating this question, however, did not evaluate the involvement of comorbid disorders, of which anxiety disorders (ANX) are particularly prevalent. Here, we investigated the structural connectivity alterations observed in MDD with and without comorbid ANX. To this end, we reconstructed structural brain networks of n = 781 individuals with a diagnosis of MDD who had at least one diagnosis of an ANX (n = 249) and those without any diagnosis of ANX (n = 532), as well as n = 906 healthy controls (HC) from structural and diffusion-weighted MRI. The network-based statistic (NBS) toolbox was employed to evaluate network-level differences in structural connectivity among the three groups. Transdiagnostic analyses were conducted to explore the dimensional relationship between anxiety and structural connectivity. NBS revealed decreased structural connectivity in MDD patients without comorbid ANX and increased structural connectivity in MDD patients with comorbid ANX relative to HC, with both effects found in spatially overlapping white matter connections. Transdiagnostic analyses suggested that increases in anxiety were associated with increased structural connectivity across all groups. Our finding that hyperconnectivity rather than hypoconnectivity characterizes the structural connectome of MDD patients with comorbid ANX challenges the applicability of the dysconnection syndrome hypothesis to MDD with comorbid ANX, warranting symptom-based investigations of brain changes in mental disorders.
Jung M, Park J, Kang Y
… +8 more, Shin D, Kang J, Moon HJ, Jung J, Kaiser M, Auer D, Ham BJ, Han KM
Neuropsychopharmacology
· 2026 Mar · PMID 41513848
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A history of suicide attempts is one of the strongest predictors of future suicidal behavior in major depressive disorder (MDD). However, the resting-state functional connectivity (rs-FC) alterations that specifically di...A history of suicide attempts is one of the strongest predictors of future suicidal behavior in major depressive disorder (MDD). However, the resting-state functional connectivity (rs-FC) alterations that specifically differentiate MDD patients with a suicidal attempt history (SD) from those without (NSD) remain poorly understood. This study aimed to identify suicide attempt-specific rs-FC alterations using a two-stage multivariate pattern analysis (MVPA) framework-first contrasting the MDD group with the healthy control (HC) group, then directly comparing the SD group with the NSD group-and to examine whether the identified FC features were related to suicidal ideation or childhood trauma. Rs-FC data were collected from 204 adults (61 SD, 62 NSD, 81 HCs). Significant clusters from each MVPA were used as regions of interest (ROIs) for follow-up ROI-to-ROI and seed-to-voxel analyses, and associations with the Beck Scale for Suicide Ideation (SSI) and Childhood Trauma Questionnaire (CTQ) scores were examined. FC patterns that distinguished the SD group from the NSD group consistently involved visual network regions. The SD group showed lower FC between visual areas and prefrontal regions. Among ROI-level differences, the right intracalcarine cortex-right inferior temporal gyrus FC showed a negative correlation with CTQ-physical neglect subscale scores in the SD group (r = -0.427, pFDR = 0.017). Seed-to-voxel analyses revealed that lower visual-frontal FC was associated with greater suicidal ideation in the MDD group (e.g., left cuneus-left frontal pole, r = -0.341, pFDR = 0.023). These findings suggest a dysfunctional brain network linking childhood trauma, disrupted sensory-cognitive integration, and suicide attempt risk in MDD.
Bella A, Abdallah K, Rodrigues-Amorim D
… +7 more, Diego AM, Decraene C, Hener P, Di Marino C, Finn DP, Yalcin I, Roche M
Neuropsychopharmacology
· 2026 May · PMID 41513847
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Pre-surgical stress is a well-recognised risk factor for persistent post-surgical pain, and while the precise underlying neurobiological mechanisms remain unknown, neuro-immune interactions are believed to play a pivotal...Pre-surgical stress is a well-recognised risk factor for persistent post-surgical pain, and while the precise underlying neurobiological mechanisms remain unknown, neuro-immune interactions are believed to play a pivotal role. Here, we investigated the effect of repeated restraint stress (RRS) on post-surgical somatosensory hypersensitivity and affective responding in male rats and examined underlying mechanisms. We showed that RRS induced behavioural despair, reduced body weight gain and elevated faecal corticosterone levels in male Sprague-Dawley rats. Following paw incision surgery, animals pre-exposed to RRS exhibited exacerbated mechanical and heat hypersensitivity, pain-related aversion, and anxiety-like behaviour compared to non-stress counterparts. RNAseq analysis revealed alterations in expression of glial markers and inflammasome pathways in the dorsal horn of the spinal cord in the RRS + paw incision group, compared to paw incision alone, data further confirmed by immunohistochemistry and RT-qPCR analysis. Intrathecal administration of Interleukin-1 receptor antagonist (IL-1Ra) or MCC950 (an NLRP3 inhibitor) attenuated the RRS-induced increase in pain-related aversion and mechanical hypersensitivity post-surgery. Chronic administration of the β-adrenergic receptor antagonist propranolol, but not the glucocorticoid receptor antagonist RU486, attenuated the RRS-induced exacerbation of mechanical hypersensitivity, pain-related aversion and anxiety-like behaviour post-surgery. These findings suggest that RRS exacerbates and prolongs post-surgical somatosensory and affective pain responding via β-adrenergic receptor activation and increased spinal microglial NLRP3-IL-1β signalling. These data provide further insight into the mechanisms by which chronic stress and mood disorders exacerbate and prolong post-surgical pain.
Huerta Sanchez LL, Siao NM, Chaudhari SR
… +13 more, Barrios JE, Na AY, Tadros MG, McConnell ML, Kaplan RM, Lane CR, Doan HHT, Liger AB, Chou TC, Marcon S, Cano FJ, Kippin TE, Szumlinski KK
Neuropsychopharmacology
· 2026 Jun · PMID 41507314
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The incubation of craving is a term coined to characterize the behavioral phenomenon wherein cue-elicited craving strengthens over a period of abstinence. Incubated cocaine-craving is mediated, at least in part, by incre...The incubation of craving is a term coined to characterize the behavioral phenomenon wherein cue-elicited craving strengthens over a period of abstinence. Incubated cocaine-craving is mediated, at least in part, by increased glutamate release within the prelimbic cortex (PL). We hypothesized that this glutamate release stimulates NMDA-type glutamate receptors (NMDARs), leading to calcium-dependent activation of CaMKII signaling that drives incubated craving. To test this hypothesis, adult male and female Sprague-Dawley rats were trained to self-administer either intravenous cocaine or sucrose pellets (6 h/day × 10 days) and tested for cue-elicited cocaine- or sucrose-craving in early versus later (i.e., after incubation) withdrawal. Incubated cocaine-seeking was associated with increased CaMKII activity in the PL, but no change in NMDAR subunits. In contrast, incubated sucrose-craving was associated with many sex-dependent changes in both NMDAR subunit expression and CaMKII activation that were subregion-selective. An intra-PL infusion of the NMDA antagonist D-AP5 (2.5 or 7.5 µg/side) or the CaMKII inhibitor myr-AIP (10 pg/side) blocked both incubated cocaine- and sucrose-craving, with no effects detected in early withdrawal. Co-infusion of both D-AP5 and myr-AIP exerted a larger effect on incubated cocaine-craving than either antagonist alone. These data corroborate earlier evidence for distinct biochemical correlates within mPFC between incubated cocaine- and sucrose-craving and, for the first time, demonstrate that both NMDAR and CaMKII activation within the PL are common drivers of incubated craving of potential relevance to the design of anti-craving medications in the contexts of both drug and food reinforcers.
Abbott JA, Weaver MG, Liu B
… +2 more, Schwarz SR, Popescu GK
Neuropsychopharmacology
· 2026 Jul · PMID 41501539
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Positive allosteric modulators (PAMs) of NMDA receptors hold promise to alleviate functional deficits associated with neuropsychiatric disorders. GNE-9278 is a synthetic PAM that binds to the obligatory GluN1 subunit of...Positive allosteric modulators (PAMs) of NMDA receptors hold promise to alleviate functional deficits associated with neuropsychiatric disorders. GNE-9278 is a synthetic PAM that binds to the obligatory GluN1 subunit of NMDA receptors, yet it displays substantial subtype-specific efficacies. To examine the underlying mechanism by which GNE-9278 potentiates NMDA receptor responses, we examined electrical activity from endogenous and recombinant NMDA receptors and measured changes in kinetics, unitary conductance, and Ca permeability for GluN2A- and GluN2D-containing receptors. We found that GNE-9278 stabilized the open states of both receptor types and increased their open state occupancies at equilibrium. This change was small for GluN2A receptors, whose open probability (Po), remained around 0.5, and was substantial for GluN2D, which increased four-fold to 0.24. Moreover, specifically when acting on GluN2D receptors, GNE-9278 increased the channel unitary conductance (γ), from 43 pS to 56 pS, and their Ca permeability (P/P), from 1.4 to 2.9. These results show large and complex effects of GNE-9278 on GluN2D receptors, which together boost these receptors' excitatory signal and impact on synaptic plasticity and cellular fate. This new information should guide the use of drugs acting at the GNE-9278-binding site for research and therapeutic purposes.
Valles TE, Shamas M, Hawkins H
… +19 more, Matthews C, Ngo D, Peltekian H, Artin H, Distler MG, DeYoung DZ, Einstein EH, Ginder ND, Koek RJ, Krantz DE, Leuchter MK, Oughli HA, Slan AR, Strouse TB, Tadayonnejad R, Wilke SA, Young AS, Corlier J, Leuchter AF
Neuropsychopharmacology
· 2026 Apr · PMID 41501538
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Repetitive Transcranial Magnetic Stimulation (rTMS) engages brain networks for the treatment of Major Depressive Disorder (MDD), using either rhythmic (e.g., 10 Hz) or patterned (e.g., intermittent Theta Burst, or iTBS)...Repetitive Transcranial Magnetic Stimulation (rTMS) engages brain networks for the treatment of Major Depressive Disorder (MDD), using either rhythmic (e.g., 10 Hz) or patterned (e.g., intermittent Theta Burst, or iTBS) stimulation protocols. The distinct effects of these protocols on brain function are not well understood. Sixteen subjects with MDD underwent a TMS-electroencephalography (TMS-EEG) "interrogation" paradigm, in which a broad range of rhythmic and patterned stimulation frequencies were administered in a randomized order to the left dorsolateral prefrontal cortex (L-DLPFC). rTMS-induced changes in oscillatory activity and effective connectivity to the DLPFC were examined at each frequency. Linear mixed-effects models revealed widespread changes in power and connectivity, with magnitude and regional distribution of change dependent upon both protocol and frequency of stimulation. Increases in beta band power were most prominent with patterned stimulation, while rhythmic stimulation increased both alpha and beta power at stimulation frequencies greater than 7 Hz (p < 0.05). Source localization showed that patterned and rhythmic stimulation elicited activation in distinct subregions of the cingulate. Rhythmic and patterned stimulation also had distinct effects on connectivity: notably, only rhythmic stimulation increased connectivity with regions near the stimulation site, while only patterned stimulation decreased connectivity to the left precuneus. Both protocols increased the effective connectivity to the orbitofrontal cortex in the theta and beta response bands (p < 0.05). These results indicate that rhythmic and patterned rTMS engage distinct brain regions in a protocol- and frequency-dependent manner. Future studies should examine how these mechanistic differences may relate to clinical outcomes.
Stine C, Pasqualini AL, Achanta AS
… +4 more, Johnson JC, Jadhav S, Marcus DJ, Bruchas MR
Neuropsychopharmacology
· 2026 Apr · PMID 41422177
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Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid neuropeptide, and its G-protein coupled receptor NOPR have been implicated in motivation, feeding behaviors, and aversion. Stress-induced dysfunction in these states i...Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid neuropeptide, and its G-protein coupled receptor NOPR have been implicated in motivation, feeding behaviors, and aversion. Stress-induced dysfunction in these states is central to the development of numerous psychiatric disorders, and the N/OFQ-NOPR system's role in reward- and stress-related responses has driven broad interest in NOPR as a therapeutic target for anxiety and depression. However, the impact of stress on N/OFQ signaling in the context of its influence on discrete midbrain reward circuitry remains unknown. To this end, we focused on a possible candidate population of N/OFQ neurons in the paranigral ventral tegmental area (pnVTA) that have been shown to act locally on NOPR-containing VTA dopamine neurons to suppress motivation. Here we report and characterize pnVTA sensitivity during exposure to a diverse range of stressors. Our results indicate that pnVTA neurons become recruited during exposure to a variety of acute stressor types, suggesting that this N/OFQ population in the pnVTA could act as a critical bridge between stress and motivation.
Wooldridge LM, Wu JWK, Jo AY
… +8 more, Zinn M, Lee AM, Mahmood M, Cohen SA, McCall NM, Oswell CS, Rogers SA, Corder G
Neuropsychopharmacology
· 2026 May · PMID 41419678
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Aversion to opioid withdrawal is a significant barrier to achieving lasting opioid abstinence. The central amygdala (CeA), a key brain region for pain, threat-detection, autonomic engagement, and valence assignment, is a...Aversion to opioid withdrawal is a significant barrier to achieving lasting opioid abstinence. The central amygdala (CeA), a key brain region for pain, threat-detection, autonomic engagement, and valence assignment, is active during opioid withdrawal. However, the role of molecularly distinct CeA neural populations in withdrawal remains underexplored. Here, we investigated the activity dynamics, brain-wide connectivity, and functional contribution of Protein Kinase C-delta (PKCδ)-expressing neurons in the CeA lateral capsule (CeLC) during fentanyl withdrawal in mice. Mapping activity-dependent gene expression in CeLC neurons revealed a highly withdrawal-active subregion in the anterior half of the CeA. Fiber photometry calcium imaging showed that opioid-naïve CeLC neurons respond to salient noxious and startling stimuli. In fentanyl-dependent mice, naloxone-precipitated withdrawal increased spontaneous neural activity and enhanced responses to noxious stimuli. Chronic inhibition of CeLC neurons throughout fentanyl exposure, via viral overexpression of the potassium channel Kir2.1, attenuated withdrawal symptoms in fentanyl-dependent mice. Lastly, we identified putative opioid-sensitive inputs to CeLC neurons using rabies-mediated monosynaptic circuit tracing and color-switching tracers to map mu-opioid receptor-expressing inputs to the CeLC. Collectively, these findings suggest that the hyperactivity of CeLC neurons underlies the somatic signs of fentanyl withdrawal, offering new insights into the amygdala cell-types and circuits involved in opioid dependence.
Davis MT, Weiss ER, DellaGioia N
… +4 more, Boster S, Asch RH, Moisieienko K, Esterlis I
Neuropsychopharmacology
· 2026 Mar · PMID 41413678
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Chronic pain (CP) is a significant source of personal and public health burden with high prevalence (up to one in five in the United States) and few safe, effective treatment options. This study examined relationships be...Chronic pain (CP) is a significant source of personal and public health burden with high prevalence (up to one in five in the United States) and few safe, effective treatment options. This study examined relationships between metabotropic glutamate receptor 5 (mGlu5) availability and CP in vivo for the first time. A transdiagnostic sample of individuals (major depressive disorder; bipolar disorder; healthy controls; N = 112) with and without CP or acute pain completed clinical assessments and participated in an [F]FPEB positron emission tomography (PET) scan. Results indicated that mGlu5 availability was 13.5-15.7% lower in individuals with pain relative to those with no pain (p's = -0.002-0.029) in brain regions implicated in the neurophysiology of pain. Results did not change when controlling for demographics or psychiatric diagnosis. Exploratory analyses demonstrated lower mGlu5 availability in individuals with CP (10.3-14.2% difference) or both acute and CP (15.9-21.1% difference) than those with acute pain only, suggesting specific associations between mGlu5 and CP. Individuals with pain reported more severe depression (p's = 0.008-0.022) and anxiety (p = 0.009), sleep disturbances (p < 0.001), and worse cognitive functioning (p's = 0.009-0.025). Across various regions, mGlu5 availability was negatively associated with depression (r's = -0.24-0.33), anxiety (r = -0.27), and executive dysfunction (r's = -0.24-0.33); mGlu5 was not related to sleep disturbance. This study demonstrated lower mGlu5 availability in individuals with pain across psychiatric groups and presents mGlu5 as a promising treatment target for pain with low abuse potential, warranting future research examining mGlu5 for pain reduction.