Neuropsychopharmacology [JOURNAL]
Sun
200 papers
Age matters: a narrative review and machine learning analysis on shared and separate multidimensional risk domains for early and late onset suicidal behavior.
Galfalvy H, Campbell E, Wong MT … +3 more , Gujral S, Szücs A, Szanto K
Neuropsychopharmacology · 2026 Jan · PMID 41577995 · Publisher ↗
There is considerable heterogeneity among late-life suicide attempters who can present stark differences in their suicidal trajectories. This work provides a narrative review of sources of heterogeneity of suicide risk i...
There is considerable heterogeneity among late-life suicide attempters who can present stark differences in their suicidal trajectories. This work provides a narrative review of sources of heterogeneity of suicide risk in late-life depression and describes a quantitative study of the relative importance of multidimensional risk domains, in discriminating suicide attempters, split into early- and late-onset cases, from depressed non-attempters. The sample comprised 382 depressed middle-aged and older adults (aged 50 years or older, mean age = 63.5 years). Penalized binomial logistic regression and Random Forest models were fit using cross-validation in 100 versions of a training dataset of 83 variables, grouped into seven domains, to distinguish early- and late-onset suicide attempters from depressed non-attempters, and evaluated on testing datasets. Variable and domain importances were defined based on the frequency of each variable in the final models. Variables from the behavioral control and planning domain had high importance in differentiating both early-onset and late-onset attempters from depressed non-attempers. Early-life history as well as mood/anxiety/emotion regulation were important in distinguishing the early-onset group from depressed non-attempters, whereas social dynamics/interactions and cognition/decision-making were important in distinguishing the late-onset group from depressed non-attempters. This study underscores the importance of examining multiple risk factors for suicide together, and the advantages of considering known sources of heterogeneity in populations at risk in the development of more comprehensive and personalized suicide risk assessment tools and guidelines.
Prolonged grief disorder in later life: advancing our understanding of biopsychosocial mechanisms to guide future personalized interventions.
Goveas JS, Hwang G, Blair NP … +2 more , Stein EA, Reynolds CF
Neuropsychopharmacology · 2026 Jan · PMID 41577994 · Full text
Grief is a near-universal yet profoundly traumatic human experience, symbolizing a testament to the depth of our emotional bonds while reminding us of life's fragility. Although most individuals adapt to loss over time,...
Grief is a near-universal yet profoundly traumatic human experience, symbolizing a testament to the depth of our emotional bonds while reminding us of life's fragility. Although most individuals adapt to loss over time, 3-10% develop Prolonged Grief Disorder (PGD), a chronic and debilitating condition recognized in both the DSM-5-TR and ICD-11. Older adults are particularly vulnerable: PGD in later life poses significant public health risks, including adverse physical health outcomes, cognitive decline, and increased premature mortality, underscoring the urgent need for early identification and effective interventions in this population. This narrative review examines psychological, social, and neurobiological perspectives on grief, highlighting distinctions between acute, integrated, and PGD trajectories. We trace the evolution of PGD as a diagnostic entity and review its risk factors, clinical presentation, comorbidities, assessment, and current treatment approaches. We then propose a neurobiological model of late-life PGD, grounded in cognitive neuroscience and emphasizing the roles of key intrinsic brain networks: the Salience Network, Default Mode Network, and Executive Control Network. Finally, we outline future directions for the field, calling for neuroimaging studies that integrate biological markers with psychosocial factors to refine diagnosis and inform targeted interventions. This review advocates for a biopsychosocial framework to advance understanding and treatment of PGD in older adults.
A dual role of hippocampal perineuronal nets in plasticity and protection is revealed by improvement and impairment of diet-induced memory dysfunction.
Reichelt AC, Hashad AM, Ghosh-Swaby OR … +8 more , Skirzewski M, Scott GA, Machado M, Kramar CP, Princz-Lebel O, Inoue W, Bussey TJ, Saksida LM
Neuropsychopharmacology · 2026 Jun · PMID 41571987 · Full text
Alterations to perineuronal nets (PNNs) are linked to cognitive deficits observed in multiple neuropsychiatric and neurodegenerative conditions. PNNs are proposed both to limit neuronal plasticity and to protect neuronal...
Alterations to perineuronal nets (PNNs) are linked to cognitive deficits observed in multiple neuropsychiatric and neurodegenerative conditions. PNNs are proposed both to limit neuronal plasticity and to protect neuronal populations critical for cognitive function. Here, we assessed these two distinct proposed functions of PNNs in the same experimental procedure, varying only the timing of PNN manipulation. Enzymatic degradation of hippocampal PNNs 4 weeks after an obesogenic high-fat high-sugar (HFHS) diet - which causes hippocampal-dependent memory impairments - restored memory performance, demonstrating a key role of PNNs in plasticity. In contrast, degradation of hippocampal PNNs prior to HFHS diet exacerbated memory deficits, demonstrating PNNs' role in neuroprotection. Because PNNs primarily surround PV neurons (PVNs), we hypothesized that the mechanism underlying these effects of PNN degradation would involve, at least in part, alterations in hippocampal PVN function. Thus, to see whether PNN degradation alters the function of hippocampal PVNs, we took fiber photometry measurements across multi-day timescales and found that hippocampal PNN degradation alters calcium events in PVNs. We then went on to explicitly manipulate PVNs and found that chemogenetic inhibition of hippocampal PVNs in mice on a standard diet impaired memory performance, and activation of hippocampal PVNs in mice on a HFHS diet restored memory performance, bidirectional effects that mirror the bidirectional effects of PNN degradation. Taken together, these findings support the dual plasticity and protection hypothesis of PNN function, provide evidence that key mechanisms of memory involve the interaction of PNNs and PVNs, and point to PNNs as a potential therapeutic target in cognitive decline.
AI in geriatric psychiatry: precision meets human experience.
Mizuno A, Erickson Z, Jimenez DE … +1 more , Aizenstein HJ
Neuropsychopharmacology · 2026 Jan · PMID 41571986 · Publisher ↗
Artificial intelligence (AI) and robotics are rapidly transforming geriatric psychiatry, offering powerful tools for early detection, personalized treatment, and enhanced care delivery. As the global population ages, the...
Artificial intelligence (AI) and robotics are rapidly transforming geriatric psychiatry, offering powerful tools for early detection, personalized treatment, and enhanced care delivery. As the global population ages, these technologies promise not only greater efficiency but also new avenues for delivering scalable, accessible mental health support. However, as AI increasingly engages with domains once considered uniquely human-emotional intelligence, decision-making, and interpersonal connection-it raises deeper questions about the boundary between AI-simulated interaction and authentic human connection. This review examines the intersection of computational precision and existential complexity, emphasizing how theoretical frameworks such as the Theory of Computing (TOC) and Theory of Mind (ToM) can guide ethical and human-centered integration. While AI systems may convincingly simulate empathy or companionship, they cannot share subjective experience, vulnerability, or existential depth. By contrasting computational precision with the irreducible aspects of human complexity, we advocate for a transdisciplinary approach that embraces both the transformative potential of technology and the irreplaceable richness of human connection-especially in the later stages of life, when questions of purpose, mortality, and selfhood become most profound.
The spectrum of bipolar disorder in older adults.
Eyler LT, Klaus F, Van Dyne A … +3 more , Ng HX, Dols A, Sajatovic M
Neuropsychopharmacology · 2026 Jan · PMID 41571985 · Publisher ↗
The absolute number and relative proportion of individuals with older-age bipolar disorder (OABD) is expected to rise due to the global aging of the population, necessitating a greater understanding of the unique charact...
The absolute number and relative proportion of individuals with older-age bipolar disorder (OABD) is expected to rise due to the global aging of the population, necessitating a greater understanding of the unique characteristics of OABD and the trajectory of aging with BD in order to improve the health span of people with BD. This review summarizes current knowledge on OABD, examining its clinical presentation, neurobiology, and treatment, as well as identifying key gaps and future directions for research. OABD is characterized by relatively greater cognitive impairment and somatic burden, despite potentially reduced mood symptom severity compared to younger-age bipolar disorder (YABD). This significantly impacts functional outcomes in older age, highlighting the need for age-adjusted clinical strategies. Individual differences in illness course, treatment history, and psychotic features influence the clinical presentation and prognosis in OABD. One powerful strategy to better understand OABD is to bring together existing data from across the globe through large-scale collaborations. In the realm of BD, this is exemplified by several ongoing efforts including the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) initiative and the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder (ENIGMA-BD) working group. Evidence on the trajectory of bipolar disorder (BD) across the lifespan is mixed, with some individuals showing accelerated cognitive and biological aging. Biomarker studies reveal overlaps between YABD and OABD, but also suggest age-specific alterations in inflammation and oxidative stress pathways. Lithium remains a first-line pharmacological treatment in OABD, with emerging evidence supporting other pharmacologic and behavioral interventions, although large-scale, age-specific trials remain limited. Neuromodulation treatment approaches appear promising but remain relatively unexplored in OABD. The review highlights current knowledge gaps, particularly the need for longitudinal research to identify early predictors of impairment, and to guide potential preventative strategies. This summary emphasizes the potential of global consortia and multi-center studies to deepen insights into BD aging trajectories with high generalizability. Ultimately, a lifespan approach that incorporates lived experience, early intervention, and global collaboration is essential to promoting health and well-being in individuals with OABD.
Acetazolamide inhibition of carbonic anhydrase 4 reverses opioid-induced synaptic rearrangements in nucleus accumbens and reduces drug-seeking behavior.
Gupta SC, Taugher-Hebl RJ, Ghobbeh A … +4 more , Jahnke MT, Fan R, LaLumiere RT, Wemmie JA
Neuropsychopharmacology · 2026 Jul · PMID 41565998 · Full text
Persistent vulnerability to drug-seeking is driven by enduring synaptic adaptations, yet current μ-opioid receptor-targeting pharmacotherapies provide limited efficacy against these neuroadaptations. Thus, there is a cri...
Persistent vulnerability to drug-seeking is driven by enduring synaptic adaptations, yet current μ-opioid receptor-targeting pharmacotherapies provide limited efficacy against these neuroadaptations. Thus, there is a critical need for mechanistically distinct, non-opioid interventions. We recently found that carbonic anhydrase 4 (CA4) disruption reduces cocaine-induced synaptic adaptations and drug-seeking. Building on this foundation, we sought to determine whether deleting CA4 or pharmacological inhibition with acetazolamide (AZD), a clinically employed carbonic anhydrase inhibitor-could mitigate opioid withdrawal-associated plasticity and thus might reduce relapse vulnerability. We studied synaptic and behavioral adaptations to withdrawal from oxycodone in mice and found that prolonged withdrawal from oxycodone increased the AMPAR/NMDAR ratio and promoted synaptic incorporation of Ca-permeable AMPARs in nucleus accumbens core (NAcC) medium spiny neurons (MSNs). We found synaptic changes after protracted withdrawal from multiple opioids, which were most pronounced in D1-expressing MSNs, and were prevented by CA4 disruption. Moreover, AZD reversed withdrawal-induced synaptic alterations both in vitro and in vivo, in a CA4- and acid-sensing ion channel 1A (ASIC1A)-dependent manner. Unlike withdrawal from cocaine, withdrawal from oxycodone did not alter dendritic spine density in NAcC MSNs, suggesting a distinct mode of plasticity. Finally, following oxycodone self-administration, both CA4 deletion and a single systemic AZD dose reduced drug-seeking after prolonged abstinence. Together, these findings identify CA4 as a regulator of opioid-induced synaptic adaptations and suggest AZD as a promising, readily translatable pharmacological intervention. By targeting a pathway independent of classical opioid receptor signaling, CA4 inhibition represents a mechanistically distinct strategy that may reduce relapse vulnerability in OUD.
The psychoactive cannabinoid THC inhibits peripheral nociceptors by targeting Na1.7 and Na1.8 nociceptive sodium channels.
Maatuf Y, Iskimov A, Binshtok AM … +1 more , Priel A
Neuropsychopharmacology · 2026 May · PMID 41565997 · Full text
Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, is widely recognized for its central effects mediated by cannabinoid receptors. Here, we uncover a distinct peripheral mechanism by which THC...
Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, is widely recognized for its central effects mediated by cannabinoid receptors. Here, we uncover a distinct peripheral mechanism by which THC inhibits the excitability of nociceptive neurons. We show that THC directly targets the nociceptive voltage-gated sodium channels Na1.7 and Na1.8 through the conserved local anesthetic binding site. This interaction reduces sodium currents and suppresses action potential generation in peripheral sensory neurons. Our findings demonstrate that, beyond its central psychoactivity, THC exerts direct peripheral nociceptor inhibition via modulation of Na1.7 and Na1.8, offering new insight into cannabinoid-based analgesia independent of cannabinoid receptor signaling.
A pathway from the anterior cingulate cortex to the lateral habenula controls chronic pain-induced depression in male mice.
Journée SH, Mathis VP, Waegaert R … +11 more , Ozkan S, Langlois E, Ortiz-Teba P, Ayazgok B, Becker LJ, Gaikwad M, Barrot M, Hugel S, Harsan L, Lutz PE, Yalcin I
Neuropsychopharmacology · 2026 Jun · PMID 41559454 · Full text
Chronic pain induces long-lasting changes in the anterior cingulate cortex (ACC) activity that contribute to the development of comorbid mood disorders. However, how such alterations propagate throughout the ACC connecto...
Chronic pain induces long-lasting changes in the anterior cingulate cortex (ACC) activity that contribute to the development of comorbid mood disorders. However, how such alterations propagate throughout the ACC connectome remains to be elucidated. Here, we aimed to study the role of the ACC neurons projecting to the lateral habenula (LHb) (ACC) in chronic pain-induced depression (CPID). CPID was induced using sciatic nerve cuffing in male C57BL/6J mice, and anxiodepressive-like behaviors were evaluated using a battery of behavioral tests. Fiber photometry was used to study the Ca dynamics in the ACC, LHb, and ACC neurons We combined viral Translating Ribosome Affinity Purification (vTRAP) and RNA sequencing to study the molecular alterations in the ACC neurons. Finally, we used an optogenetic approach to study the functional role of this pathway in CPID. Our results confirmed a functional connectivity between the ACC and LHb and demonstrated that this connection plays a critical role in emotional processing. Activation of ACC neurons elicited Ca responses in the LHb and induced anxiodepressive-like behaviors in naive mice. Cell-type specific transcriptomic analysis revealed that CPID altered the expression of genes involved in neuronal excitability, such as genes related to sphingolipid metabolism, glycophospholipid,s and Ca channels in ACC neurons. Interestingly, inhibition of this hyperactivity alleviated chronic pain- but not stress-induced anxiodepressive-like behaviors, demonstrating that the ACC pathway selectively contributed to nerve-injury induced emotional dysregulation. These results reveal that hyperactivity of the neuronal pathway linking the ACC to the LHb is essential for CPID in male mice.
Multiple sources of β2*-nicotinic acetylcholine receptor binding are differentially affected during tobacco smoking abstinence as revealed by Independent Component Analysis of [F]Flubatine PET images.
Raval NR, Calakos KC, Zheng MQ … +7 more , Huttner A, Esterlis I, Huang H, Calhoun VD, Picciotto MR, Cosgrove KP, Hillmer AT
Neuropsychopharmacology · 2026 Jun · PMID 41559453 · Full text
Tobacco smoking, a major cause of preventable mortality, upregulates β2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChR) in most brain regions. Although the α4 subunit most frequently co-assembles with β2...
Tobacco smoking, a major cause of preventable mortality, upregulates β2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChR) in most brain regions. Although the α4 subunit most frequently co-assembles with β2, other subunits likely assemble with β2 and contribute to distinct aspects of nicotine-mediated behaviors, but these factors are poorly understood in people. This work performed independent component analysis (ICA) of [F]Flubatine positron emission tomography (PET) image data to identify maximally independent sources of specific binding to β2*-nAChRs. We then compared their magnitudes (loading coefficients) in people who recently stopped smoking cigarettes (abstinent smokers; n = 26) and people who never smoked cigarettes (non-smokers; n = 20). ICA identified 3 reproducible components: IC1 (36% of variance) in medial thalamus, lateral thalamus, and red nucleus; IC2 (18% of variance) in ventral thalamus, lateral geniculate, and midbrain; IC3 (19% of variance) in cerebellum and optic circuitry in midbrain. Nicotine challenge in an independent sample (n = 9) reduced loading coefficients of all components, confirming specific binding to nAChRs. Post-mortem autoradiography of cerebellum showed greatest [F]Flubatine displacement by α3/α6β2*-nAChR blocker (α-Conotoxin MII) but low displacement by α6β2*-nAChR blocker (α-Conotoxin PIA), suggesting that IC3 measures α3β2*-nAChRs specific binding - a novel finding in living people. Loading coefficients of IC1 and IC2 were significantly lower in abstinent smokers compared to non-smokers. IC3 loading coefficients were significantly higher during extended smoking abstinence, and exploratory analyses suggested initial evidence for daily smoking amount correlating with nicotine dependence severity. These results could inform novel treatment development to help people quit smoking.
Epigenetic treatment of synaptic and behavioral deficits in Dyrk1a-mutant mice.
Lin CH, Yu M, Patel PJ … +2 more , Li P, Yan Z
Neuropsychopharmacology · 2026 Jul · PMID 41559452 · Full text
Haploinsufficiency of Dyrk1a, which encodes the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), has been causally linked to autism. Here we examined transcriptomic, electrophysiological and behavi...
Haploinsufficiency of Dyrk1a, which encodes the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), has been causally linked to autism. Here we examined transcriptomic, electrophysiological and behavioral alterations in mice carrying a loss-of-function mutation of Dyrk1a (Dyrk). We found that genes downregulated in prefrontal cortex (PFC) of male and female Dyrk mice were enriched in chemical synaptic transmission and trans-synaptic signaling. In PFC pyramidal neurons of Dyrk mice, the frequency of synaptic-driven spontaneous action potentials (sAP) was significantly reduced, and glutamatergic excitatory postsynaptic currents (EPSC) and GABAergic inhibitory postsynaptic currents (IPSC) were markedly diminished. Furthermore, autism-like social preference deficits and elevated anxiety were manifested in Dyrk mice of both sexes. A short treatment of Dyrk mice with an inhibitor of the epigenetic corepressor lysine-specific histone demethylase 1A (LSD1) led to a significant elevation of sAP frequency, EPSC and IPSC in PFC pyramidal neurons of Dyrk mice. Moreover, the LSD1 inhibitor ameliorated social deficits in Dyrk mice and reduced anxiety in Dyrk males. Therefore, these data have not only revealed synaptic and behavioral deficits in PFC induced by Dyrk1a mutation, but also uncovered the therapeutic potential of LSD1 inhibition in Dyrk1a-deficient conditions.
Excitation-inhibition homeostasis in Alzheimer's disease: a selective multiscale review of mechanisms, sex differences, and therapeutic opportunities.
Burns AP, Duran MI, Fortel I … +4 more , Lazarov O, Zhan L, Bendlin B, Leow A
Neuropsychopharmacology · 2026 Jan · PMID 41554957 · Full text
Alzheimer's disease is increasingly viewed as a breakdown of balanced excitation-inhibition (E/I) homeostasis layered atop classical proteinopathy. Restoring circuit-level neural excitation and inhibition is rapidly beco...
Alzheimer's disease is increasingly viewed as a breakdown of balanced excitation-inhibition (E/I) homeostasis layered atop classical proteinopathy. Restoring circuit-level neural excitation and inhibition is rapidly becoming a tractable therapeutic strategy, guiding trials of circuit-modulating drugs such as levetiracetam. To date, however, findings across species and modalities remain fragmented, and it is unclear how to contextualize AD-focused E/I findings across scales and methodologies. Synthesizing over 150 studies of E/I homeostasis in AD, we organize the results into several prevailing themes: excitatory/inhibitory effects of amyloid and tau, whether hyperexcitation precedes amyloid plaque deposition, progressive oscillatory slowing (a shift of aggregate neural signal frequencies towards lower frequencies) as AD worsens, early preclinical hyperexcitation peaking in MCI and transitioning to hypoexcitation in AD, sex differences in E/I trajectories, APOE4 as a mediating factor, the contribution of neuroinflammation and metabolic dysfunction to E/I imbalance, and E/I-focused trials/experiments, particularly involving levetiracetam. These dominant themes are interpreted in a framework of multidimensional E/I homeostasis, rather than a single-axis imbalance. To support this integration, we first outline the microscale, mesoscale, and macroscale techniques used to assess E/I in AD, ranging from patch clamping and extracellular recordings to EEG/MEG and fMRI. By charting these multiscale E/I shifts, our synthesis offers a unifying framework to guide future experimental work and accelerate the design of biomarker-driven trials of E/I-targeted therapies in Alzheimer's disease.
Vascular cognitive impairment and dementia: Prevention, treatments, mechanisms and management options for the future.
Lennon MJ, Sachdev PS
Neuropsychopharmacology · 2026 Jan · PMID 41554956 · Publisher ↗
Vascular Cognitive Impairment and Dementia (VCID), the second most common form of dementia, is becoming increasingly prevalent worldwide. However, currently there are no FDA-approved therapies for VCID. In this review, w...
Vascular Cognitive Impairment and Dementia (VCID), the second most common form of dementia, is becoming increasingly prevalent worldwide. However, currently there are no FDA-approved therapies for VCID. In this review, we explore treatments with extant supporting evidence as well as treatments in development and outline the path forward for future research. Donepezil, rivastigmine, and memantine all have some evidence as cognitive enhancers in patients with Vascular Dementia (VaD) and are approved in several non-US jurisdictions. Nutraceuticals, such as Ginkgo biloba and butylphthalide, have some supportive data and may be similarly helpful. Prevention of VCID is an important objective, and there is support for the intensive control of hypertension and treatment of hyperglycemia to prevent cognitive decline. Asymptomatic cerebral small vessel disease is commonly detected in neuropsychiatric cohorts and healthy individuals, and protocols and trials are being developed to help guide management to minimize the risk of cognitive impairment. A range of novel treatment strategies, including noninvasive neurostimulation, stimulant treatment, and neurotrophic factors, are being explored. Future research into VCID treatment needs to incorporate a range of novel technologies, including blood-based biomarkers, automation of brain image segmentation and quantification using artificial intelligence, automated remotely administered neuropsychological testing, and rational drug discovery.
Modulation of accumbens dopamine by MCH neurons during learning and consummatory behavior.
Potter LE, Toth BA, Manna J … +4 more , Baron L, Lyons HC, Evans JR, Burgess CR
Neuropsychopharmacology · 2026 Jun · PMID 41554955 · Full text
The formation of sensory cue-reward associations is essential for survival, but in the modern calorie-rich and advertising-intensive environment, such associations may become maladaptive - leading to negative health cons...
The formation of sensory cue-reward associations is essential for survival, but in the modern calorie-rich and advertising-intensive environment, such associations may become maladaptive - leading to negative health consequences such as obesity or diabetes. Recent research has demonstrated the importance of hypothalamic melanin-concentrating hormone (MCH)-expressing neurons in driving hedonically-motivated feeding and in forming these associations. The MCH system interacts with mesolimbic dopamine (DA) transmission, offering a potential mechanism for the effects of MCH neurons on hedonic feeding and associative conditioning. However, this interaction has not been fully characterized in vivo with modern approaches that offer high temporal and spatial resolution. We characterized MCH-DA interactions during feeding and food-motivated Pavlovian conditioning using in vivo fiber photometry in the lateral hypothalamus/zona incerta (LH/ZI) and nucleus accumbens (NAc). We found that MCH neuron activity and DA release in the medial-shell of the NAc (mNAcSh) were co-activated during consumption and in response to reward-predicting cues. During consumption, DA release preceded MCH activity, while responses to reward-predicting cues emerged in MCH neurons earlier than in the DA system. Lastly, gain and loss-of function of the MCH system could bidirectionally modulate DA release in the mNAcSh. These results indicate that physiological co-activation of the MCH and DA systems occurs during food-motivated learning, and demonstrate a capacity for bidirectional modulation of DA release in the mNAcSh by the MCH system.
Incentive salience, not psychomotor sensitization or tolerance, drives escalation of cocaine self-administration in heterogeneous stock rats.
Ramborger J, Mosquera J, Brennan M … +13 more , Sichel B, Othman D, Plasil S, Sneddon E, Zahedi S, Morgan A, Chonwattanagul S, Bai K, China L, La T, Maturin L, Carrette LLG, George O
Neuropsychopharmacology · 2026 Jun · PMID 41548027 · Full text
Sensitization and tolerance are two phenomena often studied independently despite overlapping neurobiological substrates. Each has extensive research showing their influence on the development and maintenance of addictio...
Sensitization and tolerance are two phenomena often studied independently despite overlapping neurobiological substrates. Each has extensive research showing their influence on the development and maintenance of addiction, but the degree to which they drive escalation in cocaine self-administration is poorly understood. Using self-administration, intravenous noncontingent infusions, and pose-estimation machine vision, we found that incentive salience, not psychomotor sensitization or tolerance, drove the escalation of cocaine self-administration in heterogenous stock rats. Individual differences in psychomotor sensitization or tolerance were found to have no effect on cocaine intake. Incentive salience as measured by locomotion and active lever entrances per meter traveled occurring before the self-administration session began (pre-lever activity measures) during Short Access (2 h) was found to predict intake during Long Access (6 h). Both pre-lever locomotion and active lever entrances per meter were found to increase during Long Access and after two-to-three days of abstinence. Critically, rats with low pre-lever activity during Short Access escalated both their intake and pre-lever measures by the end of Long Access to levels comparable with high pre-lever activity rats who maintained their elevated responding. These findings support the notion that incentive salience during Short Access is a catalyst to escalated use and an early marker of addiction vulnerability. Moreover, they suggest that individuals initially resistant to incentive salience can, with sufficient exposure, become sensitized and escalate cocaine use to the same level as more susceptible individuals. Analysis of pre-lever activity offers a novel longitudinal behavioral marker to predict vulnerability and provides a framework for understanding individual trajectories of addiction.
Oxytocin neurons in the anterior and posterior paraventricular nucleus have distinct behavioral functions and electrophysiological profiles.
Chrisman AN, Sugimoto C, Butler-Struben H … +9 more , Minie VA, Eagle AL, Anderson D, Duque-Wilckens N, Ramos A, Lewis YI, Archdeacon SC, Robison AJ, Trainor BC
Neuropsychopharmacology · 2026 Apr · PMID 41548026 · Full text
Oxytocin is a neuropeptide that can promote or inhibit affiliative social behaviors. Recent evidence suggests that these diverse effects are mediated by distinct oxytocin receptor-expressing neurons. An outstanding quest...
Oxytocin is a neuropeptide that can promote or inhibit affiliative social behaviors. Recent evidence suggests that these diverse effects are mediated by distinct oxytocin receptor-expressing neurons. An outstanding question is whether these behavioral effects are also driven by distinct or overlapping populations of oxytocin-producing neurons. The paraventricular nucleus (PVN) of the hypothalamus is a major source of oxytocin and sends projections to the mesolimbic dopamine system and extended amygdala. Previous work found that social defeat stress increased oxytocin neuron activity in the anterior PVN (aPVN) but not posterior PVN (pPVN). We reduced oxytocin synthesis with antisense morpholino oligonucleotides in either anterior or posterior PVN in California mice (Peromyscus californicus), a strong model system for studying effects of social stress on brain function and behavior. Antisense morpholinos in aPVN had no effect on behavior in unstressed females but increased social approach and reduced social vigilance in females exposed to social defeat stress. In pPVN, antisense morpholinos reduced social approach in unstressed male and female California mice. We then used Oxt mice to compare electrophysiological profiles of oxytocin in aPVN and pPVN with a population of oxytocin neurons in the bed nucleus of the stria terminalis (BNST). Oxytocin neurons in aPVN and BNST had higher post-synaptic events and responded more strongly to current injections than oxytocin neurons in pPVN, though they had similar excitatory and inhibitory input balance at the observed resting membrane potential. These findings shed light on to functional and physiological heterogeneity of PVN oxytocin neurons. Our results suggest that context-dependent behavioral effects of oxytocin are mediated by different populations of oxytocin neurons.
Premature aging in serious mental illness.
Diniz BS, Fries GR, Kuo CL … +2 more , Xu M, Lenze EJ
Neuropsychopharmacology · 2026 Jan · PMID 41548025 · Publisher ↗
Serious mental illnesses (SMIs), including major depressive disorder, bipolar disorder, and schizophrenia, have long been linked to cognitive decline, multiple chronic medical conditions, and premature mortality. These f...
Serious mental illnesses (SMIs), including major depressive disorder, bipolar disorder, and schizophrenia, have long been linked to cognitive decline, multiple chronic medical conditions, and premature mortality. These factors significantly contribute to the severe disability seen in SMIs, extending beyond the severity of psychopathology and indicating a premature aging phenotype associated with these conditions. The mechanisms that underlie the relationship between SMIs and the premature aging phenotype are not well understood, but recent evidence suggests that individuals with SMIs may exhibit accelerated biological aging. In this review, we present a comprehensive analysis of the current literature, demonstrating the potential association of SMIs (focusing on mood disorders and schizophrenia spectrum disorders) with abnormalities across various hallmarks of biological aging. We further evaluate how these abnormalities result in more severe psychopathology, poorer treatment outcomes, and a premature aging phenotype in SMIs. We also explore how the hallmarks of biological aging can be affected by behavioral and lifestyle factors, their interconnectedness, and whether they can be considered novel treatment targets for SMIs. In summary, we present robust evidence that accelerated biological aging is a significant biological characteristic of SMIs, contributing to the multiple adverse outcomes observed in these conditions.
Intrinsic connectivity patterns of striatal subfields predict individual dimensions of psychopathology and are associated with cholinergic and serotonergic neurotransmission in schizophrenia.
He Z, He W, Chen Z … +18 more , Wei W, Liu X, Dukart J, Li W, Baker JT, Holmes AJ, Hoffstaedter F, Nickl-Jockschat T, Derntl B, Kogler L, Jardri R, Gruber O, Aleman A, Sommer IE, Patil KR, Lu Y, Eickhoff SB, Chen J
Neuropsychopharmacology · 2026 Apr · PMID 41548024 · Full text
Symptoms of schizophrenia may reflect different pathophysiological processes in the striatum, but the links between striatal subfield connectivity, symptom dimensions, and molecular architectures remain unclear. Using co...
Symptoms of schizophrenia may reflect different pathophysiological processes in the striatum, but the links between striatal subfield connectivity, symptom dimensions, and molecular architectures remain unclear. Using connectivity profiles from 12 striatal subfields to predict negative, positive, affective, and cognitive symptoms in schizophrenia, we identified consistent connectivity features through cross-validations and validated with leave-one-site-out analysis and an independent dataset. Feature importance scores for brain parcels linked through consistent connectivity features that predicted symptoms were spatially correlated with density maps of 19 receptors/transporters from prior molecular imaging in healthy populations using partial least squares. We found that the connectivity profiles of the rostral and ventral striatal subfields significantly predicted affective and cognitive symptoms, respectively, and these predictions were generalized to the independent sample. Feature importance scores for brain parcels connected to the ventral striatum (predicting cognitive symptoms) were spatially correlated with density maps of both the vesicular acetylcholine transporter and the serotonin 1 A receptor. By contrast, importance scores for parcels linked to rostral striatal connectivity (predicting affective symptoms) were specifically associated with the spatial distribution of the serotonin 1 A receptor. Here, we show specific striatal connectivity patterns related to symptom dimensions and indicate multiple neurotransmitter systems to underlie the reward-related disturbances in schizophrenia.
Neuromodulation and cognition in late-life depression.
Mirjalili M, Blumberger DM, Brunoni AR … +2 more , Mulsant BH, Rajji TK
Neuropsychopharmacology · 2026 Jan · PMID 41545465 · Publisher ↗
Late-life depression (LLD) is associated with cognitive decline and increased risk of dementia. Emerging evidence indicates that impaired cortical synaptic plasticity (due to multiple causes including genetic, developmen...
Late-life depression (LLD) is associated with cognitive decline and increased risk of dementia. Emerging evidence indicates that impaired cortical synaptic plasticity (due to multiple causes including genetic, developmental, neurodegenerative, vascular conditions, chronic stress, and chronic inflammation) may drive this vulnerability. We focus on how disruptions in prefrontal cortex plasticity related to depression contribute to dementia risk and review plasticity-inducing non-surgical neuromodulations. These neuromodulations include electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), transcranial electrical stimulation (tES), and focused ultrasound (FUS). These strategies could promote cortical plasticity and, in turn, improve network connectivity and prefrontal function, potentially reducing cognitive decline. Then, we discuss future directions that prioritize personalized, mechanism-based interventions, and use preclinical models to optimize neuromodulation protocols. These approaches aim to address the heterogeneity of LLD and improve outcomes by tailoring treatments based on individual characteristics.
Psychedelic therapeutics in psychiatric conditions.
Harvey PD, Nemeroff CB
Neuropsychopharmacology · 2026 Jan · PMID 41545464 · Publisher ↗
Interest in psychedelic therapies is booming, with hundreds of studies in process. Despite the interest, there are no approved psychedelic treatments for any psychiatric condition. Further, the one large-scale developmen...
Interest in psychedelic therapies is booming, with hundreds of studies in process. Despite the interest, there are no approved psychedelic treatments for any psychiatric condition. Further, the one large-scale development program using MDMA that reached the FDA was disapproved by the agency for reasons that could apply to clinical trials for classical psychedelics. We review the definitions of psychedelics, the current status of psychedelic therapies, conditions targeted, compounds under investigation, and the research/clinical strategies employed. Some treatment interventions include pharmacologically assisted psychotherapy, with both benefits and challenges associated with this strategy. There is debate about whether the psychedelic experience is a required fundamental element for therapeutic potential with the induced psychedelic state, rendering blinded clinical trials challenging. We address current societal issues, such as the deregulation of formerly illegal substances in some areas, that may affect development decisions. Our review also considers regulatory issues, including alternatives to blinded trials and whether some therapeutic targets, such as adjustment disorder, may pose hurdles if current regulatory standards are applied to these trials. The interest in psychedelic treatment is considerable, although the path forward has some complexities.
Choreographing time: toward therapy-aligned entactogens for complex PTSD.
Parikh A
Neuropsychopharmacology · 2026 Apr · PMID 41545463 · Full text
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